Atypical Cutaneous Sporotrichosis in an Immunocompetent Adult: Response to Potassium Iodide.

PubMed

Gandhi, Nikita; Chander, Ram; Jain, Arpita; Sanke, Sarita; Garg, Taru

2016-01-01

Cutaneous sporotrichosis, also known as "Rose Gardener's disease," caused by dimorphic fungus Sporothrix schenkii, is usually characterized by indolent nodular or nodulo-ulcerative lesions arranged in a linear pattern. We report bizarre nonlinear presentation of Sporotrichosis, in an immunocompetent adult occurring after a visit to Amazon rain forest, speculating infection with more virulent species of Sporothrix. The diagnosis was reached with the help of periodic acid-Schiff positive yeast cells and cigar shaped bodies seen in skin biopsy along with the therapeutic response to potassium iodide.

Neuropsychiatric symptoms are common in immunocompetent adult patients with Toxoplasma gondii acute lymphadenitis.

PubMed

Wong, Weng Kit; Upton, Arlo; Thomas, Mark G

2013-05-01

Chronic toxoplasmosis has been shown to be strongly associated with a range of neuropsychiatric effects including schizophrenia and suicide. However there have not been any prospective, community-based studies of the neuropsychiatric effects of acute toxoplasmosis in adult immunocompetent patients. Adult patients with a positive serum IgM anti-Toxoplasma gondii test result, in the context of an acute illness with lymphadenopathy, were invited to complete a questionnaire seeking information relating to the nature, severity, and duration of symptoms in the months following the diagnosis of acute toxoplasmosis. Laboratory testing identified a total of 187 adults who had a positive serum IgM anti-T. gondii test result between 1 January and 30 November 2011. Consent to contact 108/187 (58%) patients was provided by their family doctor; 37 (34%) of these 108 patients completed and returned the questionnaire. Questionnaires from the 31/108 (29%) patients who reported swollen lymph nodes during their illness were included in the study. Fatigue (90%), headache (74%), difficulty concentrating (52%), and muscle aches (52%) were the most commonly reported symptoms. These symptoms commonly persisted for at least 4 weeks. Twenty-seven of 31 (87%) subjects reported a moderate or severe reduction in their overall physical and mental health during the first 2 months of illness. Acute toxoplasmosis in immunocompetent adults commonly causes moderately severe neuropsychiatric symptoms that might result from replication of the organism in the central nervous system with consequent effects on brain function. Patients should be advised that such symptoms are common and reassured that they usually resolve completely within a few months.

Atypical Cutaneous Sporotrichosis in an Immunocompetent Adult: Response to Potassium Iodide

PubMed Central

Gandhi, Nikita; Chander, Ram; Jain, Arpita; Sanke, Sarita; Garg, Taru

2016-01-01

Cutaneous sporotrichosis, also known as “Rose Gardener's disease,” caused by dimorphic fungus Sporothrix schenkii, is usually characterized by indolent nodular or nodulo-ulcerative lesions arranged in a linear pattern. We report bizarre nonlinear presentation of Sporotrichosis, in an immunocompetent adult occurring after a visit to Amazon rain forest, speculating infection with more virulent species of Sporothrix. The diagnosis was reached with the help of periodic acid-Schiff positive yeast cells and cigar shaped bodies seen in skin biopsy along with the therapeutic response to potassium iodide. PMID:27057047

Growth and development of Gymnophalloides seoi in immunocompetent and immunosuppressed C3H/HeN mice

PubMed Central

Chung, Won-Jae; Kook, Jina; Seo, Min; Park, Yun-Kyu; Guk, Sang-Mee; Choi, Min-Ho; Lee, Soon-Hyung

1999-01-01

The growth and development of Gymnophalloides seoi were studied in C3H/HeN mice and effects of immunosuppression of the host on the worm development were observed. Two hundred metacercariae of G. seoi were orally administered to each mouse, and worms were recovered on days 1, 3, 5, 7, 14 and 21 post-infection (PI). The worm recovery rate was significantly higher in immunosuppressed (ImSP) mice than in immunocompetent (ImCT) mice except on days 1 and 3 PI. The worms attained sexual maturity by day 3 PI with eggs in the uterus, and worm dimensions and the number of uterine eggs continuously increased until day 14 PI in ImSP mice. Worms recovered from ImSP mice were significantly larger in size than those from ImCT mice on days 1 and 3 PI, and the number of uterine eggs was significantly larger in ImSP mice on days 5 and 7 PI. Genital organs such as the ovary, testes, and vitellaria, that were already developed in the metacercarial stage, grew a little in size until day 14 PI. The results show that the C3H/HeN mouse is, though not excellent, a suitable laboratory host for G. seoi. PMID:10188379

Immunocompetent Mouse Model for Tracking Cancer Progression | NCI Technology Transfer Center | TTC

Cancer.gov

The National Cancer Institute seeks licensees or research collaborators to develop and commercialize transgenic mice having immunocompetent rat growth hormone-firefly Luciferase-enhanced green fluorescent protein.

Comparison of Pathogenesis and Host Immune Responses to Candida glabrata and Candida albicans in Systemically Infected Immunocompetent Mice

PubMed Central

Brieland, Joan; Essig, David; Jackson, Craig; Frank, Doyle; Loebenberg, David; Menzel, Fred; Arnold, Brian; DiDomenico, Beth; Hare, Roberta

2001-01-01

Cytokine-mediated host defense against Candida glabrata infection was compared to that against C. albicans, using immunocompetent murine models of systemic candidiasis. The pathogenesis of infection was evaluated morphologically and by culture of target organs, while the kinetics of induction of cytokine mRNAs and corresponding proteins were determined in kidneys by real-time reverse transcription-PCR and cytokine-specific murine enzyme-linked immunosorbent assays, respectively. Systemic infection with C. glabrata resulted in a chronic, nonfatal infection with recovery of organisms from kidneys, while intravenous inoculation with C. albicans resulted in rapid mortality with logarithmic growth of organisms in kidneys and recovery of C. albicans from the spleen, liver, and lungs. Survival of C. glabrata-infected mice was associated with rapid induction of mRNAs and corresponding immunoreactive proteins for the proinflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin-12 (IL-12), and gamma interferon (IFN-γ) and the lack of induction of protein for the anti-inflammatory cytokine IL-10. In contrast, mortality in C. albicans-infected mice was associated with induction of mRNA and corresponding protein for IL-10 but delayed (i.e., TNF-α) or absent (i.e., IL-12 and IFN-γ) induction of immunoreactive proinflammatory cytokines. Mice were subsequently treated with cytokine-specific neutralizing monoclonal antibodies (MAbs) to TNF-α, IL-12, or IFN-γ, and the effect on growth of C. glabrata in kidneys was assessed. Neutralization of endogenous TNF-α resulted in a significant increase in C. glabrata organisms compared to similarly infected mice administered an isotype-matched control MAb, while neutralization of endogenous IL-12 or IFN-γ had no significant effect on C. glabrata replication. These results demonstrate that in response to intravenous inoculation of C. glabrata, immunocompetent mice develop chronic nonfatal renal infections which are

[Clinical and biological manifestations in primary parvovirus B19 infection in immunocompetent adult: a retrospective study of 26 cases].

PubMed

Parra, D; Mekki, Y; Durieu, I; Broussolle, C; Sève, P

2014-05-01

Parvovirus B19 causes erythema infectiosum in children, transient aplastic anemia in patients with hemoglobinopathies, pur red cell aplasia in immunocompromised persons and hydrops fetalis in pregnancy. The spectrum of clinical and biological manifestations in immunocompetent adult continues to grow up. We report on a case series of 26 patients with primary parvovirus B19 infection in immunocompetent adults. This is a retrospective study over the period 2000 to 2010 in two departments of internal medecine. The diagnostic was clinical, serological or molecular. There was a female predominance (sex-ratio 3.33/1). Median patient age at diagnostic was 38.8 years (range: 18-68). The predominant symptoms were fever (65%), peripheral and symmetrical polyarthralgia (62%) and skin rash (58%). Two patients had neurological manifestations (sixth cranial nerve palsy, distal paresthesia) and one patient had myocarditis. Abnormal laboratory values included increased acute phase reactants (73%), thrombocytopenia (43%), lymphopenia (38%) and elevated liver enzymes (37%). Antinuclear (19%), anti-DNA (28%) and anti-phospholipids antibodies (14%), and hypocomplementemia (32%) were observed. False reaction with anti-CMV and anti-EBV IgM positivity was documented in 27% of cases. Two patients had persistent parvovirus B19 infection. The diversity of the clinical manifestations of parvovirus B19 infection may be misleading for the clinician. However, the diagnosis should be suspected in immunocompetent adults to limit the risk of transmission to the patients who could develop a severe infection such as pregnant women or immunocompromised patients. Copyright © 2013 Société nationale française de médecine interne (SNFMI). Published by Elsevier SAS. All rights reserved.

Acute human herpes virus 7 (HHV-7) encephalitis in an immunocompetent adult patient: a case report and review of literature.

PubMed

Riva, Nicoletta; Franconi, Iacopo; Meschiari, Marianna; Franceschini, Erica; Puzzolante, Cinzia; Cuomo, Gianluca; Bianchi, Alessandro; Cavalleri, Francesca; Genovese, Maurilio; Mussini, Cristina

2017-06-01

We report a case of an acute HHV-7 encephalitis involving the nucleus of the VI cranial nerve in an immunocompetent host. The patient was an adult male admitted to our Clinic with headache, diplopia, fever, nausea, vertigo, asthenia and general malaise. PCR for viral and bacterial genomes was run on both serum and cerebral spinal fluid (CSF) after performing lumbar puncture, resulting positive only for HHV-7 DNA on CSF. MRI showed hyperintensity in FLAIR signal in the dorsal pons, in the area of the VI cranial nerve nucleus. Empirical therapy with Acyclovir and Dexamethasone was started at the time of admission and was continued after the microbiology results. After three days of therapy diplopia, fever and other previous clinical manifestations improved and the patient recovered normal sight. Our case report contributes to a better understanding of the presentation, diagnosis and treatment of HHV-7 encephalitis in immunocompetent patients due to reactivation in adult age.

Acute epiglottitis due to Serratia marcescens in an immunocompetent adult.

PubMed

Musham, Chaitanya K; Jarathi, Archana; Agarwal, Abhishek

2012-08-01

Acute epiglottitis (AE) is inflammation of the epiglottis and contiguous tissues, which carries a potential for complete airway obstruction. With routine pediatric immunization for Hemophilus influenzae serotype b, epiglottitis is now more prevalent in adults, with a shift in the causative organisms and a change in the natural history of this disease. Over the past 5 decades, Serratia marcescens has gone from being recognized as a harmless saprophyte to an important opportunistic human pathogen. It is known to be associated with outbreaks of nosocomial infections, but it is an uncommon cause of serious invasive infections in patients presenting from the community. The authors present a fatal case of AE caused by S marcescens in a previously immunocompetent 58-year-old woman, which was complicated by fasciitis, myositis and bacteremia. To the authors' knowledge, till date, only 3 cases of AE by S marcescens have been reported, all in immunocompromised patients.

Radioimmunotargeting of human tumour cells in immunocompetent animals.

PubMed Central

Fjeld, J. G.; Bruland, O. S.; Benestad, H. B.; Schjerven, L.; Stigbrand, T.; Nustad, K.

1990-01-01

A tumour model system is reported that for many purposes may be an alternative to xenografted nude mice. The model allows immunotargeting of human tumour cells in immunocompetent animals. The target cells are contained in i.p. diffusion chambers (DC) with micropore membrane walls that are permeable to molecules, including the cell specific monoclonal antibodies (MoAb), but impermeable to cells. Thus, the tumour cells are protected from the host immunocompetent cells. In the work here presented the model was tested in immunocompetent mice and pigs, with tumour cells and antibody preparations that had demonstrated specific targeting in the nude mouse xenograft model. Hence, the DC were filled with cells from the human cell lines Hep-2 (expressing placental alkaline phosphatase, PLALP), or OHS (a sarcoma cell line), and the MoAb preparations injected i.v. were a 125I-labelled Fab fragment of the PLALP specific antibody H7, or a 125I-labelled F(ab')2 fragment of the sarcoma specific antibody TP-1. Specific targeting of the human tumour cells was demonstrated in both mice and pigs. The target: blood ratios were comparable in the two species, reaching a maximum of about 15 after 24 h with the Fab preparation, and a ratio of 25 after 72 h with the F(ab')2. The target uptake relative to injected dose was lower in pigs than in mice, but the difference between the two species was smaller than expected, presumably due to a slower antibody clearance in the pigs than in the mice. An artificial cell targeting system like this has several advantages in the search for solutions to many of the fundamental problems experienced in immunotargeting. Firstly, parallel binding experiments can be carried out in vitro with the same target. Because in vitro results are only influenced by the diffusion into the DC and the immunological binding characteristics of the antibodies, targeting differences between antibody preparations due to these factors can then be distinguished from differences

Human herpesvirus 6 encephalitis followed by acute disseminated encephalomyelitis in an immunocompetent adult.

PubMed

Horie, Junichi; Suzuki, Keisuke; Nakamura, Toshiki; Okamura, Madoka; Iwasaki, Akio; Hirata, Koichi

2017-04-28

A 26-year-old, otherwise healthy man presented with visual abnormality followed by loss of consciousness and convulsion. The patient then developed headache and fever 14 days later. Brain MRI showed hyperintensities in the left cingulate cortex. The cerrebrospinal fluid examinations showed mononuclear pleocytosis and positive PCR results for human herpesvirus 6 (HHV-6). A diagnosis of HHV-6 encephalitis and symptomatic epilepsy was made. The patient's clinical symptoms improved promptly following acyclovir treatment. However, 3 months later the patient noticed dysesthesia in the trunk, the left upper limb and the right lower limb. Brain and spine MRI showed multiple brain white matter lesions, the middle cerebellar peduncle and cervical spinal lesions. The symptoms resolved following methylprednisolone pulse therapy only. We report an adult patient with HHV-6 encephalitis followed by acute disseminated encephalomyelitis whose initial presentation was epilepsy. HHV-6 encephalitis should be included in the differential diagnosis of encephalitis of unknown etiology in an immunocompetent adult.

Immediate dietary effects on migrating Mormon cricket immunocompetence

USDA-ARS?s Scientific Manuscript database

Mormon crickets form bands and walk over rangeland in the western United States seeking salt and protein. Radio-tracking adult members of a Mormon cricket band in a high Sonoran desert of Utah, we investigated a potential trade-off between immunocompetence and migratory velocity. We asked: does acce...

Cytomegalovirus colitis: an unusual cause of diarrhoea in the immunocompetent.

PubMed

Chatterjee, S; Rodgers, A D; Tennant, D; Hayat, M

2009-12-01

Cytomegalovirus (CMV) colitis is rarely reported in the immuno-competent adult and is often associated with inflammatory bowel disease (IBD), particularly ulcerative colitis (UC).  An index of suspicion in the appropriate setting is vital to diagnosing the condition. Undiagnosed CMV colitis has a significant morbidity.  A review of the natural history and diagnosis of CMV is followed by a discussion of the incidence, outcome and possible treatment of CMV in the immunocompetent patient. The possible association between CMV and IBD is also reviewed, and the question of whether this should have any bearing on treatment is discussed at some length.

Gelatin-based Hydrogel Degradation and Tissue Interaction in vivo: Insights from Multimodal Preclinical Imaging in Immunocompetent Nude Mice.

PubMed

Tondera, Christoph; Hauser, Sandra; Krüger-Genge, Anne; Jung, Friedrich; Neffe, Axel T; Lendlein, Andreas; Klopfleisch, Robert; Steinbach, Jörg; Neuber, Christin; Pietzsch, Jens

2016-01-01

Hydrogels based on gelatin have evolved as promising multifunctional biomaterials. Gelatin is crosslinked with lysine diisocyanate ethyl ester (LDI) and the molar ratio of gelatin and LDI in the starting material mixture determines elastic properties of the resulting hydrogel. In order to investigate the clinical potential of these biopolymers, hydrogels with different ratios of gelatin and diisocyanate (3-fold (G10_LNCO3) and 8-fold (G10_LNCO8) molar excess of isocyanate groups) were subcutaneously implanted in mice (uni- or bilateral implantation). Degradation and biomaterial-tissue-interaction were investigated in vivo (MRI, optical imaging, PET) and ex vivo (autoradiography, histology, serum analysis). Multimodal imaging revealed that the number of covalent net points correlates well with degradation time, which allows for targeted modification of hydrogels based on properties of the tissue to be replaced. Importantly, the degradation time was also dependent on the number of implants per animal. Despite local mechanisms of tissue remodeling no adverse tissue responses could be observed neither locally nor systemically. Finally, this preclinical investigation in immunocompetent mice clearly demonstrated a complete restoration of the original healthy tissue.

Engraftment of human induced pluripotent stem cell-derived hepatocytes in immunocompetent mice via 3D co-aggregation and encapsulation

PubMed Central

Song, Wei; Lu, Yen-Chun; Frankel, Angela S.; An, Duo; Schwartz, Robert E.; Ma, Minglin

2015-01-01

Cellular therapies for liver diseases and in vitro models for drug testing both require functional human hepatocytes (Hum-H), which have unfortunately been limited due to the paucity of donor liver tissues. Human pluripotent stem cells (hPSCs) represent a promising and potentially unlimited cell source to derive Hum-H. However, the hepatic functions of these hPSC-derived cells to date are not fully comparable to adult Hum-H and are more similar to fetal ones. In addition, it has been challenging to obtain functional hepatic engraftment of these cells with prior studies having been done in immunocompromised animals. In this report, we demonstrated successful engraftment of human induced pluripotent stem cell (iPSC)-derived hepatocyte-like cells (iPS-H) in immunocompetent mice by pre-engineering 3D cell co-aggregates with stromal cells (SCs) followed by encapsulation in recently developed biocompatible hydrogel capsules. Notably, upon transplantation, human albumin and α1-antitrypsin (A1AT) in mouse sera secreted by encapsulated iPS-H/SCs aggregates reached a level comparable to the primary Hum-H/SCs control. Further immunohistochemistry of human albumin in retrieved cell aggregates confirmed the survival and function of iPS-H. This proof-of-concept study provides a simple yet robust approach to improve the engraftment of iPS-H, and may be applicable to many stem cell-based therapies. PMID:26592180

Immunocompetence of breeding females is sensitive to cortisol levels but not to communal rearing in the degu (Octodon degus).

PubMed

Ebensperger, Luis A; León, Cecilia; Ramírez-Estrada, Juan; Abades, Sebastian; Hayes, Loren D; Nova, Esteban; Salazar, Fabián; Bhattacharjee, Joydeep; Becker, María Inés

2015-03-01

One hypothesis largely examined in social insects is that cooperation in the context of breeding benefits individuals through decreasing the burden of immunocompetence and provide passive immunity through social contact. Similarly, communal rearing in social mammals may benefit adult female members of social groups by reducing the cost of immunocompetence, and through the transfer of immunological compounds during allonursing. Yet, these benefits may come at a cost to breeders in terms of a need to increase investment in individual immunocompetence. We examined how these potential immunocompetence costs and benefits relate to reproductive success and survival in a natural population of the communally rearing rodent, Octodon degus. We related immunocompetence (based on ratios of white blood cell counts, total and specific immunoglobulins of G isotype titers) and fecal glucocorticoid metabolite (FGC) levels of adults immunized with hemocyanin from the mollusk Concholepas concholepas to measures of sociality (group size) and communal rearing (number of breeding females). Offspring immunocompetence was quantified based on circulating levels of the same immune parameters. Neither female nor offspring immunocompetence was influenced by communal rearing or sociality. These findings did not support that communal rearing and sociality enhance the ability of females to respond to immunological challenges during lactation, or contribute to enhance offspring condition (based on immunocompetence) or early survival (i.e., to 3months of age). Instead, levels of humoral and cellular components of immunocompetence were associated with variation in glucorcorticoid levels of females. We hypothesize that this covariation is driven by physiological (life-history) adjustments needed to sustain breeding. Copyright © 2014 Elsevier Inc. All rights reserved.

Antifungal Prevention of Systemic Candidiasis in Immunocompetent ICU Adults: Systematic Review and Meta-Analysis of Clinical Trials.

PubMed

Dupont, Hervé; Mahjoub, Yazine; Chouaki, Taieb; Lorne, Emmanuel; Zogheib, Elie

2017-11-01

The aim of this study was to identify the impact of antifungal prevention in critically ill immunocompetent adult patients on mortality and subsequent infection. A systematic review and meta-analysis of randomized controlled trials comparing any antifungal use versus placebo to prevent candidiasis in ICU patients were performed. Searches were performed on PubMed, Embase, Scopus, main conference proceedings, and ClinicalTrials.gov, as well as reference lists. The primary outcomes were mortality and invasive candidiasis. The secondary outcome was the rate of Candida albicans and nonalbicans strains after treatment. A random effect model was used, and sensitivity analysis was performed for both outcomes. Results are expressed as risk ratios and their 95% CIs. Nineteen trials (10 with fluconazole, four with ketoconazole, one with itraconazole, three with micafungin, and one with caspofungin) including 2,792 patients were identified. No individual trial showed a decreased mortality rate. Combined analysis showed that preventive antifungal did not decrease mortality (risk ratio, 0.88; 95% CI, 0.74-1.04; p = 0.14) but significantly decreased secondary fungal infections by 50% (risk ratio, 0.49; 95% CI, 0.35-0.68; p = 0.0001). No shift across nonalbicans strains was observed during treatment (risk ratio, 0.62; 95% CI, 0.19-1.97; p = 0.42). However, publication biases preclude any definite conclusions for prevention of infection. Antifungal prevention of systemic candidiasis in immunocompetent critically ill adults did not reduce mortality and may have decreased secondary fungal infection rates. However, significant publication bias was present.

CHANGES IN MOUSE CIRULATING LEUKOCYTE NUMBERS IN C57BL/6 MICE IMMUNOSUPPRESSED FOR CRYPTOSPORIDIUM PARVUM OOCYST PRODUCTION

EPA Science Inventory

The Iowa strain of Cryptosporidium parvum will not propagate in immunocompetent mice, but will successfully infect genetically immunocompromised Nude or SCID mice as well as immunocompetent mice which have been immunosuppressed with glucocorticoids. Using dexamethasone - tetracy...

Zika virus infection in immunocompetent pregnant mice causes fetal damage and placental pathology in the absence of fetal infection

PubMed Central

Kummer, Lawrence W.; Lanthier, Paula; Kim, In-Jeong; Kuki, Atsuo; Thomas, Stephen J.

2018-01-01

Zika virus (ZIKV) infection during human pregnancy may cause diverse and serious congenital defects in the developing fetus. Previous efforts to generate animal models of human ZIKV infection and clinical symptoms often involved manipulating mice to impair their Type I interferon (IFN) signaling, thereby allowing enhanced infection and vertical transmission of virus to the embryo. Here, we show that even pregnant mice competent to generate Type I IFN responses that can limit ZIKV infection nonetheless develop profound placental pathology and high frequency of fetal demise. We consistently found that maternal ZIKV exposure led to placental pathology and that ZIKV RNA levels measured in maternal, placental or embryonic tissues were not predictive of the pathological effects seen in the embryos. Placental pathology included trophoblast hyperplasia in the labyrinth, trophoblast giant cell necrosis in the junctional zone, and loss of embryonic vessels. Our findings suggest that, in this context of limited infection, placental pathology rather than embryonic/fetal viral infection may be a stronger contributor to adverse pregnancy outcomes in mice. Our finding demonstrates that in immunocompetent mice, direct viral infection of the embryo is not essential for fetal demise. Our immunologically unmanipulated pregnancy mouse model provides a consistent and easily measurable congenital abnormality readout to assess fetal outcome, and may serve as an additional model to test prophylactic and therapeutic interventions to protect the fetus during pregnancy, and for studying the mechanisms of ZIKV congenital immunopathogenesis. PMID:29634758

Cytokine Networking in Lungs of Immunocompetent Mice in Response to Inhaled Aspergillus fumigatus

PubMed Central

Brieland, Joan K.; Jackson, Craig; Menzel, Fred; Loebenberg, David; Cacciapuoti, Anthony; Halpern, Judy; Hurst, Stephen; Muchamuel, Tony; Debets, Reno; Kastelein, Rob; Churakova, Tatyana; Abrams, John; Hare, Roberta; O'Garra, Anne

2001-01-01

Cytokine networking in the lung in response to inhaled Aspergillus fumigatus was assessed using a murine model of primary pulmonary aspergillosis in immunocompetent Crl:CF-1 mice. Inhalation of virulent A. fumigatus (6 × 106 CFU) resulted in the induction of interleukin 18 (IL-18), tumor necrosis factor alpha (TNF-α), IL-12, and gamma interferon (IFN-γ) protein in bronchoalveolar lavage fluid and/or lung tissue. Induction of immunoreactive IL-18 preceded induction of TNF-α protein, which preceded induction of immunoreactive IL-12 and IFN-γ. Real-time reverse transcriptase (RT) PCR analysis of infected lung tissue demonstrated that induction of IL-18 protein also preceded induction of pulmonary TNF-α, IL-12, and IFN-γ mRNAs. Mice were subsequently treated with cytokine-specific neutralizing monoclonal antibodies (MAbs) to the IL-18 receptor (anti-IL-18R MAb), TNF-α (anti-TNF-α MAb), IL-12 (anti-IL-12 MAb), and/or IFN-γ (anti-IFN-γ MAb), and effects on intrapulmonary cytokine activity and growth of A. fumigatus were assessed in infected lung homogenates. Simultaneous neutralization of IL-12 and IL-18 resulted in decreased levels of immunoreactive TNF-α, while neutralization of IL-18, TNF-α, or IL-12 alone or of IL-18 and IL-12 together resulted in decreased levels of immunoreactive IFN-γ. Simultaneous neutralization of IL-12 and IL-18 or neutralization of TNF-α alone or in combination with IL-12, IL-18, or IFN-γ also resulted in a significant increase in A. fumigatus CFU in lung tissue. Taken together, these results demonstrate that endogenous IL-18, IL-12, and TNF-α, through their modulatory effects on both intrapulmonary cytokine activity and growth of A. fumigatus, play key roles in host defense against primary pulmonary aspergillosis. PMID:11179326

[Portuguese Respiratory Society guidelines for the management of community-acquired pneumonia in immunocompetent adults].

PubMed

2003-01-01

The Portuguese Respiratory Society makes a series of recommendations as to the state of the art of the diagnostic, therapeutic and preventive approach to community-acquired pneumonia in immunocompetent adults in Portugal. These proposals should be regarded as general guidelines and are not intended to replace the clinical sense used in resolving each individual case. Our main goal is to stratify the patients according to the risk of morbidity and mortality in order to justify the following decisions more rationally: the choice of place of treatment (outpatient or inpatient), diagnostic tests and antimicrobial therapy. We also make a set of recommendations for the prevention of CAP. We plan to conduct multi-centre prospective studies, preferably in collaboration with other scientific societies, in order to be able to characterise the situation in Portugal more accurately and regularly update this document.

Immunocompetence of the red turpentine beetle, Dendroctonus valens LeConte (Coleoptera: Curculionidae, Scolytinae): variation between developmental stages and sexes in populations in China.

PubMed

Shi, Zhang-Hong; Sun, Jiang-Hua

2010-11-01

Immune defense imposes fitness costs as well as benefits, so organisms should optimize, not maximize, their immune function through their life cycle. We investigated this issue in the red turpentine beetle, Dendroctonus valens LeConte (Coleoptera: Curculionidae, Scolytinae), which is a pine-killing invasive beetle in China, though it is usually considered as a secondary pest in its native range of North America. We hypothesized that pathogen pressure may affect these beetles differently throughout their life history. We measured the insect's immunocompetence throughout life, determining encapsulation ability and phenoloxidase activity in larval stages, pupae and adults. Pupae had the highest encapsulation ability, but encapsulation was not different between final instar larvae and adults. Phenoloxidase (PO) activity was highest in final instar larvae and pupae, followed by the second instar larvae and adults. Total phenoloxidase activity increased significantly from the second instar larval stage to pupae, and then decreased in adults. Although the second instar larvae had the lowest phenoloxidase activity, more than 90% of total PO existed in the hemolymph in the form of the active enzyme, as compared with pupae, in which over 60% of PO occurred as a proenzyme. Both active PO and total PO were much higher in females than in males, though no significant differences were detected between the encapsulation ability of male and female adults. This result suggests the existence of a sexual dimorphism of immunocompetence in D. valens adults. Variations in immunocompetence across developmental stages suggest that D. valens adopts diverse investment strategies in immunocompetence during different stages. Potential reasons for variation in immunocompetence among developmental stages and between the sexes of D. valens are discussed. Copyright 2010 Elsevier Ltd. All rights reserved.

Differential resource allocation in deer mice exposed to sin nombre virus.

PubMed

Lehmer, Erin M; Clay, Christine A; Wilson, Eric; St Jeor, Stephen; Dearing, M Denise

2007-01-01

The resource allocation hypothesis predicts that reproductive activity suppresses immunocompetence; however, this has never been tested in an endemic disease system with free-ranging mammals. We tested the resource allocation hypothesis in wild deer mice (Peromyscus maniculatus) with natural exposure to Sin Nombre Virus (SNV). Immunocompetence was estimated from the extent of swelling elicited after deer mice were injected with phytohemagglutinin (PHA); swelling is positively correlated with immunocompetence. After livetrapping deer mice, we determined their reproductive state and SNV infection status. Males were more likely to be seropositive for SNV than females (37% vs. 25%) and exhibited 10% less swelling after PHA injection. The swelling response of females differed with both infection status and reproductive condition. There was also a significant infection status by reproductive condition interaction: non-reproductive, seropositive females experienced the least amount of swelling, whereas females in all other categories experienced significantly greater swelling. The swelling response of males differed with both SNV infection status and reproductive condition, but there was no significant infection status by reproductive condition interaction. Seronegative males elicited greater swelling than seropositive males regardless of reproductive status. In contrast to the resource allocation hypothesis, these results do not indicate that reproductive activity suppresses immunocompetence of deer mice but rather suggest that chronic SNV infection reduces immunocompetence. Sex-based differences in swelling indicate that SNV modulates the immune system of female deer mice differently than it does that of males, particularly during reproduction. We propose that differences in resource allocation between males and females could result from inherent sex-based differences in parental investment.

Latent Microsporidiosis Caused by Encephalitozoon cuniculi in Immunocompetent Hosts: A Murine Model Demonstrating the Ineffectiveness of the Immune System and Treatment with Albendazole

PubMed Central

Kotkova, Michaela; Sak, Bohumil; Kvetonova, Dana; Kvac, Martin

2013-01-01

Background Microsporidia are obligate intracellular parasites causing severe infections with lethal outcome in immunocompromised hosts. However, these pathogens are more frequently reported as latent infections in immunocompetent individuals and raises questions about the potential risk of reactivation following induced immunosuppression. Aims To evaluate the possibility latent microsporidiosis, efficacy or albendazole, and reactivation, the authors monitored the course of E. cuniculi infection in immunocompetent BALB/c mice and immunodeficient SCID mice using molecular methods. Methods Mice were per orally infected with 107 spores of E. cuniculi. Selected groups were treated with albendazole, re-infected or chemically immunosuppressed by dexamethasone. The presence of microsporidia in the host’s organs and feces were determined using PCR methods. Changes in numbers of lymphocytes in blood and in spleen after induction of immunosuppression were confirmed using flow cytometry analysis. Results Whereas E. cuniculi caused lethal microsporidiosis in SCID mice, the infection in BABL/c mice remained asymptomatic despite parasite dissemination into many organs during the acute infection phase. Albendazole treatment led to microsporidia elimination from organs in BALB/c mice. In SCID mice, however, only a temporary reduction in number of affected organs was observed and infection re-established post-treatment. Dexamethasone treatment resulted in a chronic microsporidia infection disseminating into most organs in BALB/c mice. Although the presence of E. cuniculi in organs of albendazole- treated mice was undetectable by PCR, it was striking that infection was reactivated by immunosuppression treatment. Conclusion Our results demonstrated that microsporidia can successfully survive in organs of immunocompetent hosts and are able to reactivate from undetectable levels and spread within these hosts after induction of immunosuppression. These findings stress the danger of

Polyphenon E 10% ointment: in immunocompetent adults with external genital and perianal warts.

PubMed

Hoy, Sheridan M

2012-08-01

Polyphenon E 10% ointment, which contains a mixture of green tea catechins, is indicated for the treatment of external genital and perianal warts (Condylomata acuminata) in immunocompetent patients aged ≥18 years. In two double-blind, multinational studies in adults with external genital and perianal warts, polyphenon E 10% ointment for up to 16 weeks was significantly more effective than vehicle with regard to the complete clearance of all warts (i.e. those at baseline and newly appearing during treatment) [primary endpoint]. In gender subgroup analyses, polyphenon E 10% ointment was more effective than vehicle in both men and women in one of two individual studies, and in pooled data from both studies. Polyphenon E 10% ointment was also significantly more effective than vehicle with regard to several secondary endpoints, including the complete clearance of baseline warts and partial clearance of at least 50% of all warts in both studies. Rates of recurrence of any warts or development of new warts were low (<9%) in both treatment arms during a 12-week follow-up period in both studies. Polyphenon E 10% ointment was generally well tolerated in adults with external genital and perianal warts. According to pooled data from the two clinical studies, the majority of adverse events associated with polyphenon E 10% ointment involved application site and local skin reactions at the treatment site.

A novel homologous model for gene therapy of dwarfism by non-viral transfer of the mouse growth hormone gene into immunocompetent dwarf mice.

PubMed

Cecchi, Claudia R; Higuti, Eliza; Oliveira, Nelio A J; Lima, Eliana R; Jakobsen, Maria; Dagnaes-Hansen, Frederick; Gissel, Hanne; Aagaard, Lars; Jensen, Thomas G; Jorge, Alexander A L; Bartolini, Paolo; Peroni, Cibele N

2014-02-01

The possibilities for non-viral GH gene therapy are studied in immunocompetent dwarf mice (lit/lit). As expression vector we used a plasmid previously employed in immunodeficient dwarf mice (pUBI-hGH-gDNA) by replacing the human GH gene with the genomic sequence of mouse-GH DNA (pUBI-mGH-gDNA). HEK-293 human cells transfected with pUBI-mGH-gDNA produced 3.0 µg mGH/10(6) cells/day compared to 3.7 µg hGH/10(6) cells/day for pUBIhGH- gDNA transfected cells. The weight of lit/lit mice treated with the same two plasmids (50 µg DNA/mouse) by electrotransfer into the quadriceps muscle was followed for 3 months. The weight increase up to 15 days for mGH, hGH and saline treated mice were 0.130, 0.112 and 0.027 g/mouse/day. Most sera from hGH-treated mice contained anti-hGH antibodies already on day 15, with the highest titers on day 45, while no significant anti-mGH antibodies were observed in mGH-treated mice. At the end of 3 months, the weight increase for mGH-treated mice was 34.3%, while the nose-to-tail and femur lengths increased 9.5% and 24.3%. Mouse-GH and hGH circulating levels were 4-5 ng/mL 15 days after treatment, versus control levels of ~0.7 ng GH/mL (P<0.001). In mGH-treated mice, mIGF-I determined on days 15, 45 and 94 were 1.5- to 3-fold higher than the control and 1.2- to 1.6-fold higher than hGH-treated mice. The described homologous model represents an important progress forming the basis for preclinical testing of non-viral gene therapy for GH deficiency.

Annual incidence rates of herpes zoster among an immunocompetent population in the United States.

PubMed

Johnson, Barbara H; Palmer, Liisa; Gatwood, Justin; Lenhart, Gregory; Kawai, Kosuke; Acosta, Camilo J

2015-11-06

Herpes zoster (HZ), also known as shingles, is a painful and commonly occurring condition in the United States. In spite of a universally recommended vaccine for use in immunocompetent adults aged 60 years and older, HZ continues to impact the American public, and a better understanding of its current incidence is needed. The objective of the current study is to estimate the overall and age- and gender-specific incidence rates (IRs) of HZ among an immunocompetent US population in 2011 following availability of a vaccine. Claims data from the Truven Health MarketScan® Research databases between 01/01/2011 and 12/31/2011 were extracted. Immunocompetent adult patients, enrolled as of January 1, 2011 were analyzed. The denominator was defined as eligible subjects who were immunocompetent, had no evidence of zoster vaccination, and no diagnosis of HZ (International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis code 053.xx) in the 90 days prior to January 1, 2011. Subjects contributed person-days to the denominator until the occurrence of one of the following events: end of continuous enrollment in the database, a claim for zoster vaccination, diagnosis of HZ or end of the observation period (December 31, 2011). The numerator was defined as enrollees within the denominator file exhibiting evidence of HZ. Annual IRs were calculated for the entire population in the database as well as by gender and age group; standardized IRs were also produced using the 2010 US Census data. The overall annual IR of HZ across all ages was 4.47 per 1000 person-years (95% confidence interval [CI]: 4.44-4.50) which monotonically increased with age from 0.86 (95% CI: 0.84-0.88) for those aged ≤ 19 to 12.78 (95% CI: 12.49-13.07) for patients ≥ 80 years. The IR was 8.46 (95% CI: 8.39-8.52) among adults ≥ 50 years and 10.46 (95% CI: 10.35-10.56) among those aged ≥ 60 years. Women compared to men had higher HZ incidence (5.25, 95% CI: 5.21-5.29 vs. 3.66, 95

Neuropathogenesis of Zika Virus in a Highly Susceptible Immunocompetent Mouse Model after Antibody Blockade of Type I Interferon (Open Access Publisher’s Version)

DTIC Science & Technology

2017-01-09

death, astrogliosis, microgliosis, scattered necrotic cellular debris, and inflammatory cell infiltrates. This model of ZIKV pathogenesis will be...these models is they utilize immunodeficient knockout mice lacking key compo- nents of the innate antiviral response. We describe the use of a lethal...murine model for ZIKV where the innate response of immunocompetent mice is suppressed only at the time of infection. We show that the mice develop

Disseminated Herpes Zoster Ophthalmicus in an Immunocompetent 8-Year Old Boy

PubMed Central

Oladokun, Regina Eziuka; Olomukoro, Chikodili N; Owa, Adewale B.

2013-01-01

Varicella results from a primary infection with the varicella virus while herpes zoster is caused by a reactivation of a latent infection. Dissemination of herpes zoster is uncommon in immunocompetent individuals. Reports of disseminated herpes zoster in children are even less common than in adults. An unusual case of disseminated herpes zoster ophthalmicus in an 8-year old immunocompetent black boy is presented. He had a previous primary Varicella zoster virus infection at three years of age. In the current report, he presented during an on-going chicken pox outbreak and survived with no significant complications. A breakthrough varicella virus re-infection or a reactivation is possible, both of which could present as zoster. This case emphasizes the need for prevention of varicella virus infection through universal childhood immunization and effective infection control strategies in health care settings. PMID:24765504

Disseminated herpes zoster ophthalmicus in an immunocompetent 8-year old boy.

PubMed

Oladokun, Regina Eziuka; Olomukoro, Chikodili N; Owa, Adewale B

2013-08-02

Varicella results from a primary infection with the varicella virus while herpes zoster is caused by a reactivation of a latent infection. Dissemination of herpes zoster is uncommon in immunocompetent individuals. Reports of disseminated herpes zoster in children are even less common than in adults. An unusual case of disseminated herpes zoster ophthalmicus in an 8-year old immunocompetent black boy is presented. He had a previous primary Varicella zoster virus infection at three years of age. In the current report, he presented during an on-going chicken pox outbreak and survived with no significant complications. A breakthrough varicella virus re-infection or a reactivation is possible, both of which could present as zoster. This case emphasizes the need for prevention of varicella virus infection through universal childhood immunization and effective infection control strategies in health care settings.

Brazilian guidelines for community-acquired pneumonia in immunocompetent adults - 2009.

PubMed

Corrêa, Ricardo de Amorim; Lundgren, Fernando Luiz Cavalcanti; Pereira-Silva, Jorge Luiz; Frare e Silva, Rodney Luiz; Cardoso, Alexandre Pinto; Lemos, Antônio Carlos Moreira; Rossi, Flávia; Michel, Gustavo; Ribeiro, Liany; Cavalcanti, Manuela Araújo de Nóbrega; de Figueiredo, Mara Rúbia Fernandes; Holanda, Marcelo Alcântara; Valery, Maria Inês Bueno de André; Aidê, Miguel Abidon; Chatkin, Moema Nudilemon; Messeder, Octávio; Teixeira, Paulo José Zimermann; Martins, Ricardo Luiz de Melo; da Rocha, Rosali Teixeira

2009-06-01

Community-acquired pneumonia continues to be the acute infectious disease that has the greatest medical and social impact regarding morbidity and treatment costs. Children and the elderly are more susceptible to severe complications, thereby justifying the fact that the prevention measures adopted have focused on these age brackets. Despite the advances in the knowledge of etiology and physiopathology, as well as the improvement in preliminary clinical and therapeutic methods, various questions merit further investigation. This is due to the clinical, social, demographical and structural diversity, which cannot be fully predicted. Consequently, guidelines are published in order to compile the most recent knowledge in a systematic way and to promote the rational use of that knowledge in medical practice. Therefore, guidelines are not a rigid set of rules that must be followed, but first and foremost a tool to be used in a critical way, bearing in mind the variability of biological and human responses within their individual and social contexts. This document represents the conclusion of a detailed discussion among the members of the Scientific Board and Respiratory Infection Committee of the Brazilian Thoracic Association. The objective of the work group was to present relevant topics in order to update the previous guidelines. We attempted to avoid the repetition of consensual concepts. The principal objective of creating this document was to present a compilation of the recent advances published in the literature and, consequently, to contribute to improving the quality of the medical care provided to immunocompetent adult patients with community-acquired pneumonia.

Targeting Protein Kinase CK2: Evaluating CX-4945 Potential for GL261 Glioblastoma Therapy in Immunocompetent Mice

PubMed Central

Ferrer-Font, Laura; Villamañan, Lucia; Arias-Ramos, Nuria; Vilardell, Jordi; Plana, Maria; Ruzzene, Maria; Pinna, Lorenzo A.; Itarte, Emilio; Arús, Carles; Candiota, Ana Paula

2017-01-01

Glioblastoma (GBM) causes poor survival in patients even with aggressive treatment. Temozolomide (TMZ) is the standard chemotherapeutic choice for GBM treatment but resistance always ensues. Protein kinase CK2 (CK2) contributes to tumour development and proliferation in cancer, and it is overexpressed in human GBM. Accordingly, targeting CK2 in GBM may benefit patients. Our goal has been to evaluate whether CK2 inhibitors (iCK2s) could increase survival in an immunocompetent preclinical GBM model. Cultured GL261 cells were treated with different iCK2s including CX-4945, and target effects evaluated in vitro. CX-4945 was found to decrease CK2 activity and Akt(S129) phosphorylation in GL261 cells. Longitudinal in vivo studies with CX-4945 alone or in combination with TMZ were performed in tumour-bearing mice. Increase in survival (p < 0.05) was found with combined CX-4945 and TMZ metronomic treatment (54.7 ± 11.9 days, n = 6) when compared to individual metronomic treatments (CX-4945: 24.5 ± 2.0 and TMZ: 38.7 ± 2.7, n = 6) and controls (22.5 ± 1.2, n = 6). Despite this, CX-4945 did not improve mice outcome when administered on every/alternate days, either alone or in combination with 3-cycle TMZ. The highest survival rate was obtained with the metronomic combined TMZ+CX-4945 every 6 days, pointing to the participation of the immune system or other ancillary mechanism in therapy response. PMID:28208677

Ralstonia pickettii-Induced Ataxia in Immunodeficient Mice

PubMed Central

Berard, Marion; Medaille, Christine; Simon, Meredith; Serre, Stéphanie; Pritchett-Corning, Kathleen; Dangles-Marie, Virginie

2009-01-01

We report here the characterization of an asymmetric ataxia syndrome (head tilt and circling, with death in the most severe cases) demonstrated by profoundly immunodeficient mice housed at the Institut Curie SPF facility. The immune system of the affected mice had been genetically modified so that they were deficient in both B and T cells. Extensive bacteriologic, parasitic, serologic, and histopathologic analysis of the affected animals and their healthy controls led us to identify Ralstonia pickettii as the causative agent of the ataxic syndrome. The outbreak was managed through a test-and-cull process. Even though they also carried Ralstonia pickettii, immunocompetent mice that were kept in the same facility, did not show any of the signs that were expressed by their immunodeficient counterparts. This case highlights the difficulty of maintaining immunocompetent and immunodeficient mice in the same microbiologic unit and the importance of enlarging the spectrum of health monitoring to opportunistic agents when investigating clinical cases in populations of immunocompromised rodents. PMID:19389312

[Pneumocystis jiroveci infection in immunocompetent patients with pulmonary disorders, in Portugal].

PubMed

Matos, Olga; Costa, Marina Célia; Correia, Isabel; Monteiro, Paula; Vieira, Jorge Roldão; Soares, Jorge; Bonnet, Marina; Esteves, Francisco; Antunes, Francisco

2006-01-01

The use of molecular tools with a great capacity to detect and differentiate strains of Pneumocystis has resulted: in the identification of low numbers of P. jiroveci organisms in clinically silent, colonized, immunocompromised patients and in immunocompetent persons. Considering this information, the aim of this study was to determine the prevalence of P. jiroveci carriers (subclinical infections) in Portuguese patients with pulmonary disorders and in healthy individuals. A total of 45 pulmonary specimens were collected from 45 immunocompetent adults with pulmonary disorders, and 37 oral washings from 37 healthy adults, between March 2001 and February 2004. All samples were analysed by indirect immunofluorescence with monoclonal antibodies and by amplification of the LSU mtrRNA by nested PCR. The results obtained in this study indicate that: 1) P. jiroveci is frequently detected (24.4%) in patients with pulmonary disorders in Portugal; 2) this population might play a role in circulation and transmission of P. jiroveci organisms in the community; 3) patients receiving corticosteroids are more likely to have detectable P. jiroveci in lungs (18%) than patients who are not receiving this immunosuppressor (12%); 4) P. jiroveci is infrequently detected in healthy adults. This may be due to very low numbers of latent organisms present in the lungs of healthy adults, difficulty in detecting few organisms, or due to the type of samples used. Screening of these individuals and notification of the results to their physician might be important: for further follow-up and whether or not prophylaxis or treatment should be prescribed; and for the clarification of the epidemiology of P. jiroveci asymptomatic infections.

Immunity to sporozoite-induced malaria infection in mice. I. The effect of immunization of T and B cell-deficient mice. [X Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, D.H.; Tigelaar, R.E.; Weinbaum, F.I.

1977-04-01

The cellular basis of immunity to sporozoites was investigated by examining the effect of immunization of T and B cell-deficient C57BL/6N x BALB/c AnN F/sub 1/ (BLCF/sub 1/) mice compared to immunocompetent controls. Immunization of T cell-deficient (ATX-BM-ATS) BLCF/sub 1/ mice with x-irradiated sporozoites did not result in the generation of protective immunity. The same immunization protocols protected all immunocompetent controls. In contrast, B cell-deficient (..mu..-suppressed) BLCF/sub 1/ mice were protected by immunization in the majority of cases. The absence of detectable serum circumsporozoite precipitins or sporozoite neutralizing activity in the ..mu..-suppressed mice that resisted a sporozoite challenge suggests amore » minor role for these humoral factors in protection. These data demonstrate a preeminent role for T cells in the induction of protective immunity in BLCF/sub 1/ mice against a P. berghei sporozoite infection.« less

Recombinant Zika virus envelope protein elicited protective immunity against Zika virus in immunocompetent mice

PubMed Central

Liu, Zhihua; Li, Min; Liu, Haitao

2018-01-01

Zika virus (ZIKV) has caused great public concerns due to its recent large outbreaks and a close association with microcephaly in fetus and Guillain-Barre syndrome in adults. Rapid development of vaccines against ZIKV is a public health priority. To this end, we have constructed and purified recombinant ZIKV envelope protein using both prokaryotic and eukaryotic expression systems, and then tested their immunogenicity and protective efficacy in immune competent mice. Both protein immunogens elicited humoral and cellular immune responses, and protected immune competent mice from ZIKV challenge in vivo. These products could be further evaluated either as stand-alone vaccine candidate, or used in a prime-and-boost regimen with other forms of ZIKV vaccine. PMID:29590178

Cryptococcal meningitis with secondary cutaneous involvement in an immunocompetent host.

PubMed

Tabassum, Saadia; Rahman, Atiya; Herekar, Fivzia; Masood, Sadia

2013-09-16

Cryptococcosis is a potentially fatal fungal disease caused by variants of Cryptococcus neoformans species.  The respiratory tract is the usual portal of entry, with a peculiar predilection to invade the central nervous system.  The skin can be secondarily involved in disseminated infection or be exceptionally involved as primary cutaneous infection by inoculation.  The disease is mostly seen in immunodeficiency states.  The diagnosis is frequently unsuspected in immunocompetent patients. We report a case of disseminated cryptococcal meningitis in an immunocompetent young adult. The cutaneous eruption prompted the accurate diagnosis.  The patient, a 20-year-old female, had fever, cough, headache and intractable vomiting for the past two months and was being managed as a case of tuberculous meningitis. Two weeks after starting antituberculous treatment she developed umbilicated papules on the head and neck region. Necessary laboratory workup identified C. neoformans in cerebrospinal fluid (CSF) and skin specimens.  The titers of cryptococcal antigen were measured in CSF and serum for diagnostic and prognostic purposes.  Anti-fungal treatment resulted in regression of the cutaneous lesions and resolution of systemic complaints. The case highlights the need for high degree of suspicion, especially in healthy young adults, in the diagnosis of cryptococcosis. The cutaneous eruptions can be the first manifestation or a diagnostic clue of enormous significance.

Intratumoral delivery of low doses of anti-CD40 mAb combined with monophosphoryl lipid A induces local and systemic antitumor effects in immunocompetent and T cell-deficient mice

PubMed Central

Van De Voort, Tyler J.; Felder, Mildred A. R.; Yang, Richard K.; Sondel, Paul M.; Rakhmilevich, Alexander L.

2012-01-01

In this study, an agonistic anti-CD40 monoclonal antibody was combined with monophosphoryl lipid A (MPL), a nontoxic derivative of LPS and agonist of toll-like receptor 4, to assess the immunomodulatory and antitumor synergy between the two agents in mice. Anti-CD40 was capable of priming macrophages to subsequent ex vivo activation by MPL in immunocompetent and T cell-depleted mice. Intraperitoneal injections of anti-CD40+MPL induced additive to synergistic suppression of poorly immunogenic B16-F10 melanoma growing subcutaneously in syngeneic mice. When anti-CD40+MPL were injected directly into the subcutaneous tumor, the combination treatment was more effective, even with a 25-fold reduction in dose. Low-dose intratumoral treatment also slowed the growth of a secondary tumor growing simultaneously at a distant, untreated site. Antitumor effects were also induced in immunodeficient SCID mice and in T cell-depleted C57BL/6 mice. Taken together, our results show that the antitumor effects of anti-CD40 are enhanced by subsequent treatment with MPL, even in T cell-deficient hosts. These preclinical data suggest that an anti-CD40+MPL combined regimen is appropriate for clinical testing in human patients, including cancer patients that may be immunosuppressed from prior chemotherapy. PMID:23211623

Herpes zoster vaccine and the incidence of recurrent herpes zoster in an immunocompetent elderly population.

PubMed

Tseng, Hung Fu; Chi, Margaret; Smith, Ning; Marcy, Stephen M; Sy, Lina S; Jacobsen, Steven J

2012-07-15

The benefit of vaccinating immunocompetent patients who have had shingles has not been examined. The study assessed the association between vaccination and the incidence of herpes zoster recurrence among persons with a recent episode of clinically diagnosed herpes zoster. This is a matched cohort study in Kaiser Permanente Southern California. Study populations were immunocompetent elderly individuals ≥ 60 years old with a recent episode of herpes zoster. Incidence of recurrent herpes zoster was compared between the vaccinated and the unvaccinated matched cohorts. A total of 1036 vaccinated and 5180 unvaccinated members were included. On the basis of clinically confirmed cases, the incidence of recurrent herpes zoster among persons aged <70 years was 0.99 (95% confidence interval [CI], .02-5.54) and 2.20 (95% CI, 1.10-3.93) cases per 1000 person-years in the vaccinated and unvaccinated cohorts, respectively. The adjusted hazard ratio was 0.39 (95% CI, .05-4.45) among persons aged <70 years and 1.05 (95% CI, .30-3.69) among persons aged ≥ 70 years. The risk of herpes zoster recurrence following a recent initial episode is fairly low among immunocompetent adults, regardless of vaccination status. Such a low risk suggests that one should evaluate the necessity of immediately vaccinating immunocompetent patients who had a recent herpes zoster episode.

Pseudomonas aeruginosa Bacteremia among Immunocompetent and Immunocompromised Patients: Relation to Initial Antibiotic Therapy and Survival.

PubMed

Migiyama, Yohei; Yanagihara, Katsunori; Kaku, Norihito; Harada, Yosuke; Yamada, Koichi; Nagaoka, Kentaro; Morinaga, Yoshitomo; Akamatsu, Norihiko; Matsuda, Junichi; Izumikawa, Koichi; Kohrogi, Hirotsugu; Kohno, Shigeru

2016-01-01

Pseudomonas aeruginosa bacteremia occurs mainly in immunocompromised patients. However, P. aeruginosa bacteremia in immunocompetent patients has also been reported. The aim of this study was to evaluate the clinical characteristics of P. aeruginosa bacteremia in relation to the immune status of the patients. The medical records of 126 adult patients with P. aeruginosa bacteremia in Nagasaki University Hospital were retrospectively reviewed between January 2003 and December 2012. Of 126 patients with P. aeruginosa bacteremia, 60 patients (47.6%) were classified as immunocompetent. Mortality in immunocompetent patients tended to be lower than in immunocompromised patients (7-day mortality, 8% vs. 30%, P < 0.01; 30-day mortality, 23% vs. 39%, P = 0.053). Multivariate analysis showed that a higher sequential organ failure assessment score (hazard ratio [HR]: 1.27, P < 0.01) and underlying malignancies (HR: 3.33, P < 0.01) were independently associated with 30-day mortality. Initial antibiotic therapy (HR: 0.21, P < 0.01) and patients' immune status (HR: 0.29, P = 0.02) also had a significant impact on survival. However, there was a significant interaction between these 2 variables (P = 0.03 for interaction). A subgroup analysis showed that in immunocompromised, but not immunocompetent patients, initial appropriate antibiotic therapy was associated with lower mortality (30-day mortality 20.5% vs. 66.7%, P < 0.01 by log-rank test).

Selection of genetic variants of lymphocytic choriomeningitis virus in spleens of persistently infected mice. Role in suppression of cytotoxic T lymphocyte response and viral persistence

PubMed Central

1984-01-01

We studied the mechanism of lymphocytic choriomeningitis virus (LCMV) persistence and the suppression of cytotoxic T lymphocyte (CTL) responses in BALB/c WEHI mice infected at birth with LCMV Armstrong strain. Using adoptive transfer experiments we found that spleen cells from persistently infected (carrier) mice actively suppressed the expected LCMV-specific CTL response of spleen cells from normal adult mice. The suppression was specific for the CTL response and LCMV - specific antibody responses were not affected. Associated with the specific CTL suppression was the establishment of persistent LCMV infection. The transfer of spleen or lymph node cells containing LCMV - specific CTL resulted in virus clearance and prevented establishment of the carrier state. The suppression of LCMV -specific CTL responses by carrier spleen cells is not mediated by a suppressor cell, but is due to the presence of genetic variants of LCMV in spleens of carrier mice. Such virus variants selectively suppress LCMV-specific CTL responses and cause persistent infections in immunocompetent mice. In striking contrast, wild-type LCMV Armstrong, from which these variants were generated, induces a potent CTL response in immunocompetent mice and the LCMV infection is rapidly cleared. Our results show that LCMV variants that emerge during infection in vivo play a crucial role in the suppression of virus-specific CTL responses and in the maintenance of virus persistence. PMID:6332167

The Next Generation of Orthotopic Thyroid Cancer Models: Immunocompetent Orthotopic Mouse Models of BRAFV600E-Positive Papillary and Anaplastic Thyroid Carcinoma

PubMed Central

Vanden Borre, Pierre; McFadden, David G.; Gunda, Viswanath; Sadow, Peter M.; Varmeh, Shohreh; Bernasconi, Maria; Jacks, Tyler

2014-01-01

Background: While the development of new treatments for aggressive thyroid cancer has advanced in the last 10 years, progress has trailed headways made with other malignancies. A lack of reliable authenticated human cell lines and reproducible animal models is one major roadblock to preclinical testing of novel therapeutics. Existing xenograft and orthotopic mouse models of aggressive thyroid cancer rely on the implantation of highly passaged human thyroid carcinoma lines in immunodeficient mice. Genetically engineered models of papillary and undifferentiated (anaplastic) thyroid carcinoma (PTC and ATC) are immunocompetent; however, slow and stochastic tumor development hinders high-throughput testing. Novel models of PTC and ATC in which tumors arise rapidly and synchronously in immunocompetent mice would facilitate the investigation of novel therapeutics and approaches. Methods: We characterized and utilized mouse cell lines derived from PTC and ATC tumors arising in genetically engineered mice with thyroid-specific expression of endogenous BrafV600E/WT and deletion of either Trp53 (p53) or Pten. These murine thyroid cancer cells were transduced with luciferase- and GFP-expressing lentivirus and implanted into the thyroid glands of immunocompetent syngeneic B6129SF1/J mice in which the growth characteristics were assessed. Results: Large locally aggressive thyroid tumors form within one week of implantation. Tumors recapitulate their histologic subtype, including well-differentiated PTC and ATC, and exhibit CD3+, CD8+, B220+, and CD163+ immune cell infiltration. Tumor progression can be followed in vivo using luciferase and ex vivo using GFP. Metastatic spread is not detected at early time points. Conclusions: We describe the development of the next generation of murine orthotopic thyroid cancer models. The implantation of genetically defined murine BRAF-mutated PTC and ATC cell lines into syngeneic mice results in rapid and synchronous tumor formation. This

Acute pancreatitis: rare complication of chicken pox in an immunocompetent host.

PubMed

Kumar, Sunil; Jain, A P; Pandit, A K

2007-01-01

Chicken pox is a highly contagious infection, caused by the varicella zoster virus. Although generally a benign, self-limited disease, varicella may be associated with serious complications especially in adults. We present acute pancreatitis- a rare complication, in otherwise healthy patients suffering from chicken pox. The presence of pancreatitis in association with chickenpox in immunocompetent patients can influence the outcome of the latter. This interesting case will hopefully increase awareness about this complication and its fatality in chicken pox.

In kittiwakes food availability partially explains the seasonal decline in humoral immunocompetence

USGS Publications Warehouse

Gasparini, J.; Roulin, A.; Gill, V.A.; Hatch, Shyla A.; Boulinier, T.

2006-01-01

1. The immune system plays an important role in fitness, and interindividual variation in immunocompetence is due to several factors including food supply. 2. Seasonal variation in food resources may therefore explain why immunocompetence in bird nestlings usually declines throughout the breeding season, with chicks born early in the season receiving more food than chicks born later, and thereby possibly developing a more potent immune system. Although there are studies supporting this hypothesis, none has been experimental. 3. We performed an experiment in the kittiwake Rissa tridactyla by manipulating the food supply of pairs that were left to produce a first brood, and of pairs that were induced to produce a late replacement brood. 4. If food supply mediates, at least partially, seasonal variations in chick immunocompetence, non-food-supplemented chicks would show a stronger seasonal decline in immunocompetence than food-supplemented chicks. 5. Food supplementation improved humoral immunocompetence (the production of immunoglobulins Y), but not T-cell immunocompetence (phytohaemagglutinin, PHA response). T-cell immunocompetence of food-supplemented and non-food- supplemented chicks decreased through the season but to a similar extent, whereas the humoral immunocompetence of non-food-supplemented chicks decreased more strongly than that of food-supplemented chicks. 6. Our results suggest that the seasonal decline in humoral immunocompetence can be explained, at least partly, by variations in food supply throughout the breeding season. ?? 2006 British Ecological Society.

Do pheromones reveal male immunocompetence?

PubMed Central

Rantala, Markus J; Jokinen, Ilmari; Kortet, Raine; Vainikka, Anssi; Suhonen, Jukka

2002-01-01

Pheromones function not only as mate attractors, but they may also relay important information to prospective mates. It has been shown that vertebrates can distinguish, via olfactory mechanisms, major histocompatibility complex types in their prospective mates. However, whether pheromones can transmit information about immunocompetence is unknown. Here, we show that female mealworm beetles (Tenebrio molitor) prefer pheromones from males with better immunocompetence, indicated by a faster encapsulation rate against a novel antigen, and higher levels of phenoloxidase in haemolymph. Thus, the present study indicates that pheromones could transmit information about males' parasite resistance ability and may work as a reliable sexual ornament for female choice. PMID:12204128

Treatment of a Solid Tumor Using Engineered Drug-Resistant Immunocompetent Cells and Cytotoxic Chemotherapy

PubMed Central

Dasgupta, Anindya; Shields, Jordan E.

2012-01-01

Abstract Multimodal therapy approaches, such as combining chemotherapy agents with cellular immunotherapy, suffers from potential drug-mediated toxicity to immune effector cells. Overcoming such toxic effects of anticancer cellular products is a potential critical barrier to the development of combined therapeutic approaches. We are evaluating an anticancer strategy that focuses on overcoming such a barrier by genetically engineering drug-resistant variants of immunocompetent cells, thereby allowing for the coadministration of cellular therapy with cytotoxic chemotherapy, a method we refer to as drug-resistant immunotherapy (DRI). The strategy relies on the use of cDNA sequences that confer drug resistance and recombinant lentiviral vectors to transfer nucleic acid sequences into immunocompetent cells. In the present study, we evaluated a DRI-based strategy that incorporates the immunocompetent cell line NK-92, which has intrinsic antitumor properties, genetically engineered to be resistant to both temozolomide and trimetrexate. These immune effector cells efficiently lysed neuroblastoma cell lines, which we show are also sensitive to both chemotherapy agents. The antitumor efficacy of the DRI strategy was demonstrated in vivo, whereby neuroblastoma-bearing NOD/SCID/γ-chain knockout (NSG) mice treated with dual drug-resistant NK-92 cell therapy followed by dual cytotoxic chemotherapy showed tumor regression and significantly enhanced survival compared with animals receiving either nonengineered cell-based therapy and chemotherapy, immunotherapy alone, or chemotherapy alone. These data show there is a benefit to using drug-resistant cellular therapy when combined with cytotoxic chemotherapy approaches. PMID:22397715

[Cytomegalovirus retinitis in immunocompetent patients].

PubMed

Yoshinaga, Wakako; Mizushima, Yuka; Abematsu, Noriko; Nakao, Kumiko; Sakamoto, Taiji

2008-08-01

Cytomegalovirus (CMV) retinitis usually affects severely immunosuppressed individuals. We report two immunocompetent patients who developed CMV retinitis. Case 1 was a 65-year-old man who was referred to us with blurred vision and floaters of 2 weeks duration in his left eye. Slit-lamp biomicroscopy showed keratic precipitates, aqueous cells, and vitreous opacity in his left eye. Funduscopic examination revealed yellow-white retinal lesions with arterial sheathing in the superotemporal midperiphery. Case 2 was a 63-year-old man who presented with a 2-week history of blurred vision in his left eye. Ophthalmologic examination of the left eye showed keratic precipitates, aqueous cells, vitreous opacity, and yellow-white lesions in the superotemporal peripheral retina. In both cases, CMV DNA was detected in the aqueous humor and therefore the diagnosis was CMV retinitis. CMV retinitis in both cases was indolent and was resolved in one month without treatment with antiviral drugs. Although both patients had diabetes mellitus, the results of their laboratory examinations were unremarkable and they were immunocompetent. Unlike CMV retinitis in immunocompromised patients, CMV retinitis in immunocompetent patients had significant anterior and vitreous inflammation but did not require antiviral treatment. A possible association between CMV retinitis and diabetes mellitus was suggested.

Chickenpox-related pulmonary granulomas in immunocompetent adults: clinicopathologic and molecular features of an underrated occurrence.

PubMed

Rossi, Giulio; Cavazza, Alberto; Gennari, William; Marchioni, Alessandro; Graziano, Paolo; Caminati, Antonella; Mengoli, Maria Cecilia; Magnani, Rita; Colby, Thomas V

2012-10-01

Pulmonary granulomas represent a common inflammatory reaction to several lung infective or noninfective diseases. However, little is known about the histology and clinical presentation of chickenpox-related granulomas in immunocompetent subjects. We collected a series of 8 adult patients (mean age, 40 y; range, 33 to 53 y) with several bilateral pulmonary granulomas incidentally discovered after imaging studies. All patients were asymptomatic and had experienced a varicella-zoster virus (VZV) infection as adults but were clinically suspected to have a metastatic neoplasm of unknown origin. Chest computed tomography scan revealed numerous, tiny (few millimeters to 1 cm in size) nodules randomly dispersed through the lungs. Positron emission tomography scan performed in 4 patients was negative. All patients underwent video-assisted thoracoscopic surgical resection and were still alive and well. At histology, granulomas consisted of well-defined, rounded, small nodules centered by a deeply eosinophilic, acellular necrosis rimmed by lamellar dense collagen and a chronic inflammatory infiltrate with or without multinucleated giant cells. Chickenpox-related granulomas were included in the differential diagnosis along with several other granulomatous diseases. Polymerase chain reaction-based molecular analysis for VZV performed on paraffin sections detected VZV DNA in all 8 cases. By contrast, 85 cases of pulmonary granulomas of different etiologies were simultaneously studied by molecular analysis with negative results. Pathologists should be familiar with the peculiar morphologic appearance of chickenpox-related granulomas. A careful search for a history of VZV infection in adulthood and molecular studies may be very helpful in confirming the diagnosis.

Susceptibility to disease varies with ontogeny and immunocompetence in a threatened amphibian.

PubMed

Abu Bakar, Amalina; Bower, Deborah S; Stockwell, Michelle P; Clulow, Simon; Clulow, John; Mahony, Michael J

2016-08-01

Ontogenetic changes in disease susceptibility have been demonstrated in many vertebrate taxa, as immature immune systems and limited prior exposure to pathogens can place less developed juveniles at a greater disease risk. By causing the disease chytridiomycosis, Batrachochytrium dendrobatidis (Bd) infection has led to the decline of many amphibian species. Despite increasing knowledge on how Bd varies in its effects among species, little is known on the interaction between susceptibility and development within host species. We compared the ontogenetic susceptibility of post-metamorphic green and golden bell frogs Litoria aurea to chytridiomycosis by simultaneously measuring three host-pathogen responses as indicators of the development of the fungus-infection load, survival rate, and host immunocompetence-following Bd exposure in three life stages (recently metamorphosed juveniles, subadults, adults) over 95 days. Frogs exposed to Bd as recently metamorphosed juveniles acquired higher infection loads and experienced lower immune function and lower survivorship than subadults and adults, indicating an ontogenetic decline in chytridiomycosis susceptibility. By corresponding with an intrinsic developmental maturation in immunocompetence seen in uninfected frogs, we suggest these developmental changes in host susceptibility in L. aurea may be immune mediated. Consequently, the physiological relationship between ontogeny and immunity may affect host population structure and demography through variation in life stage survival, and understanding this can shape management targets for effective amphibian conservation.

Non-healing genital herpes mimicking donovanosis in an immunocompetent man.

PubMed

Gupta, Vishal; Khute, Prakash; Patel, Anjali; Gupta, Somesh

2016-01-01

Although atypical presentations of herpetic infection in immunocompetent individuals are common, they very rarely have the extensive, chronic and verrucous appearances seen in the immunocompromised host. We report a case of genital herpes manifesting as painless chronic non-healing genital ulcers with exuberant granulation tissue in an immunocompetent man. Owing to this morphology, the ulcers were initially mistaken for donovanosis. To the best of our knowledge, such a presentation of genital herpes in an immunocompetent individual has not been described previously. © The Author(s) 2015.

Studying skin tumourigenesis and progression in immunocompetent hairless SKH1-hr mice using chronic 7,12-dimethylbenz(a)anthracene topical applications to develop a useful experimental skin cancer model.

PubMed

Thomas, Giju; Tuk, Bastiaan; Song, Ji-Ying; Truong, Hoa; Gerritsen, Hans C; de Gruijl, Frank R; Sterenborg, Henricus J C M

2017-02-01

Previous studies have established that 7,12-dimethylbenz(a)anthracene (DMBA) can initiate skin tumourigenesis in conventional furred mouse models by acting on hair follicle stem cells. However, further cancer progression depends on repeated applications of tumour promoter agents. This study evaluated the timeline involved in skin tumourigenesis and progression in immunocompetent hairless SKH1-hr mice with dysfunctional hair follicles using only DMBA with no additional tumour promoter agents. The results showed that topical application of 30 µg (117 nmol) of DMBA over the back and flank regions of the mouse once a week and 15 µg (58.5 nmol) twice a week produced skin tumours after 7-8 weeks. However, by week 14 a heavy benign tumour load required the mice to be euthanized. Lowering the DMBA dose to 15 µg (58.5 nmol) once a week produced tumours more slowly and allowed the mice to be studied for a longer period to week 23. This low-dose DMBA regimen yielded a high percentage of malignant tumours (58.8%) after 23 weekly applications. Additionally DMBA-treated skin showed an increase in mean epidermal thickness in comparison to untreated and acetone-treated skin. Despite the aberrant hair follicles in SKH1-hr mice, this chemically driven skin cancer model in hairless mice can serve as a suitable alternative to the ultraviolet-induced skin cancer models and can be reliably replicated as demonstrated by both the pilot and main experiments.

Isolation and genotyping of Toxoplasma gondii causing fatal systemic toxoplasmosis in an immunocompetent 10-year-old cat.

PubMed

Spycher, Andrea; Geigy, Caroline; Howard, Judith; Posthaus, Horst; Gendron, Karine; Gottstein, Bruno; Debache, Karim; Herrmann, Daland C; Schares, Gereon; Frey, Caroline F

2011-01-01

A 10-year-old male, neutered domestic shorthair cat was presented with fever, anorexia, vomiting, and diarrhea. Serologic testing for Feline immunodeficiency virus and Feline leukemia virus were negative. Fine-needle aspirates of mesenteric lymph nodes revealed the presence of banana-shaped apicomplexan parasites. The cat died after 4 days of hospitalization. Postmortem polymerase chain reaction (PCR) analysis confirmed the presence of Toxoplasma gondii in all examined organs. Parasites were ex vivo isolated in outbred mice and subsequently transferred into cell culture. Genotyping, using genetic markers for SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1, and Apico for PCR-restriction fragment length polymorphism, revealed infection with type II T. gondii displaying type II alleles at all loci except Apico, which exhibited a type I allele. This is the most frequently identified genotype among cats acting as definitive hosts in central Europe, but to the authors' knowledge, it has never been associated with systemic toxoplasmosis in an adult, immunocompetent cat.

Microglial K+ Channel Expression in Young Adult and Aged Mice

PubMed Central

Schilling, Tom; Eder, Claudia

2015-01-01

The K+ channel expression pattern of microglia strongly depends on the cells' microenvironment and has been recognized as a sensitive marker of the cells' functional state. While numerous studies have been performed on microglia in vitro, our knowledge about microglial K+ channels and their regulation in vivo is limited. Here, we have investigated K+ currents of microglia in striatum, neocortex and entorhinal cortex of young adult and aged mice. Although almost all microglial cells exhibited inward rectifier K+ currents upon membrane hyperpolarization, their mean current density was significantly enhanced in aged mice compared with that determined in young adult mice. Some microglial cells additionally exhibited outward rectifier K+ currents in response to depolarizing voltage pulses. In aged mice, microglial outward rectifier K+ current density was significantly larger than in young adult mice due to the increased number of aged microglial cells expressing these channels. Aged dystrophic microglia exhibited outward rectifier K+ currents more frequently than aged ramified microglia. The majority of microglial cells expressed functional BK-type, but not IK- or SK-type, Ca2+-activated K+ channels, while no differences were found in their expression levels between microglia of young adult and aged mice. Neither microglial K+ channel pattern nor K+ channel expression levels differed markedly between the three brain regions investigated. It is concluded that age-related changes in microglial phenotype are accompanied by changes in the expression of microglial voltage-activated, but not Ca2+-activated, K+ channels. PMID:25472417

Research opportunities on immunocompetence in space

NASA Technical Reports Server (NTRS)

Beisel, W. R. (Editor); Talbot, J. M. (Editor)

1985-01-01

The most significant of the available data on the effects of space flight on immunocompetences and the potential operational and clinical significance of reported changes are as follows: (1) reduced postflight blastogenic response of peripheral lymphocytes from space crew members; (2) postflight neutrophilia persisting up to 7 days; (3) gingival inflammation of the Skylab astronauts; (4) postflight lymphocytopenia, eosinopenia, and monocytopenia; (5) modifications and shifts in the microflora of space crews and spacecraft; and (6) microbial contamination of cabin air and drinking water. These responses and data disclose numerous gaps in the knowledge that is essential for an adequate understanding of space-related changes in immunocompetence.

Long-term patterns of immune investment by wild deer mice infected with Sin Nombre virus.

PubMed

Lehmer, Erin M; Jones, Jeremy D; Bego, Mariana G; Varner, Johanna M; Jeor, Stephen St; Clay, Christine A; Dearing, M Denise

2010-01-01

Immunocompetence of animals fluctuates seasonally, However, there is little consensus on the cause of these fluctuations. Some studies have suggested that these patterns are influenced by changes in reproductive condition, whereas others have suggested that differences result from seasonal variations in energy expenditures. The objective of our study was to examine these contrasting views of immunity by evaluating seasonal patterns of immune response and reproduction in wild populations of deer mice Peromyscus maniculatus exposed to Sin Nombre virus (SNV). Over three consecutive fall (September, October, November) and three consecutive spring (March, April, May) sampling periods, we used titration enzyme-linked immunosorbent assay (ELISA) to quantify virus-specific antibody production in 48 deer mice infected with SNV. Levels of reproductive hormones were quantified using ELISA. SNV antibody titers reached their lowest level during November (geometric mean titer [GMT] = 420) and their highest levels during September (GMT = 5,545) and May (GMT = 3,582), suggesting that the immune response of deer mice to SNV has seasonal patterns. The seeming decrease in antibody titer over winter coupled with the consistency in body masses suggests that during winter, immunocompetence may be compromised to offset the energetic costs of maintenance functions, including those associated with maintaining body mass. Deer mice showed distinct sex-based differences in SNV antibody production, with males producing higher antibody titers (GMT = 3,333) than females (GMT = 1,477). Levels of reproductive hormones do not appear to influence antibody production in either males or females, as there was no correlation between estradiol concentrations and SNV antibody titer in female deer mice (r² = 0.26), nor was there a significant relationship between levels of testosterone and SNV antibody titers in males (r² = 0.28). Collectively, this study demonstrates that immunocompetence of wild deer

Dynamic Viral Dissemination in Mice Infected with Yellow Fever Virus Strain 17D

PubMed Central

Erickson, Andrea K.

2013-01-01

Arboviruses such as yellow fever virus (YFV) are transmitted between arthropod vectors and vertebrate hosts. While barriers limiting arbovirus population diversity have been observed in mosquitoes, whether barriers exist in vertebrate hosts is unclear. To investigate whether arboviruses encounter bottlenecks during dissemination in the vertebrate host, we infected immunocompetent mice and immune-deficient mice lacking alpha/beta interferon (IFN-α/β) receptors (IFNAR−/− mice) with a pool of genetically marked viruses to evaluate dissemination and host barriers. We used the live attenuated vaccine strain YFV-17D, which contains many mutations compared with virulent YFV. We found that intramuscularly injected immunocompetent mice did not develop disease and that viral dissemination was restricted. Conversely, 32% of intramuscularly injected IFNAR−/− mice developed disease. By following the genetically marked viruses over time, we found broad dissemination in IFNAR−/− mice followed by clearance. The patterns of viral dissemination were similar in mice that developed disease and mice that did not develop disease. Unlike our previous results with poliovirus, these results suggest that YFV-17D encounters no major barriers during dissemination within a vertebrate host in the absence of the type I IFN response. PMID:24027319

Do men’s faces really signal heritable immunocompetence?

PubMed Central

2013-01-01

In the literature on human mate choice, masculine facial morphology is often proposed to be an intersexual signal of heritable immunocompetence, and hence an important component of men’s attractiveness. This hypothesis has received considerable research attention, and is increasingly treated as plausible and well supported. In this article, we propose that the strength of the evidence for the immunocompetence hypothesis is somewhat overstated, and that a number of difficulties have been under-acknowledged. Such difficulties include (1) the tentative nature of the evidence regarding masculinity and disease in humans, (2) the complex and uncertain picture emerging from the animal literature on sexual ornaments and immunity, (3) the absence of consistent, cross-cultural support for the predictions of the immunocompetence hypothesis regarding preferences for masculinized stimuli, and (4) evidence that facial masculinity contributes very little, if anything, to overall attractiveness in real men. Furthermore, alternative explanations for patterns of preferences, in particular the proposal that masculinity is primarily an intrasexual signal, have been neglected. We suggest that immunocompetence perspectives on masculinity, whilst appealing in many ways, should still be regarded as speculative, and that other perspectives–and other traits–should be the subject of greater attention for researchers studying human mate preferences. PMID:23555177

Jejunal brush border microvillous alterations in Giardia muris-infected mice: role of T lymphocytes and interleukin-6.

PubMed

Scott, K G; Logan, M R; Klammer, G M; Teoh, D A; Buret, A G

2000-06-01

Intestinal colonization with the protozoan Giardia causes diffuse brush border microvillous alterations and disaccharidase deficiencies, which in turn are responsible for intestinal malabsorption and maldigestion. The role of T cells and/or cytokines in the pathogenesis of Giardia-induced microvillous injury remains unclear. The aim of this study was to assess the role of T cells and interleukin-6 (IL-6) in the brush border pathophysiology of acute murine giardiasis in vivo. Athymic nude (nu(-)/nu(-)) CD-1 mice and isogenic immunocompetent (nu(+)/nu(+)) CD-1 mice (4 weeks old) received an axenic Giardia muris trophozoite inoculum or vehicle (control) via orogastric gavage. Weight gain and food intake were assessed daily. On day 6, segments of jejunum were assessed for parasite load, brush border ultrastructure, IL-6 content, maltase and sucrase activities, villus-crypt architecture, and intraepithelial lymphocyte (IEL) infiltration. Despite similar parasitic loads on day 6, infected immunocompetent animals, but not infected nude mice, showed a diffuse loss of brush border microvillous surface area, which was correlated with a significant reduction in maltase and sucrase activities and a decrease in jejunal IL-6 concentration. In both athymic control and infected mice, jejunal brush border surface area and disaccharidases were high, but levels of tissue IL-6 were low and comparable to the concentration measured in immunocompetent infected animals. In both immunocompetent and nude mice, infection caused a small but significant increase in the numbers of IELs. These findings suggest that the enterocyte brush border injury and malfunction seen in giardiasis is, at least in part, mediated by thymus-derived T lymphocytes and that suppressed jejunal IL-6 does not necessarily accompany microvillous shortening.

Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice.

PubMed

La Merrill, Michele A; Sethi, Sunjay; Benard, Ludovic; Moshier, Erin; Haraldsson, Borje; Buettner, Christoph

2016-11-01

Dichlorodiphenyltrichloroethane (DDT) was used extensively to control malaria, typhus, body lice, and bubonic plague worldwide, until countries began restricting its use in the 1970s. However, the use of DDT to control vector-borne diseases continues in developing countries. Prenatal DDT exposure is associated with elevated blood pressure in humans. We hypothesized that perinatal DDT exposure causes hypertension in adult mice. DDT was administered to C57BL/6J dams from gestational day 11.5 to postnatal day 5. Blood pressure (BP) and myocardial wall thickness were measured in male and female adult offspring. Adult mice were treated with an angiotensin converting enzyme (ACE) inhibitor, captopril, to evaluate sensitivity to amelioration of DDT-associated hypertension by ACE inhibition. We further assessed the influence of DDT exposure on the expression of mRNAs that regulate BP through renal ion transport. Adult mice perinatally exposed to DDT exhibited chronically increased systolic BP, increased myocardial wall thickness, and elevated expression of mRNAs of several renal ion transporters. Captopril completely reversed hypertension in mice perinatally exposed to DDT. These data demonstrate that perinatal exposure to DDT causes hypertension and cardiac hypertrophy in adult offspring. A key mechanism underpinning this hypertension is an overactivated renin angiotensin system because ACE inhibition reverses the hypertension induced by perinatal DDT exposure. Citation: La Merrill M, Sethi S, Benard L, Moshier E, Haraldsson B, Buettner C. 2016. Perinatal DDT exposure induces hypertension and cardiac hypertrophy in adult mice. Environ Health Perspect 124:1722-1727; http://dx.doi.org/10.1289/EHP164.

Impaired fear extinction learning in adult heterozygous BDNF knock-out mice.

PubMed

Psotta, Laura; Lessmann, Volkmar; Endres, Thomas

2013-07-01

Brain-derived neurotrophic factor (BDNF) is a crucial regulator of neuroplasticity, which underlies learning and memory processes in different brain areas. To investigate the role of BDNF in the extinction of amygdala-dependent cued fear memories, we analyzed fear extinction learning in heterozygous BDNF knock-out mice, which possess a reduction of endogenous BDNF protein levels to ~50% of wild-type animals. Since BDNF expression has been shown to decline with aging of animals, we tested the performance in extinction learning of these mice at 2 months (young adults) and 7 months (older adults) of age. The present study shows that older adult heterozygous BDNF knock-out mice, which have a chronic 50% lack of BDNF, also possess a deficit in the acquisition of extinction memory, while extinction learning remains unaffected in young adult heterozygous BDNF knock-out mice. This deficit in extinction learning is accompanied by a reduction of BDNF protein in the hippocampus, amygdala and the prefrontal cortex. Copyright © 2013 Elsevier Inc. All rights reserved.

Severe polymyositis due to Toxoplasma gondii in an adult immunocompetent patient: a case report and review of the literature.

PubMed

Cuomo, G; D'Abrosca, V; Rizzo, V; Nardiello, S; La Montagna, G; Gaeta, G B; Valentini, G

2013-08-01

Toxoplasmosis, a worldwide zoonosis caused by a coccidian parasite Toxoplasma gondii, is more often asymptomatic in immunocompetent patients. We report the case of a 38-year-old immunocompetent male with a polymyositis as the presenting manifestation of T. gondii infection. The patient was hospitalized for a 30-day history of fever (T max 39.5°C), muscle pain, and progressive weakness of the muscles. A diagnosis of polymyositis was made, and he was started on corticosteroid treatment, which caused no reduction of symptoms. After finding a positive polymerase chain reaction (PCR) assay for T. gondii, together with additional clinical findings, a diagnosis of acute toxoplasmosis was made. Specific treatment with pyrimethamine and sulfadiazine was started, with a progressive reduction of symptoms and normalization of laboratory tests.

Antibody targeting KIT as pretransplantation conditioning in immunocompetent mice.

PubMed

Xue, Xingkui; Pech, Nancy K; Shelley, W Christopher; Srour, Edward F; Yoder, Mervin C; Dinauer, Mary C

2010-12-09

Inherited hematologic defects that lack an in vivo selective advantage following gene correction may benefit from effective yet minimally toxic cytoreduction of endogenous hematopoietic stem cells (HSCs) prior to transplantation of gene-modified HSCs. We studied the efficacy of administering a novel sequential treatment of parenteral ACK2, an antibody that blocks KIT, followed by low-dose irradiation (LD-IR) for conditioning of wild-type and X-linked chronic granulomatous disease (X-CGD) mice. In wild-type mice, combining ACK2 and LD-IR profoundly decreased endogenous competitive long-term HSC repopulating activity, and permitted efficient and durable donor-derived HSC engraftment after congenic transplantation. ACK2 alone was ineffective. The combination of ACK2 and LD-IR was also effective conditioning in X-CGD mice for engraftment of X-CGD donor HSCs transduced ex vivo with a lentiviral vector. We conclude that combining ACK2 with LD-IR is a promising approach to effectively deplete endogenous HSCs and facilitate engraftment of transplanted donor HSCs.

Unusual MRI findings in an immunocompetent patient with EBV encephalitis: a case report

PubMed Central

2011-01-01

Blackground It is well-known that Epstein-Barr virus (EBV) can affect the central nervous system (CNS). Case presentation Herein the authors report unusual timely Magnetic Resonance Imaging (MRI) brain scan findings in an immunocompetent patient with EBV encephalitis. Diffusion weighted MRI sequence performed during the acute phase of the disease was normal, whereas the Fast Relaxation Fast Spin Echo T2 image showed diffuse signal intensity changes in white matter. The enhancement pattern suggested an inflammatory response restricted to the brain microcirculation. Acyclovir and corticosteroid therapy was administered. After three weeks, all signal intensities returned to normal and the patient showed clinical recovery. Conclusion This report demonstrates that EBV in an immunocompetent adult can present with diffuse, reversible brain white matter involvement in the acute phase of mononucleosis. Moreover, our case suggests that a negative DWI sequence is associated with a favorable improvement in severe EBV CNS infection. More extensive studies are needed to assess what other instrumental data can help to distinguish viral lesions from other causes in the acute phase of disease. PMID:21435249

Perinatal DDT Exposure Induces Hypertension and Cardiac Hypertrophy in Adult Mice

PubMed Central

La Merrill, Michele A.; Sethi, Sunjay; Benard, Ludovic; Moshier, Erin; Haraldsson, Borje; Buettner, Christoph

2016-01-01

Background: Dichlorodiphenyltrichloroethane (DDT) was used extensively to control malaria, typhus, body lice, and bubonic plague worldwide, until countries began restricting its use in the 1970s. However, the use of DDT to control vector-borne diseases continues in developing countries. Prenatal DDT exposure is associated with elevated blood pressure in humans. Objective: We hypothesized that perinatal DDT exposure causes hypertension in adult mice. Methods: DDT was administered to C57BL/6J dams from gestational day 11.5 to postnatal day 5. Blood pressure (BP) and myocardial wall thickness were measured in male and female adult offspring. Adult mice were treated with an angiotensin converting enzyme (ACE) inhibitor, captopril, to evaluate sensitivity to amelioration of DDT-associated hypertension by ACE inhibition. We further assessed the influence of DDT exposure on the expression of mRNAs that regulate BP through renal ion transport. Results: Adult mice perinatally exposed to DDT exhibited chronically increased systolic BP, increased myocardial wall thickness, and elevated expression of mRNAs of several renal ion transporters. Captopril completely reversed hypertension in mice perinatally exposed to DDT. Conclusions: These data demonstrate that perinatal exposure to DDT causes hypertension and cardiac hypertrophy in adult offspring. A key mechanism underpinning this hypertension is an overactivated renin angiotensin system because ACE inhibition reverses the hypertension induced by perinatal DDT exposure. Citation: La Merrill M, Sethi S, Benard L, Moshier E, Haraldsson B, Buettner C. 2016. Perinatal DDT exposure induces hypertension and cardiac hypertrophy in adult mice. Environ Health Perspect 124:1722–1727; http://dx.doi.org/10.1289/EHP164 PMID:27325568

A genetic and pathologic study of a DENV2 clinical isolate capable of inducing encephalitis and hematological disturbances in immunocompetent mice.

PubMed

Amorim, Jaime Henrique; Pereira Bizerra, Raíza Sales; dos Santos Alves, Rúbens Prince; Sbrogio-Almeida, Maria Elisabete; Levi, José Eduardo; Capurro, Margareth Lara; de Souza Ferreira, Luís Carlos

2012-01-01

Dengue virus (DENV) is the causative agent of dengue fever (DF), a mosquito-borne illness endemic to tropical and subtropical regions. There is currently no effective drug or vaccine formulation for the prevention of DF and its more severe forms, i.e., dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). There are two generally available experimental models for the study of DENV pathogenicity as well as the evaluation of potential vaccine candidates. The first model consists of non-human primates, which do not develop symptoms but rather a transient viremia. Second, mouse-adapted virus strains or immunocompromised mouse lineages are utilized, which display some of the pathological features of the infection observed in humans but may not be relevant to the results with regard to the wild-type original virus strains or mouse lineages. In this study, we describe a genetic and pathological study of a DENV2 clinical isolate, named JHA1, which is naturally capable of infecting and killing Balb/c mice and reproduces some of the symptoms observed in DENV-infected subjects. Sequence analyses demonstrated that the JHA1 isolate belongs to the American genotype group and carries genetic markers previously associated with neurovirulence in mouse-adapted virus strains. The JHA1 strain was lethal to immunocompetent mice following intracranial (i.c.) inoculation with a LD(50) of approximately 50 PFU. Mice infected with the JHA1 strain lost weight and exhibited general tissue damage and hematological disturbances, with similarity to those symptoms observed in infected humans. In addition, it was demonstrated that the JHA1 strain shares immunological determinants with the DENV2 NGC reference strain, as evaluated by cross-reactivity of anti-envelope glycoprotein (domain III) antibodies. The present results indicate that the JHA1 isolate may be a useful tool in the study of DENV pathogenicity and will help in the evaluation of anti-DENV vaccine formulations as well as

Persistence of polyomavirus in mice infected as adults differs from that observed in mice infected as newborns.

PubMed Central

Berke, Z; Dalianis, T

1993-01-01

By using the polymerase chain reaction (PCR) technique, a technique more sensitive than Southern analysis, which allows detection of polyomavirus DNA only in newborn and nude adult mice, it has now been possible to monitor the persistence pattern of polyomavirus DNA after infection of normal adult CBA mice for the first time. Viral signs appeared gradually, showing variations in time course and organ distribution between mice, and reached a peak activity after 2 to 3 weeks, when they could be found in bone, heart, gonads, lymph node, and skin, but disappeared by 2 to 5 months. No virus DNA was detected in the kidneys or lungs, which is in contrast to what is observed after infection of newborn mice. This finding suggests that the persistence pattern of polyomavirus is age dependent. PMID:8389934

The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults.

PubMed

McGill, F; Heyderman, R S; Michael, B D; Defres, S; Beeching, N J; Borrow, R; Glennie, L; Gaillemin, O; Wyncoll, D; Kaczmarski, E; Nadel, S; Thwaites, G; Cohen, J; Davies, N W S; Miller, A; Rhodes, A; Read, R C; Solomon, T

2016-04-01

Bacterial meningitis and meningococcal sepsis are rare conditions with high case fatality rates. Early recognition and prompt treatment saves lives. In 1999 the British Infection Society produced a consensus statement for the management of immunocompetent adults with meningitis and meningococcal sepsis. Since 1999 there have been many changes. We therefore set out to produce revised guidelines which provide a standardised evidence-based approach to the management of acute community acquired meningitis and meningococcal sepsis in adults. A working party consisting of infectious diseases physicians, neurologists, acute physicians, intensivists, microbiologists, public health experts and patient group representatives was formed. Key questions were identified and the literature reviewed. All recommendations were graded and agreed upon by the working party. The guidelines, which for the first time include viral meningitis, are written in accordance with the AGREE 2 tool and recommendations graded according to the GRADE system. Main changes from the original statement include the indications for pre-hospital antibiotics, timing of the lumbar puncture and the indications for neuroimaging. The list of investigations has been updated and more emphasis is placed on molecular diagnosis. Approaches to both antibiotic and steroid therapy have been revised. Several recommendations have been given regarding the follow-up of patients. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Normalizing the environment recapitulates adult human immune traits in laboratory mice.

PubMed

Beura, Lalit K; Hamilton, Sara E; Bi, Kevin; Schenkel, Jason M; Odumade, Oludare A; Casey, Kerry A; Thompson, Emily A; Fraser, Kathryn A; Rosato, Pamela C; Filali-Mouhim, Ali; Sekaly, Rafick P; Jenkins, Marc K; Vezys, Vaiva; Haining, W Nicholas; Jameson, Stephen C; Masopust, David

2016-04-28

Our current understanding of immunology was largely defined in laboratory mice, partly because they are inbred and genetically homogeneous, can be genetically manipulated, allow kinetic tissue analyses to be carried out from the onset of disease, and permit the use of tractable disease models. Comparably reductionist experiments are neither technically nor ethically possible in humans. However, there is growing concern that laboratory mice do not reflect relevant aspects of the human immune system, which may account for failures to translate disease treatments from bench to bedside. Laboratory mice live in abnormally hygienic specific pathogen free (SPF) barrier facilities. Here we show that standard laboratory mouse husbandry has profound effects on the immune system and that environmental changes produce mice with immune systems closer to those of adult humans. Laboratory mice--like newborn, but not adult, humans--lack effector-differentiated and mucosally distributed memory T cells. These cell populations were present in free-living barn populations of feral mice and pet store mice with diverse microbial experience, and were induced in laboratory mice after co-housing with pet store mice, suggesting that the environment is involved in the induction of these cells. Altering the living conditions of mice profoundly affected the cellular composition of the innate and adaptive immune systems, resulted in global changes in blood cell gene expression to patterns that more closely reflected the immune signatures of adult humans rather than neonates, altered resistance to infection, and influenced T-cell differentiation in response to a de novo viral infection. These data highlight the effects of environment on the basal immune state and response to infection and suggest that restoring physiological microbial exposure in laboratory mice could provide a relevant tool for modelling immunological events in free-living organisms, including humans.

Aspergillus spondylitis in immunocompetent patients.

PubMed

Govender, S; Kumar, K P

2001-01-01

Four immunocompetent patients with neurological deficit underwent anterior decompression for Aspergillus osteomyelitis of the spine. All patients improved neurologically following anterior spinal decompression and antifungal therapy. This study emphasizes the importance of obtaining a tissue diagnosis as these unusual infections may mimic tuberculosis, which is more common.

Pathogenesis of Lassa fever virus infection: I. Susceptibility of mice to recombinant Lassa Gp/LCMV chimeric virus.

PubMed

Lee, Andrew M; Cruite, Justin; Welch, Megan J; Sullivan, Brian; Oldstone, Michael B A

2013-08-01

Lassa virus (LASV) is a BSL-4 restricted agent. To allow study of infection by LASV under BSL-2 conditions, we generated a recombinant virus in which the LASV glycoprotein (Gp) was placed on the backbone of lymphocytic choriomeningitis virus (LCMV) Cl13 nucleoprotein, Z and polymerase genes (rLCMV Cl13/LASV Gp). The recombinant virus displayed high tropism for dendritic cells following in vitro or in vivo infection. Inoculation of immunocompetent adults resulted in an acute infection, generation of virus-specific CD8(+) T cells and clearance of the infection. Inoculation of newborn mice with rLCMV Cl13/LASV Gp resulted in a life-long persistent infection. Interestingly, adoptive transfer of rLCMV Cl13/LASV Gp immune memory cells into such persistently infected mice failed to purge virus but, in contrast, cleared virus from mice persistently infected with wt LCMV Cl13. Copyright © 2013 Elsevier Inc. All rights reserved.

Performance of the Architect EBV Antibody Panel for Determination of Epstein-Barr Virus Infection Stage in Immunocompetent Adolescents and Young Adults with Clinical Suspicion of Infectious Mononucleosis

PubMed Central

Patel, Mauli; Kadakia, Kinjal; Haque, Tanzina

2014-01-01

The Architect EBV antibody panel is a new chemiluminescence immunoassay system used to determine the stage of Epstein-Barr virus (EBV) infection based on the detection of IgM and IgG antibodies to viral capsid antigen (VCA) and IgG antibodies against Epstein-Barr nuclear antigen 1 (EBNA-1). We evaluated its diagnostic accuracy in immunocompetent adolescents and young adults with clinical suspicion of infectious mononucleosis (IM) using the RecomLine EBV IgM and IgG immunoblots as the reference standard. In addition, the use of the antibody panel in a sequential testing algorithm based on initial EBNA-1 IgG analysis was assessed for cost-effectiveness. Finally, we investigated the degree of cross-reactivity of the VCA IgM marker during other primary viral infections that may present with an EBV IM-like picture. High sensitivity (98.3% [95% confidence interval {CI}, 90.7 to 99.7%]) and specificity (94.2% [95% CI, 87.9 to 97.8%]) were found after testing 162 precharacterized archived serum samples. There was perfect agreement between the use of the antibody panel in sequential and parallel testing algorithms, but substantial cost savings (23%) were obtained with the sequential strategy. A high rate of reactive VCA IgM results was found in primary cytomegalovirus (CMV) infections (60.7%). In summary, the Architect EBV antibody panel performs satisfactorily in the investigation of EBV IM in immunocompetent adolescents and young adults, and the application of an EBNA-1 IgG-based sequential testing algorithm is cost-effective in this diagnostic setting. Concomitant testing for CMV is strongly recommended to aid in the interpretation of EBV serological patterns. PMID:24695777

SELF ADMINISTRATION OF OXYCODONE BY ADOLESCENT AND ADULT MICE AFFECTS STRIATAL NEUROTRANSMITTER RECEPTOR GENE EXPRESSION

PubMed Central

Mayer-Blackwell, B.; Schlussman, S. D.; Butelman, E. R.; Ho, A.; Ott, J.; Kreek, M. J.; Zhang, Y.

2014-01-01

Illicit use of prescription opioid analgesics (e.g., oxycodone) in adolescence is a pressing public health issue. Our goal was to determine whether oxycodone self administration differentially affects striatal neurotransmitter receptor gene expression in the dorsal striatum of adolescent compared to adult C57BL/6J mice. Groups of adolescent mice (4 weeks old, n= 12) and of adult mice (11 weeks old, n= 11) underwent surgery during which a catheter was implanted into their jugular veins. After recovering from surgery, mice self administered oxycodone (0.25 mg/kg/infusion) 2 h/day for 14 consecutive days or served as yoked saline controls. Mice were sacrificed within 1 h after the last self-administration session and the dorsal striatum was isolated for mRNA analysis. Gene expression was analyzed with real time PCR using a commercially available neurotransmitter receptor PCR array containing 84 genes. We found that adolescent mice self administered less oxycodone than adult mice over the 14 days. Monoamine oxidase A (Maoa) and neuropeptide Y receptor 5 mRNA levels were lower in adolescent mice than in adult mice without oxycodone exposure. Oxycodone self administration increased Maoa mRNA levels compared to controls in both age groups. There was a positive correlation of the amount of oxycodone self administered in the last session or across 14 sessions with Maoa mRNA levels. Gastrin-releasing peptide receptor mRNA showed a significant Drug × Age interaction, with point-wise significance. More genes in the dorsal striatum of adolescents (19) changed in response to oxycodone self administration compared to controls than in adult (4) mice. Overall, this study demonstrates that repeated oxycodone self administration alters neurotransmitter receptors gene expression in the dorsal striatum of adolescent and adult mice. PMID:24220688

Methylprednisolone acetate induces, and Δ7-dafachronic acid suppresses, Strongyloides stercoralis hyperinfection in NSG mice.

PubMed

Patton, John B; Bonne-Année, Sandra; Deckman, Jessica; Hess, Jessica A; Torigian, April; Nolan, Thomas J; Wang, Zhu; Kliewer, Steven A; Durham, Amy C; Lee, James J; Eberhard, Mark L; Mangelsdorf, David J; Lok, James B; Abraham, David

2018-01-02

Strongyloides stercoralis hyperinfection causes high mortality rates in humans, and, while hyperinfection can be induced by immunosuppressive glucocorticoids, the pathogenesis remains unknown. Since immunocompetent mice are resistant to infection with S. stercoralis , we hypothesized that NSG mice, which have a reduced innate immune response and lack adaptive immunity, would be susceptible to the infection and develop hyperinfection. Interestingly, despite the presence of large numbers of adult and first-stage larvae in S. stercoralis -infected NSG mice, no hyperinfection was observed even when the mice were treated with a monoclonal antibody to eliminate residual granulocyte activity. NSG mice were then infected with third-stage larvae and treated for 6 wk with methylprednisolone acetate (MPA), a synthetic glucocorticoid. MPA treatment of infected mice resulted in 50% mortality and caused a significant >10-fold increase in the number of parasitic female worms compared with infected untreated mice. In addition, autoinfective third-stage larvae, which initiate hyperinfection, were found in high numbers in MPA-treated, but not untreated, mice. Remarkably, treatment with Δ7-dafachronic acid, an agonist of the parasite nuclear receptor Ss -DAF-12, significantly reduced the worm burden in MPA-treated mice undergoing hyperinfection with S. stercoralis Overall, this study provides a useful mouse model for S. stercoralis autoinfection and suggests a therapeutic strategy for treating lethal hyperinfection.

Voluntary Wheel Running Does not Affect Lipopolysaccharide-Induced Depressive-Like Behavior in Young Adult and Aged Mice

PubMed Central

Martin, Stephen A.; Dantzer, Robert; Kelley, Keith W.; Woods, Jeffrey A.

2014-01-01

Peripheral stimulation of the innate immune system with lipopolysaccharide (LPS) causes prolonged depressive-like behavior in aged mice that is dependent on indoleamine 2,3 dioxygenase (IDO) activation. Regular moderate intensity exercise training has been shown to exert neuroprotective effects that might reduce depressive-like behavior in aged mice. The purpose of this study was to test the hypothesis that voluntary wheel running would attenuate LPS-induced depressive-like behavior and brain IDO gene expression in 4-month-old and 22-month-old C57BL/6J mice. Mice were housed with a running wheel (Voluntary Wheel Running, VWR) or no wheel (Standard) for 30 days (young adult mice) or 70 days (aged mice), after which they were intraperitoneally injected with LPS (young adult mice: 0.83 mg/kg; aged mice: 0.33 mg/kg). Young adult VWR mice ran on average 6.9 km/day, while aged VWR mice ran on average 3.4 km/day. Both young adult and aged VWR mice increased their forced exercise tolerance compared to their respective Standard control groups. VWR had no effect on LPS-induced anorexia, weight-loss, increased immobility in the tail suspension test, and decreased sucrose preference in either young adult or aged mice. Four (young adult mice) and twenty-four (aged mice) hours after injection of LPS transcripts for TNF-α, IL-1β, IL-6, and IDO were upregulated in the whole brain independently of VWR. These results indicate that prolonged physical exercise has no effect on the neuroinflammatory response to LPS and its behavioral consequences. PMID:24281669

A literature review and case report of hand, foot and mouth disease in an immunocompetent adult.

PubMed

Omaña-Cepeda, Carlos; Martínez-Valverde, Andrea; del Mar Sabater-Recolons, María; Jané-Salas, Enric; Marí-Roig, Antonio; López-López, José

2016-03-15

To report an uncommon case of hand, foot and mouth disease, (HFMD) in an immunocompetent adult; a highly infectious disease, characterized by the appearance of vesicles on the mouth, hands and feet, associated with coxsackieviruses and enteroviruses; including a literature review. A 23 year Caucasian male with no medical or surgical history, no allergies, was not taking any medication and smoked ten cigarettes a day, suffering from discomfort in the oral cavity; itching, burning and pain when swallowing associated with small erythematous lesions located on the hard palate, and small ulcers in tonsillar pillars and right buccal mucosa. Mild fever of 37.8 °C and general malaise. The patient reported he had had contact with a child diagnosed with HFMD. From his background and symptoms, the patient was diagnosed with HFMD. Following symptomatic treatment, the symptoms remitted in 7 days. A literature review in MEDLINE (PubMed). The inclusion criteria were for studies on humans over the last 5 years, using the keywords HFMD. We found 925 articles, which were subsequently reduced to 52 documents after applying the inclusion criteria. Maculopapular lesions were found on hands and feet. Dentists may have a key role diagnosing the disease. A surveillance system to predict future outbreaks, encourage early diagnosis, put appropriate public health measures in place and research vaccine development is vitally important in order to control the disease.

Oral immunization of mice with live Pneumocystis murina protects against Pneumocystis pneumonia

PubMed Central

Samuelson, Derrick R.; de la Rua, Nicholas M.; Charles, Tysheena P.; Ruan, Sanbao; Taylor, Christopher M.; Blanchard, Eugene E.; Luo, Meng; Ramsay, Alistair J.; Shellito, Judd E.; Welsh, David A.

2016-01-01

Pneumocystis pneumonia is a major cause of morbidity and mortality in immunocompromised patients; particularly those infected with human immunodeficiency virus. In this study, we evaluated the potential of oral immunization with live Pneumocystis to elicit protection against respiratory infection with Pneumocystis murina. C57BL/6 mice vaccinated with live P. murina using a prime-boost vaccination strategy were protected from a subsequent lung challenge with P. murina at 2, 7, 14, and 28 days post infection even after CD4+ T cell depletion. Specifically, vaccinated immunocompetent mice had significantly faster clearance than unvaccinated immunocompetent mice and unvaccinated CD4-depleted mice remained persistently infected with P. murina. Vaccination also increased numbers of CD4+ T cells, CD8+ T cells, CD19+ B cells, and CD11b+ macrophages in the lungs following respiratory infection. In addition, levels of lung, serum, and fecal P. murina-specific IgG and IgA were increased in vaccinated animals. Further, administration of serum from vaccinated mice significantly reduced Pneumocystis lung burden in infected animals compared to control serum. We also found that the diversity of the intestinal microbial community was altered by oral immunization with P. murina. Our data demonstrate for the first time that an oral vaccination strategy prevents Pneumocystis infection. PMID:26864029

Disrupting Jagged1-Notch signaling impairs spatial memory formation in adult mice.

PubMed

Sargin, Derya; Botly, Leigh C P; Higgs, Gemma; Marsolais, Alexander; Frankland, Paul W; Egan, Sean E; Josselyn, Sheena A

2013-07-01

It is well-known that Notch signaling plays a critical role in brain development and growing evidence implicates this signaling pathway in adult synaptic plasticity and memory formation. The Notch1 receptor is activated by two subclasses of ligands, Delta-like (including Dll1 and Dll4) and Jagged (including Jag1 and Jag2). Ligand-induced Notch1 receptor signaling is modulated by a family of Fringe proteins, including Lunatic fringe (Lfng). Although Dll1, Jag1 and Lfng are critical regulators of Notch signaling, their relative contribution to memory formation in the adult brain is unknown. To investigate the roles of these important components of Notch signaling in memory formation, we examined spatial and fear memory formation in adult mice with reduced expression of Dll1, Jag1, Lfng and Dll1 plus Lfng. We also examined motor activity, anxiety-like behavior and sensorimotor gating using the acoustic startle response in these mice. Of the lines of mutant mice tested, we found that only mice with reduced Jag1 expression (mice heterozygous for a null mutation in Jag1, Jag1(+/-)) showed a selective impairment in spatial memory formation. Importantly, all other behavior including open field activity, conditioned fear memory (both context and discrete cue), acoustic startle response and prepulse inhibition, was normal in this line of mice. These results provide the first in vivo evidence that Jag1-Notch signaling is critical for memory formation in the adult brain. Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.

Performance of the architect EBV antibody panel for determination of Epstein-Barr virus infection stage in immunocompetent adolescents and young adults with clinical suspicion of infectious mononucleosis.

PubMed

Guerrero-Ramos, Alvaro; Patel, Mauli; Kadakia, Kinjal; Haque, Tanzina

2014-06-01

The Architect EBV antibody panel is a new chemiluminescence immunoassay system used to determine the stage of Epstein-Barr virus (EBV) infection based on the detection of IgM and IgG antibodies to viral capsid antigen (VCA) and IgG antibodies against Epstein-Barr nuclear antigen 1 (EBNA-1). We evaluated its diagnostic accuracy in immunocompetent adolescents and young adults with clinical suspicion of infectious mononucleosis (IM) using the RecomLine EBV IgM and IgG immunoblots as the reference standard. In addition, the use of the antibody panel in a sequential testing algorithm based on initial EBNA-1 IgG analysis was assessed for cost-effectiveness. Finally, we investigated the degree of cross-reactivity of the VCA IgM marker during other primary viral infections that may present with an EBV IM-like picture. High sensitivity (98.3% [95% confidence interval {CI}, 90.7 to 99.7%]) and specificity (94.2% [95% CI, 87.9 to 97.8%]) were found after testing 162 precharacterized archived serum samples. There was perfect agreement between the use of the antibody panel in sequential and parallel testing algorithms, but substantial cost savings (23%) were obtained with the sequential strategy. A high rate of reactive VCA IgM results was found in primary cytomegalovirus (CMV) infections (60.7%). In summary, the Architect EBV antibody panel performs satisfactorily in the investigation of EBV IM in immunocompetent adolescents and young adults, and the application of an EBNA-1 IgG-based sequential testing algorithm is cost-effective in this diagnostic setting. Concomitant testing for CMV is strongly recommended to aid in the interpretation of EBV serological patterns. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

A single day of 5-azacytidine exposure during development induces neurodegeneration in neonatal mice and neurobehavioral deficits in adult mice.

PubMed

Subbanna, Shivakumar; Nagre, Nagaraja N; Shivakumar, Madhu; Basavarajappa, Balapal S

2016-12-01

The present study was undertaken to evaluate the immediate and long-term effects of a single-day exposure to 5-Azacytidine (5-AzaC), a DNA methyltransferase inhibitor, on neurobehavioral abnormalities in mice. Our findings suggest that the 5-AzaC treatment significantly inhibited DNA methylation, impaired extracellular signal-regulated kinase (ERK1/2) activation and reduced expression of the activity-regulated cytoskeleton-associated protein (Arc). These events lead to the activation of caspase-3 (a marker for neurodegeneration) in several brain regions, including the hippocampus and cortex, two brain areas that are essential for memory formation and memory storage, respectively. 5-AzaC treatment of P7 mice induced significant deficits in spatial memory, social recognition, and object memory in adult mice and deficits in long-term potentiation (LTP) in adult hippocampal slices. Together, these data demonstrate that the inhibition of DNA methylation by 5-AzaC treatment in P7 mice causes neurodegeneration and impairs ERK1/2 activation and Arc protein expression in neonatal mice and induces behavioral abnormalities in adult mice. DNA methylation-mediated mechanisms appear to be necessary for the proper maturation of synaptic circuits during development, and disruption of this process by 5-AzaC could lead to abnormal cognitive function. Published by Elsevier Inc.

Tomographic findings of acute pulmonary toxoplasmosis in immunocompetent patients.

PubMed

de Souza Giassi, Karina; Costa, Andre Nathan; Apanavicius, Andre; Teixeira, Fernando Bin; Fernandes, Caio Julio Cesar; Helito, Alfredo Salim; Kairalla, Ronaldo Adib

2014-11-25

Toxoplasmosis is one of the most common human zoonosis, and is generally benign in most of the individuals. Pulmonary involvement is common in immunocompromised subjects, but very rare in immunocompetents and there are scarce reports of tomographic findings in the literature. The aim of the study is to describe three immunocompetent patients diagnosed with acute pulmonary toxoplasmosis and their respective thoracic tomographic findings. Acute toxoplasmosis was diagnosed according to the results of serological tests suggestive of recent primary infection and the absence of an alternative etiology. From 2009 to 2013, three patients were diagnosed with acute respiratory failure secondary to acute toxoplasmosis. The patients were two female and one male, and were 38, 56 and 36 years old. Similarly they presented a two-week febrile illness and progressive dyspnea before admission. Laboratory tests demonstrated lymphocytosis, slight changes in liver enzymes and high inflammatory markers. Tomographic findings were bilateral smooth septal and peribronchovascular thickening (100%), ground-glass opacities (100%), atelectasis (33%), random nodules (33%), lymph node enlargement (33%) and pleural effusion (66%). All the patients improved their symptoms after treatment, and complete resolution of tomographic findings were found in the followup. These cases provide a unique description of the presentation and evolution of pulmonary tomographic manifestations of toxoplasmosis in immunocompetent patients. Toxoplasma pneumonia manifests with fever, dyspnea and a non-productive cough that may result in respiratory failure. In animal models, changes were described as interstitial pneumonitis with focal infiltrates of neutrophils that can finally evolve into a pattern of diffuse alveolar damage with focal necrosis. The tomographic findings are characterized as ground glass opacities, smooth septal and marked peribronchovascular thickening; and may mimic pulmonary congestion

Efficacy of 23-valent pneumococcal polysaccharide vaccine in preventing community-acquired pneumonia among immunocompetent adults: A systematic review and meta-analysis of randomized trials.

PubMed

Diao, Wen-Qi; Shen, Ning; Yu, Pan-Xi; Liu, Bei-Bei; He, Bei

2016-03-18

Data on the efficacy of the 23-valent pneumococcal polysaccharide vaccine (PPV-23) in preventing adult community-acquired pneumonia (CAP) among the target population of individuals aged over 65 years and high-risk individuals aged 19-64 years are conflicting. As the Advisory Committee on Immunization Practices (ACIP) has recently demonstrated PPV-23 is likely beneficial to immunocompromised adults by the Grading, Assessment, Development, and Evaluation (GRADE) framework, we conducted meta-analysis to examine its efficacy in an immunocompetent population. We searched the PUBMED, EMBASE, and Cochrane Library databases for randomized trials. Overall relative risks (RRs) with 95% confidential intervals (CIs) were calculated, and the Cochrane Q test (p, I(2)) was performed. Outcomes were assessed by the GRADE framework. Seven randomized trials involving 156,010 participants were included in this meta-analysis. High-quality evidence revealed that PPV-23 was weakly associated with the prevention of all-cause pneumonia ([RR] 0.87, [95%CI] 0.76-0.98, p=0.11, I(2)=43%), especially among the target population ([RR] 0.72, [95%CI] 0.69-0.94, p=0.58 I(2)=0%), the elderly group aged over 40 years ([RR] 0.80, [95%CI] 0.69-0.94) and the Japanese population ([RR] 0.72, [95%CI] 0.59-0.88, p=0.24, I(2)=30%). The target population included adults aged over 65 years and patients at high risk of pneumonia due to chronic lung disease, chronic obstructive pulmonary disease or living in a nursing home. Protective trends of PPV-23 in the outcomes of pneumococcal pneumonia ([RR] 0.54, [95%CI] 0.18-1.65, p=0.01, I(2)=77%) and mortality due to pneumonia ([RR] 0.67, [95%CI] 0.43-1.04, p=0.67, I(2)=0%) were observed, although the results were statistically insignificant, possibly due to the small number of trials included. PPV-23 did not prevent all-cause mortality ([RR] 1.04, [95%CI] 0.87-1.24, p=0.95, I(2)=0%). PPV-23 provided weak protection against all-cause pneumonia in an immunocompetent

Helicobacter sp. MIT 01-6451 infection during fetal and neonatal life in laboratory mice.

PubMed

Yamanaka, Hitoki; Nakanishi, Tai; Takagi, Toshikazu; Ohsawa, Makiko; Kubo, Noriaki; Yamamoto, Naoto; Takemoto, Takahira; Ohsawa, Kazutaka

2015-01-01

Helicobacter sp. MIT 01-6451 has been detected in SPF mice kept in Japan. To characterize strain MIT 01-6451, its infection route during fetal and neonatal life and effects on pregnancy were investigated using immunocompetent and immunodeficient mouse strains (BALB/c, C57BL/6, and SCID). MIT 01-6451 was detected in the uterus, vagina, and mammary glands of 50% of infected SCID mice, whereas these tissues were all negative in immunocompetent mice. No fetal infections with MIT 01-6451 were detected at 16-18 days after pregnancy in any mouse strain. In newborn mice, MIT 01-6451 was detected in intestinal tissue of C57BL/6 and SCID mice at 9-11 days after birth, but not in BALB/c mice. The IgA and IgG titers to MIT 01-6451 in sera of C57BL/6 female mice were significantly lower than those of BALB/c mice. Although no significant differences in the number of newborns per litter were observed between MIT 01-6451-infected and MIT 01-6451-free dams, the birth rate was lower in infected SCID mice than in control SCID mice. The present results indicated that MIT 01-6451 infects newborn mice after birth rather than by vertical transmission to the fetus via the placenta and that MIT 01-6451 infection shows opportunistically negative effects on the birth rate. In addition, the maternal immune response may affect infection of newborn mice with MIT 01-6451 through breast milk.

Helicobacter sp. MIT 01-6451 infection during fetal and neonatal life in laboratory mice

PubMed Central

Yamanaka, Hitoki; Nakanishi, Tai; Takagi, Toshikazu; Ohsawa, Makiko; Kubo, Noriaki; Yamamoto, Naoto; Takemoto, Takahira; Ohsawa, Kazutaka

2015-01-01

Helicobacter sp. MIT 01-6451 has been detected in SPF mice kept in Japan. To characterize strain MIT 01-6451, its infection route during fetal and neonatal life and effects on pregnancy were investigated using immunocompetent and immunodeficient mouse strains (BALB/c, C57BL/6, and SCID). MIT 01-6451 was detected in the uterus, vagina, and mammary glands of 50% of infected SCID mice, whereas these tissues were all negative in immunocompetent mice. No fetal infections with MIT 01-6451 were detected at 16–18 days after pregnancy in any mouse strain. In newborn mice, MIT 01-6451 was detected in intestinal tissue of C57BL/6 and SCID mice at 9–11 days after birth, but not in BALB/c mice. The IgA and IgG titers to MIT 01-6451 in sera of C57BL/6 female mice were significantly lower than those of BALB/c mice. Although no significant differences in the number of newborns per litter were observed between MIT 01-6451-infected and MIT 01-6451-free dams, the birth rate was lower in infected SCID mice than in control SCID mice. The present results indicated that MIT 01-6451 infects newborn mice after birth rather than by vertical transmission to the fetus via the placenta and that MIT 01-6451 infection shows opportunistically negative effects on the birth rate. In addition, the maternal immune response may affect infection of newborn mice with MIT 01-6451 through breast milk. PMID:26134357

Cutaneous Cryptococcus laurentii infection in an immunocompetent child.

PubMed

Molina-Leyva, Alejandro; Ruiz-Carrascosa, Jose C; Leyva-Garcia, Ana; Husein-Elahmed, Husein

2013-12-01

Cryptococcus laurentii is an extremely rare human pathogen. We report a case of primary cutaneous cryptococcosis caused by Cryptococcus laurentii in an immunocompetent patient, an 8-year-old child with a solitary lesion on the forearm. It was impossible to determine the source of infection and no predisposing factors were found. Oral treatment with fluconazole was totally successful. A review of the literature showed only three cases of cutaneous infection by Cryptococcus laurentii. All of the cases occurred in immunocompromised patients. To the best of our knowledge, this is the first case of Cryptococcus laurentii in an immunocompetent host. Copyright © 2013 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Cerebellar cysticercosis caused by larval Taenia crassiceps tapeworm in immunocompetent woman, Germany.

PubMed

Ntoukas, Vasileios; Tappe, Dennis; Pfütze, Daniel; Simon, Michaela; Holzmann, Thomas

2013-12-01

Human cysticercosis caused by Taenia crassiceps tapeworm larvae involves the muscles and subcutis mostly in immunocompromised patients and the eye in immunocompetent persons. We report a successfully treated cerebellar infection in an immunocompetent woman. We developed serologic tests, and the parasite was identified by histologic examination and 12s rDNA PCR and sequencing.

Premature aging of the hippocampal neurogenic niche in adult Bmal1-deficient mice.

PubMed

Ali, Amira A H; Schwarz-Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktas, Orhan; von Gall, Charlotte

2015-06-01

Hippocampal neurogenesis undergoes dramatic age-related changes. Mice with targeted deletion of the clock geneBmal1 (Bmal1(-/-)) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1(-/-) mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1(-/-) mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70 kDa and expression of the cell cycle inhibitor p21(Waf1/CIP1) were increased in adult Bmal1(-/-) mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age-dependent decline in adult neurogenesis presumably as a consequence of oxidative stress.

A Rare Presentation of Cryptococcal Meningoencephalitis in an Immunocompetent Individual

PubMed Central

Malhotra, Ashwin; Rao, Qin; Kelly, Sean; Schwartz, Danielle; Chow, Robert

2017-01-01

Cryptococcal meningoencephalitis is a leading of morbidity and mortality in immunocompromised individuals worldwide. However, there are few documented cases in immunocompetent patients. We present a rare case of disseminated Cryptococcus with progression to meningoencephalitis in an immunocompetent patient, with a possible atypical presentation. Magnetic resonance imaging of the brain and electroencephalogram to rule out brain metastasis were negative. Lumbar puncture resulted positive for Cryptococcus neoformans antigen at titers of 1:2048 and a detailed history later revealed occupational exposure to bird dander by cleaning floors and cages. Diagnosis is challenging, with delays often resulting in increased morbidity and mortality. Cerebrospinal fluid and serum Cryptococcus antigen play a key role in both diagnosis and determining treatment efficacy. Furthermore, current treatment guidelines are used for immunocompromised individuals. Due to the significant side effects of these medications, further research is needed to determine the optimal treatment duration for immunocompetent patients to minimize the need for unnecessary therapy. PMID:28959388

Isolated laryngeal leishmaniasis in an immunocompetent patient: a case report.

PubMed

Bajraktari, A; Seccia, V; Casani, A P; Franceschini, S S

Isolated laryngeal leishmaniasis in an immunocompetent patient: a case report. Isolated laryngeal Leishmaniasis presents neither explicit laryngeal lesions nor specific symptoms. In fact, it may mimic many inflammatory and neoplastic diseases. Considering the low incidence of this atypical localization, laryngeal Leishmaniasis, is rarely contemplated by physicians in differential diagnoses of laryngeal tumour lesions. We present the case of a 62-year-old immunocompetent subject who developed a single Leishmania mucosal lesion on the left vocal cord, simulating a laryngeal cancer. A case report and discussion of the clinical case by referring to the literature. Specific therapy with miltefosine led to clinical and endoscopic improvement. We had no relapse after three years of follow-up. This clinical case highlights the need to consider isolated laryngeal Leishmaniasis in the differential diagnoses of laryngeal tumour lesions, even in immunocompetent subjects who live in endemic zones, in order to ensure an early and correct therapeutic approach.

Cerebellar Cysticercosis Caused by Larval Taenia crassiceps Tapeworm in Immunocompetent Woman, Germany

PubMed Central

Ntoukas, Vasileios; Tappe, Dennis; Pfütze, Daniel; Simon, Michaela

2013-01-01

Human cysticercosis caused by Taenia crassiceps tapeworm larvae involves the muscles and subcutis mostly in immunocompromised patients and the eye in immunocompetent persons. We report a successfully treated cerebellar infection in an immunocompetent woman. We developed serologic tests, and the parasite was identified by histologic examination and 12s rDNA PCR and sequencing. PMID:24274258

Clostridium subterminale septicemia in an immunocompetent patient.

PubMed

Daganou, Maria; Kyriakoudi, Ann; Moraitou, Helen; Pontikis, Konstantinos; Avgeropoulou, Stavrina; Tripolitsioti, Paraskevi; Koutsoukou, Antonia

2016-01-01

Clostridium subterminale is a Clostridium species that has been rarely isolated in the blood of immunocompromised patients. We report a case of C. subterminale septicemia in an immunocompetent patient who presented with acute mediastinitis following spontaneous esophageal rupture.

Metastasis Risk of Cutaneous Squamous Cell Carcinoma in Organ Transplant Recipients and Immunocompetent Patients.

PubMed

Genders, Roel E; Osinga, Joris A J; Tromp, Elise E; O'Rourke, Peter; Bouwes Bavinck, Jan N; Plasmeijer, Elsemieke I

2018-06-08

Organ transplant recipients (OTRs) have a high incidence of cutaneous squamous cell carcinoma (cSCC), and immunosuppression has been reported to be an important risk factor for metastasis. The aim of this study was to identify the metastasis risk over a 10-year period for 593 patients with cSCC, of whom 134 were OTR and 459 were immunocompetent. Metastasis incidence rate was 1,046 (95% confidence interval (95% CI) 524-2,096) per 100,000 person years in OTR and 656 (95% CI; 388-1,107) in immunocompetent patients, yielding an incidence rate ratio of 1.6 (95% CI 0.67-3.81). In OTRs head/neck location, older age at transplantation and older age at diagnosis of first cSCC were associated with metastatic risk, and 7 out of 8 metastasized tumours were smaller than 2 cm. In immunocompetent patients tumour size and tumour depth were associated with metastasis. In conclusion, we were not able to demonstrate an increased incidence rate of metastasis in OTRs compared with immunocompetent patients. However, OTRs and immunocompetent patients differed with regard to risk factors for metastasis.

Age-Dependent Ocular Dominance Plasticity in Adult Mice

PubMed Central

Lehmann, Konrad; Löwel, Siegrid

2008-01-01

Background Short monocular deprivation (4 days) induces a shift in the ocular dominance of binocular neurons in the juvenile mouse visual cortex but is ineffective in adults. Recently, it has been shown that an ocular dominance shift can still be elicited in young adults (around 90 days of age) by longer periods of deprivation (7 days). Whether the same is true also for fully mature animals is not yet known. Methodology/Principal Findings We therefore studied the effects of different periods of monocular deprivation (4, 7, 14 days) on ocular dominance in C57Bl/6 mice of different ages (25 days, 90–100 days, 109–158 days, 208–230 days) using optical imaging of intrinsic signals. In addition, we used a virtual optomotor system to monitor visual acuity of the open eye in the same animals during deprivation. We observed that ocular dominance plasticity after 7 days of monocular deprivation was pronounced in young adult mice (90–100 days) but significantly weaker already in the next age group (109–158 days). In animals older than 208 days, ocular dominance plasticity was absent even after 14 days of monocular deprivation. Visual acuity of the open eye increased in all age groups, but this interocular plasticity also declined with age, although to a much lesser degree than the optically detected ocular dominance shift. Conclusions/Significance These data indicate that there is an age-dependence of both ocular dominance plasticity and the enhancement of vision after monocular deprivation in mice: ocular dominance plasticity in binocular visual cortex is most pronounced in young animals, reduced but present in adolescence and absent in fully mature animals older than 110 days of age. Mice are thus not basically different in ocular dominance plasticity from cats and monkeys which is an absolutely essential prerequisite for their use as valid model systems of human visual disorders. PMID:18769674

Development of experimental tumors formed by mouse and human embryonic stem and teratocarcinoma cells after subcutaneous and intraperitoneal transplantations into immunodeficient and immunocompetent mice.

PubMed

Gordeeva, O F; Nikonova, T M

2013-01-01

Pluripotent stem cells represent an attractive cell source for regenerative medicine. However, the risk of teratoma formation after transplantation restricts their clinical application. Therefore, to adequately evaluate the potential risk of tumorigenicity after cell transplantation into human tissues, effective animal transplantation assays need to be developed. We performed a multiparameter (cell number, transplantation site, cell type, host) comparative analysis of the efficiency of tumor development after transplantation of mouse and human embryonic stem (ES) cells and their malignant counterparts, teratocarcinoma (EC) cells, into animal recipients and revealed several key correlations. We found that the efficiency of tumor growth was higher after intraperitoneal than after subcutaneous transplantations of all cell lines studied. The minimal cell numbers sufficient for tumor growth in immunodeficient nude mice were 100-fold lower for intraperitoneal than for subcutaneous transplantations of mouse and human ES cells (10(3) vs. 10(5) and 10(4) vs. 10(6), respectively). Moreover, mouse ES and EC cells formed tumors in immunodeficient and immunocompetent mice more effectively than human ES and EC cells. After intraperitoneal transplantation of 10(3), 10(4), and 10(5) mouse ES cells, teratomas developed in 83%, 100%, and 100% of nude mice, whereas after human ES cell transplantation, teratomas developed in 0%, 17%, and 60%, respectively. In addition, malignant mouse and human EC cells initiated tumor growth after intraperitoneal transplantation significantly faster and more effectively than ES cells. Mouse and human ES cells formed different types of teratomas containing derivatives of three germ layers but different numbers of undifferentiated cells. ES cell-like sublines with differentiation potential similar to the parental cell line were recloned only from mouse, but not from human, ES cell teratomas. These findings provide new information about the possibility

[Trochanteric bursitis due to tuberculosis in an immunocompetent young woman].

PubMed

Soro Marín, Sandra; Sánchez Trenado, María Asunción; Mínguez Sánchez, María Dolores; Paulino Huertas, Marcos; García Morales, Paula Virginia; Salas Manzanedo, Verónica

2012-01-01

Soft tissue infection due to Mycobacterium tuberculosis can affect muscle, tendons, fascia, bursa and synovial tissue. Tuberculous trochanteric bursitis is a rare entity that usually affects immunocompromised patients. Manifestations usually occur insidiously, which delays diagnosis and treatment. We present the case of an immunocompetent young woman who came to our department for chronic left hip pain. The study confirms the diagnosis of tuberculous trochanteric bursitis. This case demonstrates the importance of considering a possible infectious origin of bursitis in immunocompetent patients. Copyright © 2010 Elsevier España, S.L. All rights reserved.

Genetic, molecular and physiological basis of variation in Drosophila gut immunocompetence.

PubMed

Bou Sleiman, Maroun S; Osman, Dani; Massouras, Andreas; Hoffmann, Ary A; Lemaitre, Bruno; Deplancke, Bart

2015-07-27

Gut immunocompetence involves immune, stress and regenerative processes. To investigate the determinants underlying inter-individual variation in gut immunocompetence, we perform enteric infection of 140 Drosophila lines with the entomopathogenic bacterium Pseudomonas entomophila and observe extensive variation in survival. Using genome-wide association analysis, we identify several novel immune modulators. Transcriptional profiling further shows that the intestinal molecular state differs between resistant and susceptible lines, already before infection, with one transcriptional module involving genes linked to reactive oxygen species (ROS) metabolism contributing to this difference. This genetic and molecular variation is physiologically manifested in lower ROS activity, lower susceptibility to ROS-inducing agent, faster pathogen clearance and higher stem cell activity in resistant versus susceptible lines. This study provides novel insights into the determinants underlying population-level variability in gut immunocompetence, revealing how relatively minor, but systematic genetic and transcriptional variation can mediate overt physiological differences that determine enteric infection susceptibility.

Mice with ablated adult brain neurogenesis are not impaired in antidepressant response to chronic fluoxetine.

PubMed

Jedynak, Paulina; Kos, Tomasz; Sandi, Carmen; Kaczmarek, Leszek; Filipkowski, Robert K

2014-09-01

The neurogenesis hypothesis of major depression has two main facets. One states that the illness results from decreased neurogenesis while the other claims that the very functioning of antidepressants depends on increased neurogenesis. In order to verify the latter, we have used cyclin D2 knockout mice (cD2 KO mice), known to have virtually no adult brain neurogenesis, and we demonstrate that these mice successfully respond to chronic fluoxetine. After unpredictable chronic mild stress, mutant mice showed depression-like behavior in forced swim test, which was eliminated with chronic fluoxetine treatment, despite its lack of impact on adult hippocampal neurogenesis in cD2 KO mice. Our results suggest that new neurons are not indispensable for the action of antidepressants such as fluoxetine. Using forced swim test and tail suspension test, we also did not observe depression-like behavior in control cD2 KO mice, which argues against the link between decreased adult brain neurogenesis and major depression. Copyright © 2014 Elsevier Ltd. All rights reserved.

The PHA Test Reflects Acquired T-Cell Mediated Immunocompetence in Birds

PubMed Central

Tella, José L.; Lemus, Jesús A.; Carrete, Martina; Blanco, Guillermo

2008-01-01

Background cological immunology requires techniques to reliably measure immunocompetence in wild vertebrates. The PHA-skin test, involving subcutaneous injection of a mitogen (phytohemagglutinin, PHA) and measurement of subsequent swelling as a surrogate of T-cell mediated immunocompetence, has been the test of choice due to its practicality and ease of use in the field. However, mechanisms involved in local immunological and inflammatory processes provoked by PHA are poorly known, and its use and interpretation as an acquired immune response is currently debated. Methodology Here, we present experimental work using a variety of parrot species, to ascertain whether PHA exposure produces larger secondary than primary responses as expected if the test reflects acquired immunocompetence. Moreover, we simultaneously quantified T-lymphocyte subsets (CD4+, CD5+ and CD8+) and plasma proteins circulating in the bloodstream, potentially involved in the immunological and inflammatory processes, through flow cytometry and electrophoresis. Principal Findings Our results showed stronger responses after a second PHA injection, independent of species, time elapsed and changes in body mass of birds between first and second injections, thus supporting the adaptive nature of this immune response. Furthermore, the concomitant changes in the plasma concentrations of T-lymphocyte subsets and globulins indicate a causal link between the activation of the T-cell mediated immune system and local tissue swelling. Conclusions/Significance These findings justify the widespread use of the PHA-skin test as a reliable evaluator of acquired T-cell mediated immunocompetence in diverse biological disciplines. Further experimental research should be aimed at evaluating the relative role of innate immunocompetence in wild conditions, where the access to dietary proteins varies more than in captivity, and to ascertain how PHA responses relate to particular host-parasite interactions. PMID:18820730

Psychotropic effects of Lactobacillus plantarum PS128 in early life-stressed and naïve adult mice.

PubMed

Liu, Yen-Wenn; Liu, Wei-Hsien; Wu, Chien-Chen; Juan, Yi-Chen; Wu, Yu-Chen; Tsai, Huei-Ping; Wang, Sabrina; Tsai, Ying-Chieh

2016-01-15

Ingestion of specific probiotics, namely "psychobiotics", produces psychotropic effects on behavior and affects the hypothalamic-pituitary-adrenal axis and neurochemicals in the brain. We examined the psychotropic effects of a potential psychobiotic bacterium, Lactobacillus plantarum strain PS128 (PS128), on mice subjected to early life stress (ELS) and on naïve adult mice. Behavioral tests revealed that chronic ingestion of PS128 increased the locomotor activities in both ELS and naïve adult mice in the open field test. In the elevated plus maze, PS128 significantly reduced the anxiety-like behaviors in naïve adult mice but not in the ELS mice; whereas the depression-like behaviors were reduced in ELS mice but not in naïve mice in forced swimming test and sucrose preference test. PS128 administration also reduced ELS-induced elevation of serum corticosterone under both basal and stressed states but had no effect on naïve mice. In addition, PS128 reduced inflammatory cytokine levels and increased anti-inflammatory cytokine level in the serum of ELS mice. Furthermore, the dopamine level in the prefrontal cortex (PFC) was significantly increased in PS128 treated ELS and naïve adult mice whereas serotonin (5-HT) level was increased only in the naïve adult mice. These results suggest that chronic ingestion of PS128 could ameliorate anxiety- and depression-like behaviors and modulate neurochemicals related to affective disorders. Thus PS128 shows psychotropic properties and has great potential for improving stress-related symptoms. Copyright © 2015 The Authors. Published by Elsevier B.V. All rights reserved.

Herpes zoster caused by vaccine-strain varicella zoster virus in an immunocompetent recipient of zoster vaccine.

PubMed

Tseng, Hung Fu; Schmid, D Scott; Harpaz, Rafael; LaRussa, Philip; Jensen, Nancy J; Rivailler, Pierre; Radford, Kay; Folster, Jennifer; Jacobsen, Steven J

2014-04-01

We report the first laboratory-documented case of herpes zoster caused by the attenuated varicella zoster virus (VZV) contained in Zostavax in a 68-year-old immunocompetent adult with strong evidence of prior wild-type VZV infection. The complete genome sequence of the isolate revealed that the strain carried 15 of 42 (36%) recognized varicella vaccine-associated single-nucleotide polymorphisms, including all 5 of the fixed vaccine markers present in nearly all of the strains in the vaccine. The case of herpes zoster was relatively mild and resolved without complications.

Herpes Zoster Caused by Vaccine-Strain Varicella Zoster Virus in an Immunocompetent Recipient of Zoster Vaccine

PubMed Central

Tseng, Hung Fu; Schmid, D. Scott; Harpaz, Rafael; LaRussa, Philip; Jensen, Nancy J.; Rivailler, Pierre; Radford, Kay; Folster, Jennifer; Jacobsen, Steven J.

2014-01-01

We report the first laboratory-documented case of herpes zoster caused by the attenuated varicella zoster virus (VZV) contained in Zostavax in a 68-year-old immunocompetent adult with strong evidence of prior wild-type VZV infection. The complete genome sequence of the isolate revealed that the strain carried 15 of 42 (36%) recognized varicella vaccine–associated single-nucleotide polymorphisms, including all 5 of the fixed vaccine markers present in nearly all of the strains in the vaccine. The case of herpes zoster was relatively mild and resolved without complications. PMID:24470276

Chronic active toxoplasmosis in an immunocompetent patient.

PubMed

O'Connell, S; Guy, E C; Dawson, S J; Francis, J M; Joynson, D H

1993-11-01

We report the case of an apparently immunocompetent woman whose symptoms and signs have persisted for 8 years following a serologically and histologically confirmed diagnosis of toxoplasmosis. During this period she had two successful pregnancies despite persistently increased anti-toxoplasma IgM antibodies. Neither child is infected.

Fast neutron irradiation deteriorates hippocampus-related memory ability in adult mice.

PubMed

Yang, Miyoung; Kim, Hwanseong; Kim, Juhwan; Kim, Sung-Ho; Kim, Jong-Choon; Bae, Chun-Sik; Kim, Joong-Sun; Shin, Taekyun; Moon, Changjong

2012-03-01

Object recognition memory and contextual fear conditioning task performance in adult C57BL/6 mice exposed to cranial fast neutron irradiation (0.8 Gy) were examined to evaluate hippocampus-related behavioral dysfunction following acute exposure to relatively low doses of fast neutrons. In addition, hippocampal neurogenesis changes in adult murine brain after cranial irradiation were analyzed using the neurogenesis immunohistochemical markers Ki-67 and doublecortin (DCX). In the object recognition memory test and contextual fear conditioning, mice trained 1 and 7 days after irradiation displayed significant memory deficits compared to the sham-irradiated controls. The number of Ki-67- and DCX-positive cells decreased significantly 24 h post-irradiation. These results indicate that acute exposure of the adult mouse brain to a relatively low dose of fast neutrons interrupts hippocampal functions, including learning and memory, possibly by inhibiting neurogenesis.

Candida esophagitis in an immunocompetent pregnant woman.

PubMed

Greenspoon, J S; Kivnick, S

1993-01-01

Nausea and vomiting are common during the first half of pregnancy and usually require only supportive measures. When symptoms are progressive and weight loss occurs, treatable causes should be sought by means of upper gastrointestinal endoscopy. We report a case of an immunocompetent gravida with invasive Candida albicans esophagitis. The immunocompetent primigravida developed progressive nausea, vomiting, epigastric pain, and a 4.1 kg weight loss during the second trimester of pregnancy. Treatment with metoclopramide and cimetidine for presumed gastroesophageal reflux was not effective. The patient had normal T-cell CD4 and CD8 subsets and was human immunodeficiency virus (HIV) antibody negative. Upper gastrointestinal endoscopy revealed C. albicans esophagitis which was treated with oral nystatin. The esophagitis had resolved completely when reassessed postpartum. The use of histamine(2) blockers is associated with an increased risk for fungal esophagitis and may have been a contributing cause in this case. Pregnant patients with persistent nausea, vomiting, and weight loss should be evaluated by endoscopy for fungal esophagitis.

Synapsin I and Synapsin II regulate neurogenesis in the dentate gyrus of adult mice

PubMed Central

Barbieri, Raffaella; Contestabile, Andrea; Ciardo, Maria Grazia; Forte, Nicola; Marte, Antonella; Baldelli, Pietro; Benfenati, Fabio; Onofri, Franco

2018-01-01

Adult neurogenesis is emerging as an important player in brain functions and homeostasis, while impaired or altered adult neurogenesis has been associated with a number of neuropsychiatric diseases, such as depression and epilepsy. Here we investigated the possibility that synapsins (Syns) I and II, beyond their known functions in developing and mature neurons, also play a role in adult neurogenesis. We performed a systematic evaluation of the distinct stages of neurogenesis in the hippocampal dentate gyrus of Syn I and Syn II knockout (KO) mice, before (2-months-old) and after (6-months-old) the appearance of the epileptic phenotype. We found that Syns I and II play an important role in the regulation of adult neurogenesis. In juvenile mice, Syn II deletion was associated with a specific decrease in the proliferation of neuronal progenitors, whereas Syn I deletion impaired the survival of newborn neurons. These defects were reverted after the appearance of the epileptic phenotype, with Syn I KO and Syn II KO mice exhibiting significant increases in survival and proliferation, respectively. Interestingly, long-term potentiation dependent on newborn neurons was present in both juvenile Syn mutants while, at later ages, it was only preserved in Syn II KO mice that also displayed an increased expression of brain-derived neurotrophic factor. This study suggests that Syns I and II play a role in adult neurogenesis and the defects in neurogenesis associated with Syn deletion may contribute to the alterations of cognitive functions observed in Syn-deficient mice. PMID:29721159

Synapsin I and Synapsin II regulate neurogenesis in the dentate gyrus of adult mice.

PubMed

Barbieri, Raffaella; Contestabile, Andrea; Ciardo, Maria Grazia; Forte, Nicola; Marte, Antonella; Baldelli, Pietro; Benfenati, Fabio; Onofri, Franco

2018-04-10

Adult neurogenesis is emerging as an important player in brain functions and homeostasis, while impaired or altered adult neurogenesis has been associated with a number of neuropsychiatric diseases, such as depression and epilepsy. Here we investigated the possibility that synapsins (Syns) I and II, beyond their known functions in developing and mature neurons, also play a role in adult neurogenesis. We performed a systematic evaluation of the distinct stages of neurogenesis in the hippocampal dentate gyrus of Syn I and Syn II knockout (KO) mice, before (2-months-old) and after (6-months-old) the appearance of the epileptic phenotype. We found that Syns I and II play an important role in the regulation of adult neurogenesis. In juvenile mice, Syn II deletion was associated with a specific decrease in the proliferation of neuronal progenitors, whereas Syn I deletion impaired the survival of newborn neurons. These defects were reverted after the appearance of the epileptic phenotype, with Syn I KO and Syn II KO mice exhibiting significant increases in survival and proliferation, respectively. Interestingly, long-term potentiation dependent on newborn neurons was present in both juvenile Syn mutants while, at later ages, it was only preserved in Syn II KO mice that also displayed an increased expression of brain-derived neurotrophic factor. This study suggests that Syns I and II play a role in adult neurogenesis and the defects in neurogenesis associated with Syn deletion may contribute to the alterations of cognitive functions observed in Syn-deficient mice.

Spermatogenesis arrest caused by conditional deletion of Hsp90α in adult mice

PubMed Central

Kajiwara, Chiaki; Kondo, Shiho; Uda, Shizuha; Dai, Lei; Ichiyanagi, Tomoko; Chiba, Tomoki; Ishido, Satoshi; Koji, Takehiko; Udono, Heiichiro

2012-01-01

Summary It is controversial whether a functional androgen receptor (AR) on germ cells, including spermatogonia, is essential for their development into sperm and, thus, initiation and maintenance of spermatogenesis. It was recently shown that many spermatocytes underwent apoptosis in the testes of Hsp90α KO mice. We had generated Hsp90α KO mice independently and confirmed this phenotype. However, the important question of whether Hsp90α is required to maintain spermatogenesis in adult mice in which testicular maturation is already completed could not be addressed using these conventional KO mice. To answer this question, we generated a tamoxifen-inducible deletion mutant of Hsp90α and found that conditional deletion of Hsp90α in adult mice caused even more severe apoptosis in germ cells beyond the pachytene stage, leading to complete arrest of spermatogenesis and testicular atrophy. Importantly, immunohistochemical analysis revealed that AR expression in WT testis was more evident in spermatogonia than in spermatocytes, whereas its expression was aberrant and ectopic in Hsp90α KO testis, raising the possibility that an AR abnormality in primordial germ cells is involved in spermatogenesis arrest in the Hsp90α KO mice. Our results suggest that the AR, specifically chaperoned by Hsp90α in spermatogonia, is critical for maintenance of established spermatogenesis and for survival of spermatocytes in adult testis, in addition to setting the first wave of spermatogenesis before puberty. PMID:23213375

Prefrontal cortical-specific differences in behavior and synaptic plasticity between adolescent and adult mice.

PubMed

Konstantoudaki, Xanthippi; Chalkiadaki, Kleanthi; Vasileiou, Elisabeth; Kalemaki, Katerina; Karagogeos, Domna; Sidiropoulou, Kyriaki

2018-03-01

Adolescence is a highly vulnerable period for the emergence of major neuropsychological disorders and is characterized by decreased cognitive control and increased risk-taking behavior and novelty-seeking. The prefrontal cortex (PFC) is involved in the cognitive control of impulsive and risky behavior. Although the PFC is known to reach maturation later than other cortical areas, little information is available regarding the functional changes from adolescence to adulthood in PFC, particularly compared with other primary cortical areas. This study aims to understand the development of PFC-mediated, compared with non-PFC-mediated, cognitive functions. Toward this aim, we performed cognitive behavioral tasks in adolescent and adult mice and subsequently investigated synaptic plasticity in two different cortical areas. Our results showed that adolescent mice exhibit impaired performance in PFC-dependent cognitive tasks compared with adult mice, whereas their performance in non-PFC-dependent tasks is similar to that of adults. Furthermore, adolescent mice exhibited decreased long-term potentiation (LTP) within upper-layer synapses of the PFC but not the barrel cortex. Blocking GABA A receptor function significantly augments LTP in both the adolescent and adult PFC. No change in intrinsic excitability of PFC pyramidal neurons was observed between adolescent and adult mice. Finally, increased expression of the NR2A subunit of the N-methyl-d-aspartate receptors is found only in the adult PFC, a change that could underlie the emergence of LTP. In conclusion, our results demonstrate physiological and behavioral changes during adolescence that are specific to the PFC and could underlie the reduced cognitive control in adolescents. NEW & NOTEWORTHY This study reports that adolescent mice exhibit impaired performance in cognitive functions dependent on the prefrontal cortex but not in cognitive functions dependent on other cortical regions. The current results propose reduced

Gab3-deficient mice exhibit normal development and hematopoiesis and are immunocompetent.

PubMed

Seiffert, Martina; Custodio, Joseph M; Wolf, Ingrid; Harkey, Michael; Liu, Yan; Blattman, Joseph N; Greenberg, Philip D; Rohrschneider, Larry R

2003-04-01

Gab proteins are intracellular scaffolding and docking molecules involved in signaling pathways mediated by various growth factor, cytokine, or antigen receptors. Gab3 has been shown to act downstream of the macrophage colony-stimulating factor receptor, c-Fms, and to be important for macrophage differentiation. To analyze the physiological role of Gab3, we used homologous recombination to generate mice deficient in Gab3. Gab3(-/-) mice develop normally, are visually indistinguishable from their wild-type littermates, and are healthy and fertile. To obtain a detailed expression pattern of Gab3, we generated Gab3-specific monoclonal antibodies. Immunoblotting revealed a predominant expression of Gab3 in lymphocytes and bone marrow-derived macrophages. However, detailed analysis demonstrated that hematopoiesis in mice lacking Gab3 is not impaired and that macrophages develop in normal numbers and exhibit normal function. The lack of Gab3 expression during macrophage differentiation is not compensated for by increased levels of Gab1 or Gab2 mRNA. Furthermore, Gab3-deficient mice have no major immune deficiency in T- and B-lymphocyte responses to protein antigens or during viral infection. In addition, allergic responses in Gab3-deficient mice appeared to be normal. Together, these data demonstrate that loss of Gab3 does not result in detectable defects in normal mouse development, hematopoiesis, or immune system function.

Histological evaluation of intratumoral myxoma virus treatment in an immunocompetent mouse model of melanoma

PubMed Central

Doty, Rosalinda A; Liu, Jia; McFadden, Grant; Roy, Edward J; MacNeill, Amy L

2013-01-01

Two recombinant myxoma viruses (MYXV expressing a fluorescent protein [MYXV-Tred] and MYXV-Tred encoding murine interleukin-15 [MYXV-IL15]) were evaluated for therapeutic effects in an aggressive B16F10 melanoma model in immunocompetent mice. It was hypothesized that continuous expression of IL-15 within a tumor would recruit cytotoxic effector cells to induce an antitumor immune response and improve treatment efficacy. Weekly intratumoral injections were given to evaluate the effect of treatment on the median survival time of C57BL/6 mice bearing established B16F10 melanomas. Mice that received MYXV-Tred or MYXV-IL15 lived significantly longer than mice given treatment controls. Unexpectedly, the median survival time of MYXV-IL15-treated mice was similar to that of MYXV-treated mice. At 1, 2, and 4 days postinoculation, viral plaque assays detected replicating MYXV-Tred and MYXV-IL15 within treated tumors. At these time points in MYXV-IL15-treated tumors, IL-15 concentration, lymphocyte grades, and cluster of differentiation-3+ cell counts were significantly increased when compared to other treatment groups. However, viral titers, recombinant protein expression, and lymphocyte numbers within the tumors diminished rapidly at 7 days postinoculation. These data indicate that treatment with recombinant MYXV should be repeated at least every 4 days to maintain recombinant protein expression within a murine tumor. Additionally, neutrophilic inflammation was significantly increased in MYXV-Tred- and MYXV-IL15-treated tumors at early time points. It is speculated that neutrophilic inflammation induced by intratumoral replication of recombinant MXYV contributes to the antitumoral effect of MYXV treatment in this melanoma model. These findings support the inclusion of neutrophil chemotaxins in recombinant poxvirus oncolytic virotherapy. PMID:25866742

[Disseminated cryptococcosis in an immunocompetent patient].

PubMed

Elkhihal, B; Hasnaoui, A; Ghfir, I; Moustachi, A; Aoufi, S; Lyagoubi, M

2015-09-01

Disseminated cryptococcosis is a serious opportunistic fungal infection caused by a yeast-encapsulated fungus of the genus Cryptococcus neoformans. It occurs most often in patients with a significant deficit of cellular immunity and preferentially affects the central nervous system. The skin and the lungs are the most commonly affected sites outside the neuro-subarachnoid location. We report the case of a patient apparently immunocompetent who had a disseminated cryptococcosis. The disease started with the multiple purplish skin lesions, large umbilicated on the face, groin, forearm and leg with progressively increasing volume. This symptomatology had evolved in the context of weight loss and poor general condition. The diagnosis was established by the presence of cryptococcal at the skin biopsy and cerebrospinal fluid. Research of immunosuppression common pathologies were negative. Treatment was initiated based on amphotericin B for 40 days. The patient's condition deteriorates onset of paraplegia and swallowing disorders causing death in an array of cachexia. This observation points out that disseminated cryptococcosis can occur in an immunocompetent patient. The skin lesions may be the first sign of the disease. Copyright © 2015. Published by Elsevier Masson SAS.

Rhizopus-associated soft tissue infection in an immunocompetent air-conditioning technician after a road traffic accident: a case report and review of the literature.

PubMed

Rabie, Nada B; Althaqafi, Abdulhakeem O

2012-03-01

Rhinocerebral or sinopulmonary mucromycosis is a well-recognized human fungal infection found among immunocompromised and diabetic patients. However, the infection is rare among immunocompetent hosts. We are reporting the case of an adult immunocompetent male patient working as an air-conditioning technician. The patient was a victim of a road traffic accident (RTA) and sustained multiple fractures in the proximal part of the left tibia, distal femur, and scapula. Two weeks postoperatively, Rhizopus microspores were isolated from an infected traumatic wound over the distal femur. Surgical debridement was performed, and the patient was started on amphotericin B. Occupational exposure history and workplace environmental sanitation are crucial for the prevention of this potentially fatal yet preventable infection. Copyright © 2011 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.

Vaccine-associated measles in an immunocompetent child.

PubMed

Sood, Shawn B; Suthar, Krishna; Martin, Kimberly; Mather, Keith

2017-11-01

We present a rare case of vaccine-associated measles infection in an immunocompetent, HIV-negative patient in the United States. This case depicts the impressive rash our patient manifested and highlights the importance of reviewing public health interventions to determine epidemiological links in geographical areas with low incidence of measles.

[Fever and lymphadenopathy: acute toxoplasmosis in an immunocompetent patient].

PubMed

Kaparos, Nikolaos; Favrat, Bernard; D'Acremont, Valérie

2014-11-26

Toxoplasmosis is an infectious disease caused by the intracellular parasite Toxoplasma gondii. In Switzerland about a third of the population has antibodies against this pathogen and has thus already been in contact with the parasite or has contracted the disease. Immunocompetent patients are usually asymptomatic (80-90%) during primary infection. The most common symptom is neck or occipital lymphadenopathy. Serology is the diagnostic gold standard in immunocompetent individuals. The presence of IgM antibodies is however not sufficient to make a definite diagnosis of acute toxoplasmosis. Distinction between acute and chronic toxoplasmosis requires additional serological tests (IgG avidity test). If required, the most used and probably most effective treatment is the combination of pyrimethamine and sulfadiazine, with folinic acid.

Necrotising otitis externa in the immunocompetent patient: case series.

PubMed

Unadkat, S; Kanzara, T; Watters, G

2018-01-01

Necrotising otitis externa can be a devastating form of otitis externa. It typically tends to affect patients who are immunocompromised or diabetic. To date, there is very little in the literature about necrotising otitis externa in the immunocompetent patient population. The present paper discusses both the clinical and radiological findings in three cases of necrotising otitis externa in an immunocompetent patient cohort. The common factor among all three patients was their advanced age. Diagnosing necrotising otitis externa can be challenging because of the potentially non-specific symptoms and the absence of early radiological signs, particularly if patients are neither immunocompromised nor diabetic. Elderly patients should be considered in the same light as immunocompromised and diabetic patients in the context of necrotising otitis externa.

Characterisation of the Xenogeneic Immune Response to Microencapsulated Fetal Pig Islet-Like Cell Clusters Transplanted into Immunocompetent C57BL/6 Mice

PubMed Central

Ratnapala, Sabina; Foster, Jayne; Vaghjiani, Vijesh; Manuelpillai, Ursula; Tuch, Bernard E.

2013-01-01

Xenotransplantation of microencapsulated fetal pig islet-like cell clusters (FP ICCs) offers a potential cellular therapy for type 1 diabetes. Although microcapsules prevent direct contact of the host immune system with the xenografted tissue, poor graft survival is still an issue. This study aimed to characterise the nature of the host immune cells present on the engrafted microcapsules and effects on encapsulated FP ICCs that were transplanted into immunocompetent mice. Encapsulated FP ICCs were transplanted into the peritoneal cavity of C57BL/6 mice. Grafts retrieved at days 1, 3, 7, 14 and 21 post-transplantation were analysed for pericapsular fibrotic overgrowth (PFO), cell viability, intragraft porcine gene expression, macrophages, myofibroblasts and intraperitoneal murine cytokines. Graft function was assessed ex vivo by insulin secretion studies. Xenogeneic immune response to encapsulated FP ICCs was associated with enhanced intragraft mRNA expression of porcine antigens MIP-1α, IL-8, HMGB1 and HSP90 seen within the first two weeks post-transplantation. This was associated with the recruitment of host macrophages, infiltration of myofibroblasts and collagen deposition leading to PFO which was evident from day 7 post-transplantation. This was accompanied by a decrease in cell viability and loss of FP ICC architecture. The only pro-inflammatory cytokine detected in the murine peritoneal flushing was TNF-α with levels peaking at day 7 post transplantation. This correlated with the onset of PFO at day 7 implying activated macrophages as its source. The anti-inflammatory cytokines detected were IL-5 and IL-4 with levels peaking at days 1 and 7, respectively. Porcine C-peptide was undetectable at all time points post-transplantation. PFO was absent and murine intraperitoneal cytokines were undetectable when empty microcapsules were transplanted. In conclusion, this study demonstrated that the macrophages are direct effectors of the xenogeneic immune response to

Establishment of a tamoxifen-inducible Cre-driver mouse strain for widespread and temporal genetic modification in adult mice.

PubMed

Ichise, Hirotake; Hori, Akiko; Shiozawa, Seiji; Kondo, Saki; Kanegae, Yumi; Saito, Izumu; Ichise, Taeko; Yoshida, Nobuaki

2016-07-29

Temporal genetic modification of mice using the ligand-inducible Cre/loxP system is an important technique that allows the bypass of embryonic lethal phenotypes and access to adult phenotypes. In this study, we generated a tamoxifen-inducible Cre-driver mouse strain for the purpose of widespread and temporal Cre recombination. The new line, named CM32, expresses the GFPneo-fusion gene in a wide variety of tissues before FLP recombination and tamoxifen-inducible Cre after FLP recombination. Using FLP-recombined CM32 mice (CM32Δ mice) and Cre reporter mouse lines, we evaluated the efficiency of Cre recombination with and without tamoxifen administration to adult mice, and found tamoxifen-dependent induction of Cre recombination in a variety of adult tissues. In addition, we demonstrated that conditional activation of an oncogene could be achieved in adults using CM32Δ mice. CM32Δ;T26 mice, which harbored a Cre recombination-driven, SV40 large T antigen-expressing transgene, were viable and fertile. No overt phenotype was found in the mice up to 3 months after birth. Although they displayed pineoblastomas (pinealoblastomas) and/or thymic enlargement due to background Cre recombination by 6 months after birth, they developed epidermal hyperplasia when administered tamoxifen. Collectively, our results suggest that the CM32Δ transgenic mouse line can be applied to the assessment of adult phenotypes in mice with loxP-flanked transgenes.

Postnatal colonization with human "infant-type" Bifidobacterium species alters behavior of adult gnotobiotic mice.

PubMed

Luk, Berkley; Veeraragavan, Surabi; Engevik, Melinda; Balderas, Miriam; Major, Angela; Runge, Jessica; Luna, Ruth Ann; Versalovic, James

2018-01-01

Accumulating studies have defined a role for the intestinal microbiota in modulation of host behavior. Research using gnotobiotic mice emphasizes that early microbial colonization with a complex microbiota (conventionalization) can rescue some of the behavioral abnormalities observed in mice that grow to adulthood completely devoid of bacteria (germ-free mice). However, the human infant and adult microbiomes vary greatly, and effects of the neonatal microbiome on neurodevelopment are currently not well understood. Microbe-mediated modulation of neural circuit patterning in the brain during neurodevelopment may have significant long-term implications that we are only beginning to appreciate. Modulation of the host central nervous system by the early-life microbiota is predicted to have pervasive and lasting effects on brain function and behavior. We sought to replicate this early microbe-host interaction by colonizing gnotobiotic mice at the neonatal stage with a simplified model of the human infant gut microbiota. This model consortium consisted of four "infant-type" Bifidobacterium species known to be commensal members of the human infant microbiota present in high abundance during postnatal development. Germ-free mice and mice neonatally-colonized with a complex, conventional murine microbiota were used for comparison. Motor and non-motor behaviors of the mice were tested at 6-7 weeks of age, and colonization patterns were characterized by 16S ribosomal RNA gene sequencing. Adult germ-free mice were observed to have abnormal memory, sociability, anxiety-like behaviors, and motor performance. Conventionalization at the neonatal stage rescued these behavioral abnormalities, and mice colonized with Bifidobacterium spp. also exhibited important behavioral differences relative to the germ-free controls. The ability of Bifidobacterium spp. to improve the recognition memory of both male and female germ-free mice was a prominent finding. Together, these data demonstrate

Acute Multiple Organ Failure in Adult Mice Deleted for the Developmental Regulator Wt1

PubMed Central

Chau, You-Ying; Brownstein, David; Mjoseng, Heidi; Lee, Wen-Chin; Buza-Vidas, Natalija; Nerlov, Claus; Jacobsen, Sten Eirik; Perry, Paul; Berry, Rachel; Thornburn, Anna; Sexton, David; Morton, Nik; Hohenstein, Peter; Freyer, Elisabeth; Samuel, Kay; van't Hof, Rob; Hastie, Nicholas

2011-01-01

There is much interest in the mechanisms that regulate adult tissue homeostasis and their relationship to processes governing foetal development. Mice deleted for the Wilms' tumour gene, Wt1, lack kidneys, gonads, and spleen and die at mid-gestation due to defective coronary vasculature. Wt1 is vital for maintaining the mesenchymal–epithelial balance in these tissues and is required for the epithelial-to-mesenchyme transition (EMT) that generates coronary vascular progenitors. Although Wt1 is only expressed in rare cell populations in adults including glomerular podocytes, 1% of bone marrow cells, and mesothelium, we hypothesised that this might be important for homeostasis of adult tissues; hence, we deleted the gene ubiquitously in young and adult mice. Within just a few days, the mice suffered glomerulosclerosis, atrophy of the exocrine pancreas and spleen, severe reduction in bone and fat, and failure of erythropoiesis. FACS and culture experiments showed that Wt1 has an intrinsic role in both haematopoietic and mesenchymal stem cell lineages and suggest that defects within these contribute to the phenotypes we observe. We propose that glomerulosclerosis arises in part through down regulation of nephrin, a known Wt1 target gene. Protein profiling in mutant serum showed that there was no systemic inflammatory or nutritional response in the mutant mice. However, there was a dramatic reduction in circulating IGF-1 levels, which is likely to contribute to the bone and fat phenotypes. The reduction of IGF-1 did not result from a decrease in circulating GH, and there is no apparent pathology of the pituitary and adrenal glands. These findings 1) suggest that Wt1 is a major regulator of the homeostasis of some adult tissues, through both local and systemic actions; 2) highlight the differences between foetal and adult tissue regulation; 3) point to the importance of adult mesenchyme in tissue turnover. PMID:22216009

Disseminated cutaneous sporotrichosis in an immunocompetent individual.

PubMed

Yap, Felix Boon-Bin

2011-10-01

Sporotrichosis is a subacute or chronic fungal infection caused by the ubiquitous fungus Sporothrix schenckii. Disseminated cutaneous sporotrichosis is an uncommon entity and is usually present in the immunosuppressed. Here, a case of disseminated cutaneous sporotrichosis in an immunocompetent patient is reported. This 70-year-old healthy woman presented with multiple painful ulcerated nodules on her face and upper and lower extremities of 6-month duration, associated with low-grade fever, night sweats, loss of appetite, and loss of weight. Histopathological examination of the skin biopsy revealed epidermal hyperplasia and granulomatous inflammation in the dermis, with budding yeast. Fungal culture identified S. schenckii. She had total resolution of the lesions after 2 weeks of intravenous amphotericin B and 8 months of oral itraconazole. All investigations for underlying immunosuppression and internal organ involvement were negative. This case reiterates that disseminated cutaneous sporotrichosis, although common in the immunosuppressed, can also be seen in immunocompetent patients. Copyright © 2011 International Society for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Detection of antibody to Purpureocillium lilacinum by immunofluorescent assay and flow cytometry in serum of infected C57BL/6 mice.

PubMed

de Sequeira, Danielly C M; Peixoto, Mariana L P; De Luca, Paula M; Oliveira-Ferreira, Joseli; Antas, Paulo R Z; Borba, Cintia M

2013-10-31

Purpureocillium lilacinum is an emerging pathogenic fungus that can cause different clinical manifestations ranging from cutaneous and sub-cutaneous infections to severe oculomycosis. In this study, using both conventional indirect immunofluorescence and non-conventional flow cytometry approaches, IgG antibodies were readily detected in both C57BL/6 immunocompetent and immunosuppressed mice after i.v. infection with P. lilacinum. The humoral immune response was specific, since virtually no antibodies were detected in the serum of control mice. Flow cytometry assays also showed both quantitative and qualitative differences in total IgG and its isotypes in sera of immunocompetent and immunosupressed infected mice. Although a good starting point, it is clear that the effectiveness of serological assays for P. lilacinum hyalohyphomycosis identification in clinical studies still requires further standardization. Upon further validation in humans, these techniques have the potential to be suitable to detect P. lilacinum infection in patients, thereby avoiding current laborious and time-consuming culture techniques. © 2013.

Progressive outer retinal necrosis-like retinitis in immunocompetent hosts.

PubMed

Chawla, Rohan; Tripathy, Koushik; Gogia, Varun; Venkatesh, Pradeep

2016-08-10

We describe two young immunocompetent women presenting with bilateral retinitis with outer retinal necrosis involving posterior pole with centrifugal spread and multifocal lesions simulating progressive outer retinal necrosis (PORN) like retinitis. Serology was negative for HIV and CD4 counts were normal; however, both women were on oral steroids at presentation for suspected autoimmune chorioretinitis. The retinitis in both eyes responded well to oral valaciclovir therapy. However, the eye with the more fulminant involvement developed retinal detachment with a loss of vision. Retinal atrophy was seen in the less involved eye with preservation of vision. Through these cases, we aim to describe a unique evolution of PORN-like retinitis in immunocompetent women, which was probably aggravated by a short-term immunosuppression secondary to oral steroids. 2016 BMJ Publishing Group Ltd.

Restoring auditory cortex plasticity in adult mice by restricting thalamic adenosine signaling

DOE PAGES

Blundon, Jay A.; Roy, Noah C.; Teubner, Brett J. W.; ...

2017-06-30

Circuits in the auditory cortex are highly susceptible to acoustic influences during an early postnatal critical period. The auditory cortex selectively expands neural representations of enriched acoustic stimuli, a process important for human language acquisition. Adults lack this plasticity. We show in the murine auditory cortex that juvenile plasticity can be reestablished in adulthood if acoustic stimuli are paired with disruption of ecto-5'-nucleotidase–dependent adenosine production or A1–adenosine receptor signaling in the auditory thalamus. This plasticity occurs at the level of cortical maps and individual neurons in the auditory cortex of awake adult mice and is associated with long-term improvement ofmore » tone-discrimination abilities. We determined that, in adult mice, disrupting adenosine signaling in the thalamus rejuvenates plasticity in the auditory cortex and improves auditory perception.« less

Restoring auditory cortex plasticity in adult mice by restricting thalamic adenosine signaling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blundon, Jay A.; Roy, Noah C.; Teubner, Brett J. W.

Circuits in the auditory cortex are highly susceptible to acoustic influences during an early postnatal critical period. The auditory cortex selectively expands neural representations of enriched acoustic stimuli, a process important for human language acquisition. Adults lack this plasticity. We show in the murine auditory cortex that juvenile plasticity can be reestablished in adulthood if acoustic stimuli are paired with disruption of ecto-5'-nucleotidase–dependent adenosine production or A1–adenosine receptor signaling in the auditory thalamus. This plasticity occurs at the level of cortical maps and individual neurons in the auditory cortex of awake adult mice and is associated with long-term improvement ofmore » tone-discrimination abilities. We determined that, in adult mice, disrupting adenosine signaling in the thalamus rejuvenates plasticity in the auditory cortex and improves auditory perception.« less

Nodular tertiary syphilis in an immunocompetent patient*

PubMed Central

Bittencourt, Maraya de Jesus Semblano; de Brito, Arival Cardoso; Nascimento, Bianca Angelina Macêdodo; Carvalho, Alessandra Haber; Drago, Marion Guimarães

2016-01-01

Acquired syphilis can be divided into primary, secondary, latent, and tertiary stages. About 25% of patients with untreated primary syphilis will develop late signs that generally occur after three to five years, with involvement of several organs. The authors present an immunocompetent female who developed a tertiary stage syphilis presenting with long-standing nodular plaques. PMID:27579755

Differential Sensitivity to Ethanol-Induced Circadian Rhythm Disruption in Adolescent and Adult Mice

PubMed Central

Ruby, Christina L.; Palmer, Kaitlyn N.; Zhang, Jiawen; Risinger, Megan O.; Butkowski, Melissa A.; Swartzwelder, H. Scott

2016-01-01

Background Growing evidence supports a central role for the circadian system in alcohol use disorders, but few studies have examined this relationship during adolescence. In mammals, circadian rhythms are regulated by the suprachiasmatic nucleus (SCN), a biological clock whose timing is synchronized (reset) to the environment primarily by light (photic) input. Alcohol (ethanol) disrupts circadian timing in part by attenuating photic phase-resetting responses in adult rodents. However, circadian rhythms change throughout life and it is not yet known whether ethanol has similar effects on circadian regulation during adolescence. Methods General circadian locomotor activity was monitored in male C57BL6/J mice beginning in adolescence (P27) or adulthood (P61) in a 12 h light, 12 h dark photocycle for ~2 weeks to establish baseline circadian activity measures. On the day of the experiment, mice received an acute injection of ethanol (1.5 g/kg, i.p.) or equal volume saline 15 min prior to a 30-min light pulse at Zeitgeber Time 14 (2 h into the dark phase), then were released into constant darkness (DD) for ~2 weeks to assess phase-resetting responses. Control mice of each age group received injections but no light pulse prior to DD. Results While adults showed the expected decrease in photic phase-delays induced by acute ethanol, this effect was absent in adolescent mice. Adolescents also showed baseline differences in circadian rhythmicity compared to adults, including advanced photocycle entrainment, larger photic phase-delays, a shorter free-running (endogenous) circadian period, and greater circadian rhythm amplitude. Conclusions Collectively, our results indicate that adolescent mice are less sensitive to the effect of ethanol on circadian photic phase-resetting and that their daily activity rhythms are markedly different than those of adults. PMID:27997028

Lepidium meyenii (Maca) increases litter size in normal adult female mice

PubMed Central

Ruiz-Luna, Ana C; Salazar, Stephanie; Aspajo, Norma J; Rubio, Julio; Gasco, Manuel; Gonzales, Gustavo F

2005-01-01

Background Lepidium meyenii, known as Maca, grows exclusively in the Peruvian Andes over 4000 m altitude. It has been used traditionally to increase fertility. Previous scientific studies have demonstrated that Maca increases spermatogenesis and epididymal sperm count. The present study was aimed to investigate the effects of Maca on several fertility parameters of female mice at reproductive age. Methods Adult female Balb/C mice were divided at random into three main groups: i) Reproductive indexes group, ii) Implantation sites group and iii) Assessment of uterine weight in ovariectomized mice. Animals received an aqueous extract of lyophilized Yellow Maca (1 g/Kg BW) or vehicle orally as treatment. In the fertility indexes study, animals received the treatment before, during and after gestation. The fertility index, gestation index, post-natal viability index, weaning viability index and sex ratio were calculated. Sexual maturation was evaluated in the female pups by the vaginal opening (VO) day. In the implantation study, females were checked for implantation sites at gestation day 7 and the embryos were counted. In ovariectomized mice, the uterine weight was recorded at the end of treatment. Results Implantation sites were similar in mice treated with Maca and in controls. All reproductive indexes were similar in both groups of treatment. The number of pups per dam at birth and at postnatal day 4 was significantly higher in the group treated with Maca. VO day occurred earlier as litter size was smaller. Maca did not affect VO day. In ovariectomized mice, the treatment with Maca increased significantly the uterine weights in comparison to their respective control group. Conclusion Administration of aqueous extract of Yellow Maca to adult female mice increases the litter size. Moreover, this treatment increases the uterine weight in ovariectomized animals. Our study confirms for the first time some of the traditional uses of Maca to enhance female fertility. PMID

Lepidium meyenii (Maca) increases litter size in normal adult female mice.

PubMed

Ruiz-Luna, Ana C; Salazar, Stephanie; Aspajo, Norma J; Rubio, Julio; Gasco, Manuel; Gonzales, Gustavo F

2005-05-03

Lepidium meyenii, known as Maca, grows exclusively in the Peruvian Andes over 4000 m altitude. It has been used traditionally to increase fertility. Previous scientific studies have demonstrated that Maca increases spermatogenesis and epididymal sperm count. The present study was aimed to investigate the effects of Maca on several fertility parameters of female mice at reproductive age. Adult female Balb/C mice were divided at random into three main groups: i) Reproductive indexes group, ii) Implantation sites group and iii) Assessment of uterine weight in ovariectomized mice. Animals received an aqueous extract of lyophilized Yellow Maca (1 g/Kg BW) or vehicle orally as treatment. In the fertility indexes study, animals received the treatment before, during and after gestation. The fertility index, gestation index, post-natal viability index, weaning viability index and sex ratio were calculated. Sexual maturation was evaluated in the female pups by the vaginal opening (VO) day. In the implantation study, females were checked for implantation sites at gestation day 7 and the embryos were counted. In ovariectomized mice, the uterine weight was recorded at the end of treatment. Implantation sites were similar in mice treated with Maca and in controls. All reproductive indexes were similar in both groups of treatment. The number of pups per dam at birth and at postnatal day 4 was significantly higher in the group treated with Maca. VO day occurred earlier as litter size was smaller. Maca did not affect VO day. In ovariectomized mice, the treatment with Maca increased significantly the uterine weights in comparison to their respective control group. Administration of aqueous extract of Yellow Maca to adult female mice increases the litter size. Moreover, this treatment increases the uterine weight in ovariectomized animals. Our study confirms for the first time some of the traditional uses of Maca to enhance female fertility.

Adolescent C57BL/6J mice show elevated alcohol intake, but reduced taste aversion, as compared to adult mice: a potential behavioral mechanism for binge drinking.

PubMed

Holstein, Sarah E; Spanos, Marina; Hodge, Clyde W

2011-10-01

Binge alcohol drinking during adolescence is a serious health problem that may increase future risk of an alcohol use disorder. Although there are several different procedures by which to preclinically model binge-like alcohol intake, limited-access procedures offer the advantage of achieving high voluntary alcohol intake and pharmacologically relevant blood alcohol concentrations (BACs). Therefore, in the current study, developmental differences in binge-like alcohol drinking using a limited-access cycling procedure were examined. In addition, as alcohol drinking has been negatively correlated with sensitivity to the aversive properties of alcohol, we examined developmental differences in sensitivity to an alcohol-induced conditioned taste aversion (CTA). Binge-like alcohol consumption was investigated in adolescent (4 weeks) and adult (10 weeks) male C57BL/6J mice for 2 to 4 h/d for 16 days. Developmental differences in sensitivity to an alcohol-induced CTA were examined in adolescent and adult mice, with saline or alcohol (3 or 4 g/kg) repeatedly paired with the intake of a novel tastant (NaCl). Adolescent mice showed a significant increase in alcohol intake as compared to adults, with adolescents achieving higher BACs and increasing alcohol consumption over successive cycles of the binge procedure. Conversely, adolescent mice exhibited a dose-dependent reduction in sensitivity to the aversive properties of alcohol, as compared to adult mice, with adolescent mice failing to develop a CTA to 3 g/kg alcohol. Finally, extinction of an alcohol CTA was observed following conditioning with a higher dose of alcohol in adolescent, versus adult, mice. These results indicate that adolescent mice consume more alcohol, per kilogram body weight, than adults in a binge-like model of alcohol drinking and demonstrate a blunted sensitivity to the conditioned aversive effects of alcohol. Overall, this supports a behavioral framework by which heightened binge alcohol intake during

Adolescent C57BL/6J mice show elevated alcohol intake, but reduced taste aversion, as compared to adult mice: a potential behavioral mechanism for binge drinking

PubMed Central

Holstein, Sarah E.; Spanos, Marina; Hodge, Clyde W.

2011-01-01

Background Binge alcohol drinking during adolescence is a serious health problem which may increase future risk of an alcohol use disorder. Although there are several different procedures by which to preclinically model binge-like alcohol intake, limited-access procedures offer the advantage of achieving high voluntary alcohol intake and pharmacologically relevant blood alcohol concentrations (BACs). Therefore, in the current study, developmental differences in binge-like alcohol drinking using a limited-access cycling procedure were examined. In addition, as alcohol drinking has been negatively correlated with sensitivity to the aversive properties of alcohol, we examined developmental differences in sensitivity to an alcohol-induced conditioned taste aversion (CTA). Methods Binge-like alcohol consumption was investigated in adolescent (4 wk) and adult (10 wk) male C57BL/6J mice for 2-4 h/day for 16 d. Developmental differences in sensitivity to an alcohol-induced CTA were examined in adolescent and adult mice, with saline or alcohol (3 or 4 g/kg) repeatedly paired with intake of a novel tastant (NaCl). Results Adolescent mice showed a significant increase in alcohol intake as compared to adults, with adolescents achieving higher BACs and increasing alcohol consumption over successive cycles of the binge procedure. Conversely, adolescent mice exhibited a dose-dependent reduction in sensitivity to the aversive properties of alcohol, as compared to adult mice, with adolescent mice failing to develop a CTA to 3 g/kg alcohol. Finally, extinction of an alcohol CTA was observed following conditioning with a higher dose of alcohol in adolescent, versus adult, mice. Conclusions These results indicate that adolescent mice consume more alcohol, per kg body weight, than adults in a binge-like model of alcohol drinking, and demonstrate a blunted sensitivity to the conditioned aversive effects of alcohol. Overall, this supports a behavioral framework by which heightened binge

[Pyomyositis, sacroiliitis and spondylodiscitis caused by Staphylococcus hominis in a immunocompetent woman].

PubMed

Gómez Rodríguez, N; Durán Muñoz, O

2006-12-01

In absence of risk factors, osteoarticular infections by coagulase-negative staphylococci are very infrequent. We described the case of a immunocompetent 73-year-old-woman that suffered pyomyositis, left sacroiliitis and spondylodiscitis involving the first and second thoracic vertebrae by Staphylococcus hominis. This multifocal infection occurred five-weeks after intramuscular administration of NSAI for treatment of low back pain associated with a herniated disc L4-L5. This is the first know case of a multifocal muscle skeletal infection by Staphylococcus hominis in a patient immunocompetent.

Long-lasting Effects of Minocycline on Behavior in Young but not Adult Fragile X Mice

PubMed Central

Dansie, Lorraine E.; Phommahaxay, Kelly; Okusanya, Ayodeji G.; Uwadia, Jessica; Huang, Mike; Rotschafer, Sarah E.; Razak, Khaleel A.; Ethell, Douglas W.; Ethell, Iryna M.

2013-01-01

Fragile X Syndrome (FXS) is the most common single-gene inherited form of intellectual disability with behaviors characteristic of autism. People with FXS display childhood seizures, hyperactivity, anxiety, developmental delay, attention deficits, and visual-spatial memory impairment, as well as a propensity for obsessive-compulsive disorder (OCD). Several of these aberrant behaviors and FXS-associated synaptic irregularities also occur in “fragile X mental retardation gene” knock-out (Fmr1 KO) mice. We previously reported that minocycline promotes the maturation of dendritic spines - postsynaptic sites for excitatory synapses - in the developing hippocampus of Fmr1 KO mice, which may underlie the beneficial effects of minocycline on anxiolytic behavior in young Fmr1 KO mice. In this study, we compared the effectiveness of minocycline treatment in young and adult Fmr1 KO mice, and determined the dependence of behavioral improvements on short-term versus long-term minocycline administration. We found that 4 and 8 week long treatments significantly reduced locomotor activity in both young and adult Fmr1 KO mice. Some behavioral improvements persisted in young mice post-treatment, but in adults the beneficial effects were lost soon after minocycline treatment was stopped. We also show, for the first time, that minocycline treatment partially attenuates the number and severity of audiogenic seizures in Fmr1 KO mice. This report provides further evidence that minocycline treatment has immediate and long-lasting benefits on FXS-associated behaviors in the Fmr1 KO mouse model. PMID:23660195

Monocular Deprivation in Adult Mice Alters Visual Acuity and Single-Unit Activity

ERIC Educational Resources Information Center

Evans, Scott; Lickey, Marvin E.; Pham, Tony A.; Fischer, Quentin S.; Graves, Aundrea

2007-01-01

It has been discovered recently that monocular deprivation in young adult mice induces ocular dominance plasticity (ODP). This contradicts the traditional belief that ODP is restricted to a juvenile critical period. However, questions remain. ODP of young adults has been observed only using methods that are indirectly related to vision, and the…

Postnatal Loss of Hap1 Reduces Hippocampal Neurogenesis and Causes Adult Depressive-Like Behavior in Mice

PubMed Central

Xiang, Jianxing; Yan, Sen; Li, Shi-Hua; Li, Xiao-Jiang

2015-01-01

Depression is a serious mental disorder that affects a person’s mood, thoughts, behavior, physical health, and life in general. Despite our continuous efforts to understand the disease, the etiology of depressive behavior remains perplexing. Recently, aberrant early life or postnatal neurogenesis has been linked to adult depressive behavior; however, genetic evidence for this is still lacking. Here we genetically depleted the expression of huntingtin-associated protein 1 (Hap1) in mice at various ages or in selective brain regions. Depletion of Hap1 in the early postnatal period, but not later life, led to a depressive-like phenotype when the mice reached adulthood. Deletion of Hap1 in adult mice rendered the mice more susceptible to stress-induced depressive-like behavior. Furthermore, early Hap1 depletion impaired postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus and reduced the level of c-kit, a protein expressed in neuroproliferative zones of the rodent brain and that is stabilized by Hap1. Importantly, stereotaxically injected adeno-associated virus (AAV) that directs the expression of c-kit in the hippocampus promoted postnatal hippocampal neurogenesis and ameliorated the depressive-like phenotype in conditional Hap1 KO mice, indicating a link between postnatal-born hippocampal neurons and adult depression. Our results demonstrate critical roles for Hap1 and c-kit in postnatal neurogenesis and adult depressive behavior, and also suggest that genetic variations affecting postnatal neurogenesis may lead to adult depression. PMID:25875952

Postnatal loss of hap1 reduces hippocampal neurogenesis and causes adult depressive-like behavior in mice.

PubMed

Xiang, Jianxing; Yan, Sen; Li, Shi-Hua; Li, Xiao-Jiang

2015-04-01

Depression is a serious mental disorder that affects a person's mood, thoughts, behavior, physical health, and life in general. Despite our continuous efforts to understand the disease, the etiology of depressive behavior remains perplexing. Recently, aberrant early life or postnatal neurogenesis has been linked to adult depressive behavior; however, genetic evidence for this is still lacking. Here we genetically depleted the expression of huntingtin-associated protein 1 (Hap1) in mice at various ages or in selective brain regions. Depletion of Hap1 in the early postnatal period, but not later life, led to a depressive-like phenotype when the mice reached adulthood. Deletion of Hap1 in adult mice rendered the mice more susceptible to stress-induced depressive-like behavior. Furthermore, early Hap1 depletion impaired postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus and reduced the level of c-kit, a protein expressed in neuroproliferative zones of the rodent brain and that is stabilized by Hap1. Importantly, stereotaxically injected adeno-associated virus (AAV) that directs the expression of c-kit in the hippocampus promoted postnatal hippocampal neurogenesis and ameliorated the depressive-like phenotype in conditional Hap1 KO mice, indicating a link between postnatal-born hippocampal neurons and adult depression. Our results demonstrate critical roles for Hap1 and c-kit in postnatal neurogenesis and adult depressive behavior, and also suggest that genetic variations affecting postnatal neurogenesis may lead to adult depression.

[Cladophilaphora bantiana brain abscess treated with voriconazole in an immunocompetent patient].

PubMed

Atalay, Mustafa Altay; Koç, Ayşe Nedret; Koyuncu, Sümeyra; Ulu Kiliç, Ayşegül; Kurtsoy, Ali; Alp Meşe, Emine

2014-07-01

Phaeohyphomycosis is a term used to define infections caused by darkly pigmented fungi with septate hyphae which contain melanin in their cell walls. Although fungi rarely cause central nervous system (CNS) infections, the incidence of CNS infections caused by melanin-containing fungi has been increasing in the recent years. Cladophialophora bantiana is the most frequently isolated species from cerebral phaeohyphomycosis. It mostly affects adult men in the second and third decade of life and about half of the cases occurs in immunocompetent patients. In this report, the isolation of C.bantiana from brain tissue of an immunocompetent patient who was operated with the initial diagnosis of a brain abscess, was presented. A 27 year-old male patient presenting without any chronic disease was admitted to the emergency department of our hospital with the complaints of persistent headache and diplopia. Magnetic resonance imaging (MRI) showed a space-occupying lesion in the right parietal lobe and left frontal lobe. Brain abscess was diagnosed in the patient who was referred to the neurosurgery department. Treatment was initiated with ceftriaxone and metronidazole. The abscess material sent for direct microscopic examination in the mycology laboratory was stained with Gram and Giemsa and cultured in the Sabouraud dextrose agar medium (SDA) with and without antibiotics (cycloheximide and chloramphenicol). Then, it was incubated at 37°C and 25°C. Direct examination and staining revealed a septate hyphae. The patient who received liposomal amphotericin B was referred to the infectious diseases department. Surface colors of all media including SDA with cycloheximide were olive-gray to black and contained velvety colonies. Lemon-like very long and integrated chains of conidium with poor branching in cornmeal Tween 80 agar, as well as growth at 42°C in passages, positive urease test result and cycloheximide resistance suggested C.bantiana. The isolate was confirmed as C

Adolescent mice are less sensitive to the effects of acute nicotine on context pre-exposure than adults.

PubMed

Kutlu, Munir Gunes; Braak, David C; Tumolo, Jessica M; Gould, Thomas J

2016-07-01

Adolescence is a critical developmental period associated with both increased vulnerability to substance abuse and maturation of certain brain regions important for learning and memory such as the hippocampus. In this study, we employed a hippocampus-dependent learning context pre-exposure facilitation effect (CPFE) paradigm in order to test the effects of acute nicotine on contextual processing during adolescence (post-natal day (PND) 38) and adulthood (PND 53). In Experiment 1, adolescent or adult C57BL6/J mice received either saline or one of three nicotine doses (0.09, 0.18, and 0.36mg/kg) prior to contextual pre-exposure and testing. Our results demonstrated that both adolescent and adult mice showed CPFE in the saline groups. However, adolescent mice only showed acute nicotine enhancement of CPFE with the highest nicotine dose whereas adult mice showed the enhancing effects of acute nicotine with all three doses. In Experiment 2, to determine if the lack of nicotine's effects on CPFE shown by adolescent mice is specific to the age when they are tested, mice were either given contextual pre-exposure during adolescence or adulthood and received immediate shock and testing during adulthood after a 15day delay. We found that both adolescent and adult mice showed CPFE in the saline groups when tested during adulthood. However, like Experiment 1, mice that received contextual pre-exposure during adolescence did not show acute nicotine enhancement except at the highest dose (0.36mg/kg) whereas both low (0.09mg/kg) and high (0.36mg/kg) doses enhanced CPFE in adult mice. Finally, we showed that the enhanced freezing response found with 0.36mg/kg nicotine in the 15-day experiment may be a result of decreased locomotor activity as mice that received this dose of nicotine traveled shorter distances in an open field paradigm. Overall, our results indicate that while adolescent mice showed normal contextual processing when tested both during adolescence and adulthood, they

Aspergillus meningitis and discitis from low-back procedures in an immunocompetent patient.

PubMed

Kolbe, A B Larson; McKinney, A M; Kendi, A Tuba Karagulle; Misselt, D

2007-07-01

We present a case of an immunocompetent patient who developed Aspergillus meningitis, subsequent to discitis, presumed to be from an epidural steroid injection. Magnetic resonance imaging (MRI) of the lumbar spine confirmed the diagnosis of discitis. Fluoroscopic-guided aspiration of the disc showed growth of Aspergillus fumigatus. MRI of the brain revealed involvement of the right third cranial nerve. Repeat MRIs demonstrated multiple leptomeningeal masses consistent with granulomatous meningitis. Meningitis is a rare complication of discitis, discogram, or epidural steroid injection. Aspergillus usually only infects immunocompromised patients, but rarely can affect immunocompetent patients.

Adolescent silymarin treatment increases anxiety-like behaviors in adult mice.

PubMed

Kosari-Nasab, Morteza; Rabiei, Afshin; Doosti, Mohammad-Hossein; Salari, Ali-Akbar

2014-08-01

Adolescence is one of the most important periods of brain development in mammals. There is increasing evidence that some medicines during this period can affect brain and behavioral functions in adulthood. Silymarin (SM), a mixture of flavonolignans extracted from the milk thistle Silybum marianum, is known as a hepatoprotective, anti-inflammatory, and neuroprotective drug. Although researchers have extensively studied the effects of SM during adulthood, to date there is no information on the effects of this drug during the stages of brain development on behavioral functions in adulthood. In the current study, we investigated the effects of adolescent SM treatment on body weight and anxiety-like behaviors in adult male and female mice. Adolescent NMRI mice (postnatal day 30-50) were treated orally with water or SM (50 and 100 mg/kg). Animals were weighed during drug treatment and were then subjected to open field, elevated plus maze, and light-dark box tests from postnatal day 70. The results indicated that adolescent SM treatment increased anxiety-like behaviors in open field, elevated plus maze, and light-dark box in adult mice, while not altering body weight. Collectively, these findings suggest that adolescent SM treatment may have profound effects on the development of brain and behavior in adulthood.

Antisense reduction of tau in adult mice protects against seizures.

PubMed

DeVos, Sarah L; Goncharoff, Dustin K; Chen, Guo; Kebodeaux, Carey S; Yamada, Kaoru; Stewart, Floy R; Schuler, Dorothy R; Maloney, Susan E; Wozniak, David F; Rigo, Frank; Bennett, C Frank; Cirrito, John R; Holtzman, David M; Miller, Timothy M

2013-07-31

Tau, a microtubule-associated protein, is implicated in the pathogenesis of Alzheimer's Disease (AD) in regard to both neurofibrillary tangle formation and neuronal network hyperexcitability. The genetic ablation of tau substantially reduces hyperexcitability in AD mouse lines, induced seizure models, and genetic in vivo models of epilepsy. These data demonstrate that tau is an important regulator of network excitability. However, developmental compensation in the genetic tau knock-out line may account for the protective effect against seizures. To test the efficacy of a tau reducing therapy for disorders with a detrimental hyperexcitability profile in adult animals, we identified antisense oligonucleotides that selectively decrease endogenous tau expression throughout the entire mouse CNS--brain and spinal cord tissue, interstitial fluid, and CSF--while having no effect on baseline motor or cognitive behavior. In two chemically induced seizure models, mice with reduced tau protein had less severe seizures than control mice. Total tau protein levels and seizure severity were highly correlated, such that those mice with the most severe seizures also had the highest levels of tau. Our results demonstrate that endogenous tau is integral for regulating neuronal hyperexcitability in adult animals and suggest that an antisense oligonucleotide reduction of tau could benefit those with epilepsy and perhaps other disorders associated with tau-mediated neuronal hyperexcitability.

Selenium status alters the immune response and expulsion of adult Heligmosomodies bakeri in mice

USDA-ARS?s Scientific Manuscript database

Heligmosomoides bakeri is a nematode with parasitic development exclusively in the small intestine of infected mice that induces a potent STAT6-dependent Th2 immune response. We previously demonstrated that host protective expulsion of adult H. bakeri was delayed in selenium (Se) deficient mice. ...

Evaluation of nigrostriatal dopaminergic function in adult +/+ and +/- BDNF mutant mice.

PubMed

Dluzen, D E; Gao, X; Story, G M; Anderson, L I; Kucera, J; Walro, J M

2001-07-01

Deletion of a single copy of the BDNF gene has been shown to affect the nigrostriatal dopaminergic system of young adult BDNF mice. In the present report we evaluated various indices of nigrostriatal dopaminergic function between 9-month-old wild-type (+/+) and heterozygous (+/-) BDNF mutant mice. Performance in a sensorimotor beam walking task was significantly decreased in +/- mice as indicated by increased times required to traverse both a wide (21 mm) and narrow (6 mm) beam. No differences in spontaneous locomotor behavior were observed between the +/+ and +/- mice. Amphetamine-stimulated (5 mg/kg) locomotor behavior was increased to a greater degree in the +/- mice, with the number of movements performed by these mice being significantly greater than their +/+ controls. Corpus striatal dopamine concentrations were significantly greater in the +/- BDNF mice. The absence of any significant differences for dopamine concentrations within the hypothalamus and olfactory bulb of these mice, as well as an absence of any difference in striatal norepinephrine concentrations, suggested a relative specificity of these effects to the corpus striatum. Both the +/- and +/+ mice showed similar reductions in striatal dopamine concentrations in response to a neurotoxic regimen of methamphetamine (20 mg/kg). Collectively these data show increased levels of striatal dopamine concentrations associated with altered behavioral responses involving the nigrostriatal dopaminergic system within the heterozygous BDNF mutant mice. Copyright 2001 Academic Press.

Treatment of experimental pneumonia due to penicillin-resistant Streptococcus pneumoniae in immunocompetent rats.

PubMed Central

Gavaldà, J; Capdevila, J A; Almirante, B; Otero, J; Ruiz, I; Laguarda, M; Allende, H; Crespo, E; Pigrau, C; Pahissa, A

1997-01-01

A model of pneumonia due to Streptococcus pneumoniae resistant to penicillin was developed in immunocompetent Wistar rats and was used to evaluate the efficacies of different doses of penicillin, cefotaxime, cefpirome, and vancomycin. Adult Wistar rats were challenged by intratracheal inoculation with 3 x 10(9) CFU of one strain of S. pneumoniae resistant to penicillin (MICs of penicillin, cefotaxime, cefpirome, and vancomycin, 2, 1, 0.5, and 0.5 microg/ml, respectively) suspended in brain heart broth supplemented with 0.7% agar. The rats experienced a fatal pneumonia, dying within 5 days and with peak mortality (70 to 80%) occurring 48 to 72 h after infection, and the bacterial counts in the lungs persisted from 8.87 +/- 0.3 log10 CFU/g of lung at 24 h of the infection to 9.1 +/- 0.3 log10 CFU/g at 72 h. Four hours after infection the animals were randomized into the following treatment groups: (i) control without treatment, (ii) penicillin G at 100,000 IU/kg of body weight every 2 h, (iii) penicillin G at 250,000 IU/kg every 2 h, (iv) cefotaxime at 100 mg/kg every 2 h, (v) cefpirome at 200 mg/kg every 2 h, and (vi) vancomycin at 50 mg/kg every 8 h. Two different protocols were used for the therapeutic efficacy studies: four doses of beta-lactams and one dose of vancomycin or eight doses of beta-lactams and two doses of vancomycin. Results of the therapy for experimental pneumonia caused by penicillin-resistant S. pneumoniae showed that initially, all the antimicrobial agents tested had similar efficacies, but when we prolonged the treatment, higher doses of penicillin, cefotaxime, and cefpirome were more effective than penicillin at lower doses in decreasing the residual bacterial titers in the lungs. Also, when we extended the treatment, vancomycin was more efficacious than penicillin at lower doses but was less efficacious than higher doses of penicillin or cefpirome. The model that we have developed is simple and amenable for inducing pneumonia in

Mitochondrial function, ornamentation, and immunocompetence.

PubMed

Koch, Rebecca E; Josefson, Chloe C; Hill, Geoffrey E

2017-08-01

Understanding the mechanisms that link ornamental displays and individual condition is key to understanding the evolution and function of ornaments. Immune function is an aspect of individual quality that is often associated with the expression of ornamentation, but a general explanation for why the expression of some ornaments seems to be consistently linked to immunocompetence remains elusive. We propose that condition-dependent ornaments may be linked to key aspects of immunocompetence through co-dependence on mitochondrial function. Mitochondrial involvement in immune function is rarely considered outside of the biomedical literature, but the role of mitochondria as the primary energy producers of the cell and the centres of biosynthesis, the oxidative stress response, and cellular signalling place them at the hub of a variety of immune pathways. A promising new mechanistic explanation for correlations between a wide range of ornamental traits and the properties of individual quality is that mitochondrial function may be the 'shared pathway' responsible for links between ornament production and individual condition. Herein, we first review the role of mitochondria as both signal transducers and metabolic regulators of immune function. We then describe connections between hormonal pathways and mitochondria, with implications for both immune function and the expression of ornamentation. Finally, we explore the possibility that ornament expression may link directly to mitochondrial function. Considering condition-dependent traits within the framework of mitochondrial function has the potential to unify central tenets within the study of sexual selection, eco-immunology, oxidative stress ecology, stress and reproductive hormone biology, and animal physiology. © 2016 Cambridge Philosophical Society.

Effects of acute social stress on the conditioned place preference induced by MDMA in adolescent and adult mice.

PubMed

García-Pardo, Maria P; Rodríguez-Arias, Marta; Maldonado, Concepcion; Manzanedo, Carmen; Miñarro, Jose; Aguilar, Maria A

2014-09-01

Exposure to social defeat stress increases the rewarding effects of psychostimulants in animal models, but its effect on 3,4-methylenedioxymethylamphetamine (MDMA) reward has received little attention. In the present study, we evaluated the influence of social defeat on the rewarding effects of MDMA in adolescent [postnatal day (PND) 29-40] and adult (PND 50-61) male mice using the conditioned place preference paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1.25 or 10 mg/kg of MDMA. The effects of social defeat on corticosterone levels and the motor or the anxiogenic effects of MDMA were also evaluated. Mice exposed to social defeat during adulthood did not show conditioned place preference after conditioning with either dose of MDMA. Conversely, social defeat did not affect the anxiogenic and motor effects of MDMA. Adult mice exposed to social defeat showed higher levels of corticosterone than their controls and adolescent mice. Social stress did not induce behavioural effects in adolescent mice. Our results show that stress induced by social defeat decreases the sensitivity of adult mice to the rewarding effects of MDMA.

Epstein-Barr viral load assessment in immunocompetent patients with fulminant infectious mononucleosis.

PubMed

van Laar, Jan A M; Buysse, Corinne M P; Vossen, Ann C T M; Hjálmarsson, Björn; van Den Berg, Bart; van Lom, Kirsten; Deinum, Jaap

2002-04-08

We describe 2 immunocompetent adolescents with fulminant infectious mononucleosis and virus-associated hemophagocytosis. A new quantitative polymerase chain reaction revealed high serum Epstein-Barr virus DNA levels in these patients. One patient died with an increasing viral load not responding to corticosteroids followed by antiviral and intensified immunomodulatory treatment. The other patient received corticosteroids and acyclovir at diagnosis; her rapid recovery was heralded by a steep decline of viral load. We propose monitoring the clinical course of fulminant infectious mononucleosis in immunocompetent patients by Epstein-Barr virus DNA quantification and prompt corticosteroid and antiviral therapy when viral load is high.

A humanized version of Foxp2 does not affect ultrasonic vocalization in adult mice.

PubMed

Hammerschmidt, K; Schreiweis, C; Minge, C; Pääbo, S; Fischer, J; Enard, W

2015-11-01

The transcription factor FOXP2 has been linked to severe speech and language impairments in humans. An analysis of the evolution of the FOXP2 gene has identified two amino acid substitutions that became fixed after the split of the human and chimpanzee lineages. Studying the functional consequences of these two substitutions in the endogenous Foxp2 gene of mice showed alterations in dopamine levels, striatal synaptic plasticity, neuronal morphology and cortico-striatal-dependent learning. In addition, ultrasonic vocalizations (USVs) of pups had a significantly lower average pitch than control littermates. To which degree adult USVs would be affected in mice carrying the 'humanized' Foxp2 variant remained unclear. In this study, we analyzed USVs of 68 adult male mice uttered during repeated courtship encounters with different females. Mice carrying the Foxp2(hum/hum) allele did not differ significantly in the number of call elements, their element structure or in their element composition from control littermates. We conclude that neither the structure nor the usage of USVs in adult mice is affected by the two amino acid substitutions that occurred in FOXP2 during human evolution. The reported effect for pup vocalization thus appears to be transient. These results are in line with accumulating evidence that mouse USVs are hardly influenced by vocal learning. Hence, the function and evolution of genes that are necessary, but not sufficient for vocal learning in humans, must be either studied at a different phenotypic level in mice or in other organisms. © 2015 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.

Tumors Alter Inflammation and Impair Dermal Wound Healing in Female Mice

PubMed Central

Pyter, Leah M.; Husain, Yasmin; Calero, Humberto; McKim, Daniel B.; Lin, Hsin-Yun; Godbout, Jonathan P.; Sheridan, John F.; Engeland, Christopher G.; Marucha, Phillip T.

2016-01-01

Tissue repair is an integral component of cancer treatment (e.g., due to surgery, chemotherapy, radiation). Previous work has emphasized the immunosuppressive effects of tumors on adaptive immunity and has shown that surgery incites cancer metastases. However, the extent to which and how tumors may alter the clinically-relevant innate immune process of wound healing remains an untapped potential area of improvement for treatment, quality of life, and ultimately, mortality of cancer patients. In this study, 3.5 mm full-thickness dermal excisional wounds were placed on the dorsum of immunocompetent female mice with and without non-malignant flank AT-84 murine oral squamous cell carcinomas. Wound closure rate, inflammatory cell number and inflammatory signaling in wounds, and circulating myeloid cell concentrations were compared between tumor-bearing and tumor-free mice. Tumors delayed wound closure, suppressed inflammatory signaling, and altered myeloid cell trafficking in wounds. An in vitro scratch “wounding” assay of adult dermal fibroblasts treated with tumor cell-conditioned media supported the in vivo findings. This study demonstrates that tumors are sufficient to disrupt fundamental and clinically-relevant innate immune functions. The understanding of these underlying mechanisms provides potential for therapeutic interventions capable of improving the treatment of cancer while reducing morbidities and mortality. PMID:27548621

Zfp488 promotes oligodendrocyte differentiation of neural progenitor cells in adult mice after demyelination

PubMed Central

Soundarapandian, Mangala M.; Selvaraj, Vimal; Lo, U-Ging; Golub, Mari S.; Feldman, Daniel H.; Pleasure, David E.; Deng, Wenbin

2011-01-01

Basic helix-loop-helix transcription factors Olig1 and Olig2 critically regulate oligodendrocyte development. Initially identified as a downstream effector of Olig1, an oligodendrocyte-specific zinc finger transcription repressor, Zfp488, cooperates with Olig2 function. Although Zfp488 is required for oligodendrocyte precursor formation and differentiation during embryonic development, its role in oligodendrogenesis of adult neural progenitor cells is not known. In this study, we tested whether Zfp488 could promote an oligodendrogenic fate in adult subventricular zone (SVZ) neural stem/progenitor cells (NSPCs). Using a cuprizone-induced demyelination model in mice, we examined the effect of retrovirus-mediated Zfp488 overexpression in SVZ NSPCs. Our results showed that Zfp488 efficiently promoted the differentiation of the SVZ NSPCs into mature oligodendrocytes in vivo. After cuprizone-induced demyelination injury, Zfp488-transduced mice also showed significant restoration of motor function to levels comparable to control mice. Together, these findings identify a previously unreported role for Zfp488 in adult oligodendrogenesis and functional remyelination after injury. PMID:22355521

Inducible knockdown of pregnancy-associated plasma protein-A gene expression in adult female mice extends life span.

PubMed

Bale, Laurie K; West, Sally A; Conover, Cheryl A

2017-08-01

Pregnancy-associated plasma protein-A (PAPP-A) knockout (KO) mice, generated through homologous recombination in embryonic stem cells, have a significantly increased lifespan compared to wild-type littermates. However, it is unknown whether this longevity advantage would pertain to PAPP-A gene deletion in adult animals. In the present study, we used tamoxifen (Tam)-inducible Cre recombinase-mediated excision of the floxed PAPP-A (fPAPP-A) gene in mice at 5 months of age. fPAPP-A mice, which were either positive (pos) or negative (neg) for Tam-Cre, received Tam treatment with quarterly boosters. Only female mice could be used with this experimental design. fPAPP-A/neg and fPAPP-A/pos mice had similar weights at the start of the experiment and showed equivalent weight gain. We found that fPAPP-A/pos mice had a significant extension of life span (P = 0.005). The median life span was increased by 21% for fPAPP-A/pos compared to fPAPP-A/neg mice. Analysis of mortality in life span quartiles indicated that the proportion of deaths of fPAPP-A/pos mice were lower than fPAPP-A/neg mice at young adult ages (P = 0.002 for 601-800 days) and higher than fPAPP-A/neg mice at older ages (P = 0.004 for >1000 days). Thus, survival curves and age-specific mortality indicate that female mice with knockdown of PAPP-A gene expression as adults have an extended healthy life span. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Disseminated cryptococcosis in an immunocompetent patient.

PubMed

Mada, Pradeep; Nowack, Brad; Cady, Beth; Joel Chandranesan, Andrew Stevenson

2017-07-18

Cryptococcosis is a fungal infection which is commonly associated with immune-compromised state. Disseminated infection in immunocompetent individuals is extremely rare. We present a case of a 56-year-old African American patient who presented with unilateral knee pain and swelling and was subsequently diagnosed with cryptococcal bone mass with dissemination of infection. © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Female mice lack adult germ-line stem cells but sustain oogenesis using stable primordial follicles.

PubMed

Lei, Lei; Spradling, Allan C

2013-05-21

Whether or not mammalian females generate new oocytes during adulthood from germ-line stem cells to sustain the ovarian follicle pool has recently generated controversy. We used a sensitive lineage-labeling system to determine whether stem cells are needed in female adult mice to compensate for follicular losses and to directly identify active germ-line stem cells. Primordial follicles generated during fetal life are highly stable, with a half-life during adulthood of 10 mo, and thus are sufficient to sustain adult oogenesis without a source of renewal. Moreover, in normal mice or following germ-cell depletion with Busulfan, only stable, single oocytes are lineage-labeled, rather than cell clusters indicative of new oocyte formation. Even one germ-line stem cell division per 2 wk would have been detected by our method, based on the kinetics of fetal follicle formation. Thus, adult female mice neither require nor contain active germ-line stem cells or produce new oocytes in vivo.

Subpial Adeno-associated Virus 9 (AAV9) Vector Delivery in Adult Mice.

PubMed

Tadokoro, Takahiro; Miyanohara, Atsushi; Navarro, Michael; Kamizato, Kota; Juhas, Stefan; Juhasova, Jana; Marsala, Silvia; Platoshyn, Oleksandr; Curtis, Erik; Gabel, Brandon; Ciacci, Joseph; Lukacova, Nada; Bimbova, Katarina; Marsala, Martin

2017-07-13

The successful development of a subpial adeno-associated virus 9 (AAV9) vector delivery technique in adult rats and pigs has been reported on previously. Using subpially-placed polyethylene catheters (PE-10 or PE-5) for AAV9 delivery, potent transgene expression through the spinal parenchyma (white and gray matter) in subpially-injected spinal segments has been demonstrated. Because of the wide range of transgenic mouse models of neurodegenerative diseases, there is a strong desire for the development of a potent central nervous system (CNS)-targeted vector delivery technique in adult mice. Accordingly, the present study describes the development of a spinal subpial vector delivery device and technique to permit safe and effective spinal AAV9 delivery in adult C57BL/6J mice. In spinally immobilized and anesthetized mice, the pia mater (cervical 1 and lumbar 1-2 spinal segmental level) was incised with a sharp 34 G needle using an XYZ manipulator. A second XYZ manipulator was then used to advance a blunt 36G needle into the lumbar and/or cervical subpial space. The AAV9 vector (3-5 µL; 1.2 x 10 13 genome copies (gc)) encoding green fluorescent protein (GFP) was then injected subpially. After injections, neurological function (motor and sensory) was assessed periodically, and animals were perfusion-fixed 14 days after AAV9 delivery with 4% paraformaldehyde. Analysis of horizontal or transverse spinal cord sections showed transgene expression throughout the entire spinal cord, in both gray and white matter. In addition, intense retrogradely-mediated GFP expression was seen in the descending motor axons and neurons in the motor cortex, nucleus ruber, and formatio reticularis. No neurological dysfunction was noted in any animals. These data show that the subpial vector delivery technique can successfully be used in adult mice, without causing procedure-related spinal cord injury, and is associated with highly potent transgene expression throughout the spinal neuraxis.

Gut Microbiota Contributes to Resistance Against Pneumococcal Pneumonia in Immunodeficient Rag-/- Mice.

PubMed

Felix, Krysta M; Jaimez, Ivan A; Nguyen, Thuy-Vi V; Ma, Heqing; Raslan, Walid A; Klinger, Christina N; Doyle, Kristian P; Wu, Hsin-Jung J

2018-01-01

Streptococcus pneumoniae causes infection-related mortality worldwide. Immunocompromised individuals, including young children, the elderly, and those with immunodeficiency, are especially vulnerable, yet little is known regarding S. pneumoniae- related pathogenesis and protection in immunocompromised hosts. Recently, strong interest has emerged in the gut microbiota's impact on lung diseases, or the "gut-lung axis." However, the mechanisms of gut microbiota protection against gut-distal lung diseases like pneumonia remain unclear. We investigated the role of the gut commensal, segmented filamentous bacteria (SFB), against pneumococcal pneumonia in immunocompetent and immunocompromised mouse models. For the latter, we chose the Rag -/- model, with adaptive immune deficiency. Immunocompetent adaptive protection against S. pneumoniae infection is based on antibodies against pneumococcal capsular polysaccharides, prototypical T cell independent-II (TI-II) antigens. Although SFB colonization enhanced TI-II antibodies in C57BL/6 mice, our data suggest that SFB did not further protect these immunocompetent animals. Indeed, basal B cell activity in hosts without SFB is sufficient for essential protection against S. pneumoniae . However, in immunocompromised Rag -/- mice, we demonstrate a gut-lung axis of communication, as SFB influenced lung protection by regulating innate immunity. Neutrophil resolution is crucial to recovery, since an unchecked neutrophil response causes severe tissue damage. We found no early neutrophil recruitment differences between hosts with or without SFB; however, we observed a significant drop in lung neutrophils in the resolution phase of S. pneumoniae infection, which corresponded with lower CD47 expression, a molecule that inhibits phagocytosis of apoptotic cells, in SFB-colonized Rag -/- mice. SFB promoted a shift in lung neutrophil phenotype from inflammatory neutrophils expressing high levels of CD18 and low levels of CD62L, to pro

The Regenerative Potential of Parietal Epithelial Cells in Adult Mice

PubMed Central

Berger, Katja; Schulte, Kevin; Boor, Peter; Kuppe, Christoph; van Kuppevelt, Toin H.; Floege, Jürgen; Smeets, Bart

2014-01-01

Previously, we showed that some podocytes in juvenile mice are recruited from cells lining Bowman’s capsule, suggesting that parietal epithelial cells (PECs) are a progenitor cell population for podocytes. To investigate whether PECs also replenish podocytes in adult mice, PECs were genetically labeled in an irreversible fashion in 5-week-old mice. No significant increase in labeled podocytes was observed, even after 18 months. To accelerate a potential regenerative mechanism, progressive glomerular hypertrophy was induced by progressive partial nephrectomies. Again, no significant podocyte replenishment was observed. Rather, labeled PECs exclusively invaded segments of the tuft affected by glomerulosclerosis, consistent with our previous findings. We next reassessed PEC recruitment in juvenile mice using a different reporter mouse and confirmed significant recruitment of labeled PECs onto the glomerular tuft. Moreover, some labeled cells on Bowman’s capsule expressed podocyte markers, and cells on Bowman’s capsule were also directly labeled in juvenile podocyte-specific Pod-rtTA transgenic mice. In 6-week-old mice, however, cells on Bowman’s capsule no longer expressed podocyte-specific markers. Similarly, in human kidneys, some cells on Bowman’s capsule expressed the podocyte marker synaptopodin from 2 weeks to 2 years of age but not at 7 years of age. In summary, podocyte regeneration from PECs could not be detected in aging mice or models of glomerular hypertrophy. We propose that a small fraction of committed podocytes reside on Bowman’s capsule close to the vascular stalk and are recruited onto the glomerular tuft during infancy to adolescence in mice and humans. PMID:24408873

Lyophilized airborne Clostridium botulinum spores as inocula that intestinally colonize antimicrobially pretreated adult mice.

PubMed Central

Sugiyama, H; Prather, J L; Woller, M J

1986-01-01

Adult mice, made susceptible to Clostridium botulinum by feedings of metronidazole, were immobilized with an anesthetic and held for 30 min in isolators in which a fine powder of lyophilized pathogen spores was made airborne. Exposed mice were surface decontaminated before being kept for 2 days in holding isolators. Mice were intestinally colonized by the pathogen. Colonization rates were related to spore numbers (10(4) to 10(7) type A or B) seeded into isolators. PMID:3531017

Early gestational exposure to moderate concentrations of ethanol alters adult behaviour in C57BL/6J mice.

PubMed

Sanchez Vega, Michelle C; Chong, Suyinn; Burne, Thomas H J

2013-09-01

Alcohol consumption during pregnancy has deleterious effects on the developing foetus ranging from subtle physical deficits to severe behavioural abnormalities and is encompassed under a broad umbrella term, foetal alcohol spectrum disorders (FASD). High levels of exposure show distinct effects, whereas the consequences of moderate exposures have been less well studied. The aim of this study was to examine the effects of a moderate dose ethanol exposure using an ad libitum drinking procedure during the first eight days of gestation in mice on the behavioural phenotype of adult offspring. Adult female C57Bl/6J mice were mated and exposed to either 10% (v/v) ethanol or water for the first 8 days of gestation (GD 0-8), and then offered water for the rest of gestation. Early developmental milestone achievement was assessed in offspring at postnatal days (P) 7, 14 and 21. Adult offspring underwent a comprehensive battery of behavioural tests to examine a range of behavioural domains including locomotion, exploration, anxiety, social behaviour, learned helplessness, sensorimotor gating, and nociception, as well as spatial memory in a water maze. Ethanol-exposed mice had similar postnatal developmental trajectories to water-exposed mice. However, the ethanol-exposed mice showed increased hyperlocomotion at P 14, 21 and 70 (p<0.05). Increased exploration and heightened motivation were also observed in adult mice. Furthermore, ethanol-exposed mice showed a significant improvement in memory in the water maze. The main findings were that mice had persistent and long lasting alterations in behaviour, including hyperactivity and enhanced spatial memory. These data suggest that even moderate dose ethanol exposure in early gestation has long term consequences on brain function and behaviour in mice. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

Pharmacological Blockade of the Chemokine Receptor CCR1 Protects Mice from Systemic Candidiasis of Hematogenous Origin

PubMed Central

Albert, Nathaniel D.; Swamydas, Muthulekha; Lee, Chyi-Chia R.; Loetscher, Pius

2016-01-01

ABSTRACT Systemic candidiasis is a leading cause of nosocomial bloodstream infection with a high mortality rate despite treatment. Immune-based strategies are needed to improve outcomes. We previously reported that genetic deficiency in the chemokine receptor CCR1 improves survival and ameliorates tissue damage in Candida-infected mice. Here, we found that treatment of immunocompetent Candida-infected mice with the CCR1-selective antagonist BL5923 improves survival, decreases the kidney fungal burden, and protects from renal tissue injury. PMID:27993850

Recovery from a possible cytomegalovirus meningoencephalitis-induced apparent brain stem death in an immunocompetent man: a case report.

PubMed

Rahardjo, Theresia Monica; Maskoen, Tinni Trihartini; Redjeki, Ike Sri

2016-08-26

meningoencephalitis should be considered in the differential diagnosis even for an immunocompetent adult. Third, accurate therapy and simultaneous intensive care have very important roles in the recovery process of patients with cytomegalovirus meningoencephalitis.

Conditional rescue of protein kinase C epsilon regulates ethanol preference and hypnotic sensitivity in adult mice.

PubMed

Choi, Doo-Sup; Wang, Dan; Dadgar, Jahan; Chang, Wesley S; Messing, Robert O

2002-11-15

Conventional gene targeting is a powerful tool to study the influence of specific genes on behavior. However, conclusions relevant for adult animals are limited by consequences of gene loss during development. Mice lacking protein kinase C epsilon (PKCepsilon) consume less alcohol and show greater acute sensitivity to alcohol than do wild-type mice. There are no selective inhibitors of PKCepsilon that can be administered systemically and cross the blood-brain barrier to test whether these phenotypes result from loss of PKCepsilon during development or in adulthood. Here we used conditional expression of PKCepsilon in the basal forebrain, amygdala, and cerebellum to rescue wild-type responses to alcohol in adult PKCepsilon(-/-) mice. Subsequent suppression of transgenic PKCepsilon restored PKCepsilon(-/-) behaviors. These findings establish that PKCepsilon signaling in the adult brain regulates alcohol consumption and sensitivity. If this extends to humans, then PKCepsilon inhibitors might prove useful as novel therapeutics for alcoholism.

Malignant syphilis in an immunocompetent female patient*

PubMed Central

Requena, Camila Bueno; Orasmo, Cínthia Rosane; Ocanha, Juliana Polizel; Barraviera, Silvia Regina Catharino Sartore; Marques, Mariangela Esther Alencar; Marques, Silvio Alencar

2014-01-01

Malignant syphilis is an uncommon manifestation of secondary syphilis, in which necrotic lesions may be associated with systemic signs and symptoms. Generally it occurs in an immunosuppressed patient, mainly HIV-infected, but might be observed on those who have normal immune response. Since there is an exponential increase in the number of syphilis cases, more diagnoses of malignant syphilis must be expected. We report a case in an immunocompetent female patient. PMID:25387504

Ear-Shaped Stable Auricular Cartilage Engineered from Extensively Expanded Chondrocytes in an Immunocompetent Experimental Animal Model

PubMed Central

Pomerantseva, Irina; Bichara, David A.; Tseng, Alan; Cronce, Michael J.; Cervantes, Thomas M.; Kimura, Anya M.; Neville, Craig M.; Roscioli, Nick; Vacanti, Joseph P.; Randolph, Mark A.

2016-01-01

Advancement of engineered ear in clinical practice is limited by several challenges. The complex, largely unsupported, three-dimensional auricular neocartilage structure is difficult to maintain. Neocartilage formation is challenging in an immunocompetent host due to active inflammatory and immunological responses. The large number of autologous chondrogenic cells required for engineering an adult human-sized ear presents an additional challenge because primary chondrocytes rapidly dedifferentiate during in vitro culture. The objective of this study was to engineer a stable, human ear-shaped cartilage in an immunocompetent animal model using expanded chondrocytes. The impact of basic fibroblast growth factor (bFGF) supplementation on achieving clinically relevant expansion of primary sheep chondrocytes by in vitro culture was determined. Chondrocytes expanded in standard medium were either combined with cryopreserved, primary passage 0 chondrocytes at the time of scaffold seeding or used alone as control. Disk and human ear-shaped scaffolds were made from porous collagen; ear scaffolds had an embedded, supporting titanium wire framework. Autologous chondrocyte-seeded scaffolds were implanted subcutaneously in sheep after 2 weeks of in vitro incubation. The quality of the resulting neocartilage and its stability and retention of the original ear size and shape were evaluated at 6, 12, and 20 weeks postimplantation. Neocartilage produced from chondrocytes that were expanded in the presence of bFGF was superior, and its quality improved with increased implantation time. In addition to characteristic morphological cartilage features, its glycosaminoglycan content was high and marked elastin fiber formation was present. The overall shape of engineered ears was preserved at 20 weeks postimplantation, and the dimensional changes did not exceed 10%. The wire frame within the engineered ear was able to withstand mechanical forces during wound healing and neocartilage

Anemia in new congenital adult type polycystic kidney mice.

PubMed

Koumegawa, J; Nagano, N; Arai, H; Wada, M; Kusaka, M; Takahashi, H

1991-12-01

Mechanisms for the development of anemia and the effects of recombinant human erythropoietin (r-HuEPO) on hematological parameters were studied in new congenital adult type polycystic kidney (DBA/2FG-pcy) mice. The majority of DBA/2FG-pcy mice showed progressive anemia and an elevation of blood urea nitrogen, while a minority showed progressive anemia following polycythemia. Kidneys with numerous cysts in the cortex and medulla occupied virtually the entire abdominal cavity, and the combined kidney weight taken as a percentage of body weight reached 13.5% in the DBA/2FG-pcy mouse. The osmotic fragility of DBA/2FG-pcy mice erythrocytes was significantly increased compared with that of normal control mice. In addition, two-fold increases in serum EPO levels, determined by radioimmunoassay, and a decreased number of colony forming unit-erythroid (CFU-E) were observed in the DBA/2FG-pcy mice. The administration of r-HuEPO during anemia significantly increased the red blood cell count, hemoglobin concentration, hematocrit and reticulocyte percentage in a dose-dependent manner. These findings indicate that anemia in the DBA/2FG-pcy mouse is due to increased fragility of erythrocytes, a deficiency in EPO for the degree of anemia and a decreased number or a decreased response of erythroid progenitor cells. We suggest that the DBA/2FG-pcy mouse is a useful spontaneous model of chronic progressive renal failure.

[Cytomegalovirus colitis in immunocompetent young male].

PubMed

Rasmussen, Eva; Grønbaek, Karin; Linnemann, Dorte

2009-04-06

A healthy young man was hospitalized due to fever, malaise and bloody stools for three weeks. The patient had a primary CMV infection based on biochemical, serological and ultrasonic results, and a colonoscopy was consistent with left-sided CMV colitis. He recovered spontaneously, though haematochezia remained present after six months. Development of IBD subsequent to CMV colitis has previously been described, and is now suspected in our patient. CMV colitis is a rare but possible differential diagnosis in immunocompetent patients with fever, elevated liver enzymes and bloody stools.

Pulmonary cryptococcosis in rheumatoid arthritis (RA) patients: comparison of imaging characteristics among RA, acquired immunodeficiency syndrome, and immunocompetent patients.

PubMed

Yanagawa, Noriyo; Sakai, Fumikazu; Takemura, Tamiko; Ishikawa, Satoru; Takaki, Yasunobu; Hishima, Tsunekazu; Kamata, Noriko

2013-11-01

The imaging characteristics of cryptococcosis in rheumatoid arthritis (RA) patients were analyzed by comparing them with those of acquired immunodeficiency syndrome (AIDS) and immunocompetent patients, and the imaging findings were correlated with pathological findings. Two radiologists retrospectively compared the computed tomographic (CT) findings of 35 episodes of pulmonary cryptococcosis in 31 patients with 3 kinds of underlying states (10 RA, 12 AIDS, 13 immunocompetent), focusing on the nature, number, and distribution of lesions. The pathological findings of 18 patients (8 RA, 2 AIDS, 8 immunocompetent) were analyzed by two pathologists, and then correlated with imaging findings. The frequencies of consolidation and ground glass attenuation (GGA) were significantly higher, and the frequency of peripheral distribution was significantly lower in the RA group than in the immunocompetent group. Peripheral distribution was less common and generalized distribution was more frequent in the RA group than in the AIDS group. The pathological findings of the AIDS and immunocompetent groups reflected their immune status: There was lack of a granuloma reaction in the AIDS group, and a complete granuloma reaction in the immunocompetent group, while the findings of the RA group varied, including a complete granuloma reaction, a loose granuloma reaction and a hyper-immune reaction. Cases with the last two pathologic findings were symptomatic and showed generalized or central distribution on CT. Cryptococcosis in the RA group showed characteristic radiological and pathological findings compared with the other 2 groups. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Neonatal blockade of GABA-A receptors alters behavioral and physiological phenotypes in adult mice.

PubMed

Salari, Ali-Akbar; Amani, Mohammad

2017-04-01

Gamma-aminobutyric acid (GABA) plays an inhibitory role in the mature brain, and has a complex and bidirectional effect in different parts of the immature brain which affects proliferation, migration and differentiation of neurons during development. There is also increasing evidence suggesting that activation or blockade of the GABA-A receptors during early life can induce brain and behavioral abnormalities in adulthood. We investigated whether neonatal blockade of the GABA-A receptors by bicuculline can alter anxiety- and depression-like behaviors, body weight, food intake, corticosterone and testosterone levels in adult mice (postnatal days 80-95). To this end, neonatal mice were treated with either DMSO or bicuculline (70, 150 and 300μg/kg) during postnatal days 7, 9 and 11. When grown to adulthood, mice were exposed to behavioral tests to measure anxiety- (elevated plus-maze and light-dark box) and depression-like behaviors (tail suspension test and forced swim test). Stress-induced serum corticosterone and testosterone levels, body weight and food intake were also evaluated. Neonatal bicuculline exposure at dose of 300μg/kg decreased anxiety-like behavior, stress-induced corticosterone levels and increased testosterone levels, body weight and food intake, without significantly influencing depression-like behavior in adult male mice. However, no significant changes in these parameters were observed in adult females. These findings suggest that neonatal blockade of GABA-A receptors affects anxiety-like behavior, physiological and hormonal parameters in a sex-dependent manner in mice. Taken together, these data corroborate the concept that GABA-A receptors during early life have an important role in programming neurobehavioral phenotypes in adulthood. Copyright © 2017 ISDN. Published by Elsevier Ltd. All rights reserved.

Ablation of huntingtin in adult neurons is nondeleterious but its depletion in young mice causes acute pancreatitis

PubMed Central

Wang, Guohao; Liu, Xudong; Gaertig, Marta A.; Li, Shihua; Li, Xiao-Jiang

2016-01-01

The Huntington’s disease (HD) protein, huntingtin (HTT), is essential for early development. Because suppressing the expression of mutant HTT is an important approach to treat the disease, we must first understand the normal function of Htt in adults versus younger animals. Using inducible Htt knockout mice, we found that Htt depletion does not lead to adult neurodegeneration or animal death at >4 mo of age, which was also verified by selectively depleting Htt in neurons. On the other hand, young Htt KO mice die at 2 mo of age of acute pancreatitis due to the degeneration of pancreatic acinar cells. Importantly, Htt interacts with the trypsin inhibitor, serine protease inhibitor Kazal-type 3 (Spink3), to inhibit activation of digestive enzymes in acinar cells in young mice, and transgenic HTT can rescue the early death of Htt KO mice. These findings point out age- and cell type-dependent vital functions of Htt and the safety of knocking down neuronal Htt expression in adult brains as a treatment. PMID:26951659

Selenium Status Alters the Immune Response and Expulsion of Adult Heligmosomoides bakeri Worms in Mice

PubMed Central

Cheung, Lumei; Beshah, Ethiopia; Shea-Donohue, Terez; Urban, Joseph F.

2013-01-01

Heligmosomoides bakeri is a nematode with parasitic development exclusively in the small intestine of infected mice that induces a potent STAT6-dependent Th2 immune response. We previously demonstrated that host protective expulsion of adult H. bakeri worms from a challenge infection was delayed in selenium (Se)-deficient mice. In order to explore mechanisms associated with the delayed expulsion, 3-week-old female BALB/c mice were placed on a torula yeast-based diet with or without 0.2 ppm Se, and after 5 weeks, they were inoculated with H. bakeri infective third-stage larvae (L3s). Two weeks after inoculation, the mice were treated with an anthelmintic and then rested, reinoculated with L3s, and evaluated at various times after reinoculation. Analysis of gene expression in parasite-induced cysts and surrounding tissue isolated from the intestine of infected mice showed that the local-tissue Th2 response was decreased in Se-deficient mice compared to that in Se-adequate mice. In addition, adult worms recovered from Se-deficient mice had higher ATP levels than worms from Se-adequate mice, indicating greater metabolic activity in the face of a suboptimal Se-dependent local immune response. Notably, the process of worm expulsion was restored within 2 to 4 days after feeding a Se-adequate diet to Se-deficient mice. Expulsion was associated with an increased local expression of Th2-associated genes in the small intestine, intestinal glutathione peroxidase activity, secreted Relm-β protein, anti-H. bakeri IgG1 production, and reduced worm fecundity and ATP-dependent metabolic activity. PMID:23649095

Prenatal and lactational exposure to low-doses of bisphenol A alters adult mice behavior.

PubMed

Nakamura, Keiko; Itoh, Kyoko; Dai, Hongmei; Han, Longzhe; Wang, Xiaohang; Kato, Shingo; Sugimoto, Tohru; Fushiki, Shinji

2012-01-01

Bisphenol A (BPA) is an endocrine-disrupting chemical, widely used in dentistry and various industries. We previously reported that BPA affected murine neocortical development by accelerating neuronal differentiation/migration, resulting in abnormal neocortical architecture as well as aberrant thalamocortical connections in the brains of adult mice. The aim of this study was to investigate whether prenatal and lactational BPA exposure affected behavior in adult mice. Pregnant mice were injected subcutaneously with 20μg/kg of BPA daily from embryonic day 0 (E0) until postnatal day 21 (P21). Control animals received a vehicle alone. Behavioral tests (n=15-20) were conducted at postnatal 3weeks (P3W) and P10-15W. After an open-field test, an elevated plus maze and Morris water maze tests were performed. The total distance in the elevated plus maze test at P3W and in the open-field test at P10W was significantly decreased in the BPA-exposed group, compared with the control group. Significant sex differences were observed in the time spent in the central area in the open-field test at P3W and in the total distance in the elevated plus maze test at P11W. These results indicated that prenatal and lactational BPA exposure disturbed the murine behavior in the postnatal development period and the adult mice. Copyright © 2011 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

Case report of Aspergillus osteomyelitis of the ribs in an immunocompetent patient.

PubMed

D'sa, Shilpa Reynal; Singh, Suvir; Satyendra, Sowmya; Mathews, Prasad

2013-07-01

Aspergillus is a saprophytic fungus which is universally found in the environment. Most people breathe in the spores of Aspergillus every day without development of disease. It commonly affects immunocompromised hosts. There are only few reported cases in an immunocompetent host. It most commonly affects the respiratory system, causing superficial or invasive disease. It also affects the skin, brain and eye in severely immunocompromised patients. Aspergillosis of the bone is extremely rare. Amongst all the reported cases of invasive aspergillosis the incidence of osteomyelitis is less than three percent. In these cases commonly of the spine is reported. We present a case of Aspergillus osteomyelitis of the ribs in an immunocompetent host.

Case Report of Aspergillus Osteomyelitis of the Ribs in an Immunocompetent Patient

PubMed Central

D’sa, Shilpa Reynal; Singh, Suvir; Satyendra, Sowmya; Mathews, Prasad

2013-01-01

Aspergillus is a saprophytic fungus which is universally found in the environment. Most people breathe in the spores of Aspergillus every day without development of disease. It commonly affects immunocompromised hosts. There are only few reported cases in an immunocompetent host. It most commonly affects the respiratory system, causing superficial or invasive disease. It also affects the skin, brain and eye in severely immunocompromised patients. Aspergillosis of the bone is extremely rare. Amongst all the reported cases of invasive aspergillosis the incidence of osteomyelitis is less than three percent. In these cases commonly of the spine is reported. We present a case of Aspergillus osteomyelitis of the ribs in an immunocompetent host. PMID:24049367

Abnormal motor phenotype at adult stages in mice lacking type 2 deiodinase.

PubMed

Bárez-López, Soledad; Bosch-García, Daniel; Gómez-Andrés, David; Pulido-Valdeolivas, Irene; Montero-Pedrazuela, Ana; Obregon, Maria Jesus; Guadaño-Ferraz, Ana

2014-01-01

Thyroid hormones have a key role in both the developing and adult central nervous system and skeletal muscle. The thyroid gland produces mainly thyroxine (T4) but the intracellular concentrations of 3,5,3'-triiodothyronine (T3; the transcriptionally active hormone) in the central nervous system and skeletal muscle are modulated by the activity of type 2 deiodinase (D2). To date no neurological syndrome has been associated with mutations in the DIO2 gene and previous studies in young and juvenile D2-knockout mice (D2KO) did not find gross neurological alterations, possibly due to compensatory mechanisms. This study aims to analyze the motor phenotype of 3-and-6-month-old D2KO mice to evaluate the role of D2 on the motor system at adult stages in which compensatory mechanisms could have failed. Motor abilities were explored by validated tests. In the footprint test, D2KO showed an altered global gait pattern (mice walked slower, with shorter strides and with a hindlimb wider base of support than wild-type mice). No differences were detected in the balance beam test. However, a reduced latency to fall was found in the rotarod, coat-hanger and four limb hanging wire tests indicating impairment on coordination and prehensile reflex and a reduction of muscle strength. In histological analyses of cerebellum and skeletal muscle, D2KO mice did not present gross structural abnormalities. Thyroid hormones levels and deiodinases activities were also determined. In D2KO mice, despite euthyroid T3 and high T4 plasma levels, T3 levels were significantly reduced in cerebral cortex (48% reduction) and skeletal muscle (33% reduction), but not in the cerebellum where other deiodinase (type 1) is expressed. The motor alterations observed in D2KO mice indicate an important role for D2 in T3 availability to maintain motor function and muscle strength. Our results suggest a possible implication of D2 in motor disorders.

Abnormal Motor Phenotype at Adult Stages in Mice Lacking Type 2 Deiodinase

PubMed Central

Gómez-Andrés, David; Pulido-Valdeolivas, Irene; Montero-Pedrazuela, Ana; Obregon, Maria Jesus; Guadaño-Ferraz, Ana

2014-01-01

Background Thyroid hormones have a key role in both the developing and adult central nervous system and skeletal muscle. The thyroid gland produces mainly thyroxine (T4) but the intracellular concentrations of 3,5,3′-triiodothyronine (T3; the transcriptionally active hormone) in the central nervous system and skeletal muscle are modulated by the activity of type 2 deiodinase (D2). To date no neurological syndrome has been associated with mutations in the DIO2 gene and previous studies in young and juvenile D2-knockout mice (D2KO) did not find gross neurological alterations, possibly due to compensatory mechanisms. Aim This study aims to analyze the motor phenotype of 3-and-6-month-old D2KO mice to evaluate the role of D2 on the motor system at adult stages in which compensatory mechanisms could have failed. Results Motor abilities were explored by validated tests. In the footprint test, D2KO showed an altered global gait pattern (mice walked slower, with shorter strides and with a hindlimb wider base of support than wild-type mice). No differences were detected in the balance beam test. However, a reduced latency to fall was found in the rotarod, coat-hanger and four limb hanging wire tests indicating impairment on coordination and prehensile reflex and a reduction of muscle strength. In histological analyses of cerebellum and skeletal muscle, D2KO mice did not present gross structural abnormalities. Thyroid hormones levels and deiodinases activities were also determined. In D2KO mice, despite euthyroid T3 and high T4 plasma levels, T3 levels were significantly reduced in cerebral cortex (48% reduction) and skeletal muscle (33% reduction), but not in the cerebellum where other deiodinase (type 1) is expressed. Conclusions The motor alterations observed in D2KO mice indicate an important role for D2 in T3 availability to maintain motor function and muscle strength. Our results suggest a possible implication of D2 in motor disorders. PMID:25083788

Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection.

PubMed

Ribes, Sandra; Meister, Tanja; Ott, Martina; Redlich, Sandra; Janova, Hana; Hanisch, Uwe-Karsten; Nessler, Stefan; Nau, Roland

2014-01-23

Prophylaxis with unmethylated cytosine phosphate guanidine (CpG) oligodeoxynucleotides (ODN) protects against several systemic experimental infections. Escherichia coli is a major cause of Gram-negative neonatal bacterial meningitis and also causes meningitis and meningoencephalitis in older and immunocompromised patients. Wild-type (wt) and Toll-like receptor 9 (TLR9)-deficient mice were rendered neutropenic by intraperitoneal administration of the anti-Ly-6G monoclonal antibody. Immunocompetent and neutropenic mice received intraperitoneal CpG ODN or vehicle 72 h prior to induction of E. coli K1 meningoencephalitis. Pre-treatment with CpG ODN significantly increased survival of neutropenic wt mice from 33% to 75% (P = 0.0003) but did not protect neutropenic TLR9-/- mice. The protective effect of CpG ODN was associated with an enhanced production of interleukin (IL)-12/IL-23p40 with sustained increased levels in serum and spleen at least for 17 days after conditioning compared to buffer-treated animals. CpG-treated neutropenic wt mice showed reduced bacterial concentrations and increased recruitment of Ly6ChighCCR2+ monocytes in brain and spleen 42 h after infection. The levels of macrophage inflammatory protein 1α (MIP-1α) and interferon gamma (IFN-γ) in spleen were higher 42 h after infection in CpG-treated compared to buffer-treated neutropenic animals. In immunocompetent mice, prophylaxis with CpG ODN did not significantly increase survival compared to the buffer group (60% vs. 45%, P = 0.2). These findings suggest that systemic administration of CpG ODN may help to prevent bacterial CNS infections in immunocompromised individuals.

Growth restriction, leptin, and the programming of adult behavior in mice.

PubMed

Meyer, Lauritz R; Zhu, Vivian; Miller, Alise; Roghair, Robert D

2014-12-15

Prematurity and neonatal growth restriction (GR) are risk factors for autism and attention deficit hyperactivity disorder (ADHD). Leptin production is suppressed during periods of undernutrition, and we have shown that isolated neonatal leptin deficiency leads to adult hyperactivity while neonatal leptin supplementation normalizes the brain morphology of GR mice. We hypothesized that neonatal leptin would prevent the development of GR-associated behavioral abnormalities. From postnatal day 4-14, C57BL/6 mice were randomized to daily injections of saline or leptin (80ng/g), and GR was identified by a weanling weight below the tenth percentile. The behavioral phenotypes of GR and control mice were assessed beginning at 4 months. Within the tripartite chamber, GR mice had significantly impaired social interaction. Baseline escape times from the Barnes maze were faster for GR mice (65+/-6s vs 87+/-7s for controls, p<0.05), but GR mice exhibited regression in their escape times on days 2 and 3 (56% regressed vs 22% of control saline mice, p<0.05). Compared to controls, GR mice entered the open arms of the elevated plus maze more often and stayed there longer (72+/-10s vs 36+/-5s, p<0.01). Neonatal leptin supplementation normalized the behavior of GR mice across all behavioral assays. In conclusion, GR alters the social interactions, learning and activity of mice, and supplementation with the neurotrophic hormone leptin mitigates these effects. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with postnatal growth restriction, and postnatal leptin therapy may be protective. Copyright © 2014 Elsevier B.V. All rights reserved.

Acute exposure to diesel exhaust impairs adult neurogenesis in mice: prominence in males and protective effect of pioglitazone.

PubMed

Coburn, Jacki L; Cole, Toby B; Dao, Khoi T; Costa, Lucio G

2018-05-01

Adult neurogenesis is the process by which neural stem cells give rise to new functional neurons in specific regions of the adult brain, a process that occurs throughout life. Significantly, neurodegenerative and psychiatric disorders present suppressed neurogenesis, activated microglia, and neuroinflammation. Traffic-related air pollution has been shown to adversely affect the central nervous system. As the cardinal effects of air pollution exposure are microglial activation, and ensuing oxidative stress and neuroinflammation, we investigated whether acute exposures to diesel exhaust (DE) would inhibit adult neurogenesis in mice. Mice were exposed for 6 h to DE at a PM 2.5 concentration of 250-300 μg/m 3 , followed by assessment of adult neurogenesis in the hippocampal subgranular zone (SGZ), the subventricular zone (SVZ), and olfactory bulb (OB). DE impaired cellular proliferation in the SGZ and SVZ in males, but not females. DE reduced adult neurogenesis, with male mice showing fewer new neurons in the SGZ, SVZ, and OB, and females showing fewer new neurons only in the OB. To assess whether blocking microglial activation protected against DE-induced suppression of adult hippocampal neurogenesis, male mice were pre-treated with pioglitazone (PGZ) prior to DE exposure. The effects of DE exposure on microglia, as well as neuroinflammation and oxidative stress, were reduced by PGZ. PGZ also antagonized DE-induced suppression of neurogenesis in the SGZ. These results suggest that DE exposure impairs adult neurogenesis in a sex-dependent manner, by a mechanism likely to involve microglia activation and neuroinflammation.

Identification of Malassezia species from immunocompetent and immunocompromised patients with seborrheic dermatitis.

PubMed

Prohic, A; Kasumagic-Halilovic, E

2010-12-01

Differences in prevalence, clinical and histological manifestations between seborrheic dermatitis (SD) in immunocompetent and immunocompromised patients suggest that these two populations might also differ in a spectrum of isolated Malassezia species. The purpose of our study was to analyse the prevalence of Malassezia species in immunocompromised and non-immunocompromised patients with SD and to examine if the range of isolated yeasts varies between these two study groups. Specimens were taken from 50 patients with SD: 30 without any underlying disease and 20 with confirmed immunosuppression. The samples were obtained by scraping the skin surface of the scalp and trunk lesions of all subjects and then incubated on modified Dixon agar. The yeasts isolated were identified by their morphological and physiological properties according to Guillot et al method. In both groups, the most commonly isolated species from the scalp lesions were Malassenzia restricta and Malassenzia globosa, the later being the most common species isolated from lesional trunk skin. No significant differences were found between immunocompromised and immunocompetent patients from both sampled sites. There is no difference in the distribution of Malassezia species isolated from SD lesions between immunocompetent and immunocompromised patients. However, the much higher percentage of positive cultures in immunocompromised patients confirms that impaired cellular immunity may facilitate fungal survival on the skin.

Individual differences in torpor expression in adult mice are related to relative birth weight.

PubMed

Kato, Goro A; Sakamoto, Shinsuke H; Eto, Takeshi; Okubo, Yoshinobu; Shinohara, Akio; Morita, Tetsuo; Koshimoto, Chihiro

2018-04-20

Daily torpor is a physiological adaptation in small mammals and birds, characterised by drastic reductions in metabolism and body temperature. Energy-constraining conditions, such as cold and starvation, are known to cause the expression of daily torpor. However, the reason for high degrees of inter- and intra- individual variation in torpor expression (TE) in similar situations is not clear. As littermates of altricial animals are exposed to an uneven allocation of maternal resources from conception to weaning, we tested whether early nutritional experiences have long-term effects on TE in adults. We used full-sibling littermates of laboratory mice that as adults were starved overnight to induce torpor. We measured body weight from birth until adulthood as an indicator of nutritional status, and calculated the relative body weight (RBW) as an indicator of the difference in nutritional status within a litter. After maturation, we subjected mice to five repeated torpor induction trials involving 24 hours of fasting and 5 days of recovery. Half of the female mice displayed great individual variation in TE, whereas male mice rarely exhibited daily torpor. In females, RBW at birth influenced TE, irrespective of body weight in adulthood; thus, female mice born with low RBWs displayed high TE in adulthood. In conclusion, we provide evidence that TE in mice differs among littermates, and that this variation is linked closely to heterogeneous nutritional experiences during the foetal period. © 2018. Published by The Company of Biologists Ltd.

The combination of i-leader truncation and gemcitabine improves oncolytic adenovirus efficacy in an immunocompetent model.

PubMed

Puig-Saus, C; Laborda, E; Rodríguez-García, A; Cascalló, M; Moreno, R; Alemany, R

2014-02-01

Adenovirus (Ad) i-leader protein is a small protein of unknown function. The C-terminus truncation of the i-leader protein increases Ad release from infected cells and cytotoxicity. In the current study, we use the i-leader truncation to enhance the potency of an oncolytic Ad. In vitro, an i-leader truncated oncolytic Ad is released faster to the supernatant of infected cells, generates larger plaques, and is more cytotoxic in both human and Syrian hamster cell lines. In mice bearing human tumor xenografts, the i-leader truncation enhances oncolytic efficacy. However, in a Syrian hamster pancreatic tumor model, which is immunocompetent and less permissive to human Ad, antitumor efficacy is only observed when the i-leader truncated oncolytic Ad, but not the non-truncated version, is combined with gemcitabine. This synergistic effect observed in the Syrian hamster model was not seen in vitro or in immunodeficient mice bearing the same pancreatic hamster tumors, suggesting a role of the immune system in this synergism. These results highlight the interest of the i-leader C-terminus truncation because it enhances the antitumor potency of an oncolytic Ad and provides synergistic effects with gemcitabine in the presence of an immune competent system.

Bordetella bronchoseptica pneumonia with shock in an immunocompetent patient.

PubMed

Tamion, F; Girault, C; Chevron, V; Pestel, M; Bonmarchand, G

1996-01-01

Bordetella bronchoseptica is a rarely reported cause of human infection, but is a common respiratory tract commensal of mammals. Human infection with B. bronchoseptica is almost always associated with severe underlying disease and contact with an appropriate animal reservoir. We report a case of pneumonia with shock caused by B. bronchoseptica in an immunocompetent patient.

Radiation Exposure Enhances Hepatocyte Proliferation in Neonatal Mice but not in Adult Mice.

PubMed

Shang, Yi; Sawa, Yurika; Blyth, Benjamin J; Tsuruoka, Chizuru; Nogawa, Hiroyuki; Shimada, Yoshiya; Kakinuma, Shizuko

2017-08-01

There is a natural tendency to expect that irradiation of an infant organ prior to development-related expansion will result in a higher risk of developing cancer than that of fully-developed adult tissue, and this has generally been observed. However, if tissues also vary in their initial responses to radiation depending on age, the interplay between tissue- and age-dependent risk would potentially be quite complex. We have previously shown opposing age-dependent induction of apoptosis for the intestinal epithelium and hematopoietic cells in mice, but such data are not yet available for the liver. Here, we have examined markers of DNA damage, initiation of DNA damage responses, cell cycle arrest, apoptosis and proliferation, as well as gene expression, in the B6C3F1 mouse liver over the hours and days after irradiation of mice at 1 or 7 weeks of age. We found that induction and resolution of radiation-induced DNA damage is not accompanied by significant changes in these cellular end points in the adult liver, while in infant hepatocytes modest induction of p53 accumulation and p21-mediated cell cycle arrest in a small fraction of damaged cells was overshadowed by a further stimulation of proliferation over the relatively high levels already found in the neonatal liver. We observed distinct expression of genes that regulate cell division between the ages, which may contribute to the differential responses. These data suggest that the growth factor signaling environment of the infant liver may mediate radiation-induced proliferation and increased liver cancer risk after irradiation during early life.

Cytomegalovirus colitis in immunocompetent critically ill patients.

PubMed

Siciliano, Rinaldo F; Castelli, Jussara B; Randi, Bruno A; Vieira, Ricardo D; Strabelli, Tânia M V

2014-03-01

Cytomegalovirus (CMV) is a ubiquitous virus and its reactivation may lead to CMV end-organ disease (CMV EOD) in immunocompromised patients and also in immunocompetent patients when they are critically ill. We aimed to investigate the frequency and the clinical features of proven CMV EOD in previously non-immunosuppressed patients admitted to our institution. From January 2000 to March 2013, the records of all patients with a histopathological diagnosis of CMV EOD at our teaching hospital were reviewed retrospectively. CMV EOD was diagnosed histologically by the identification of true cytomegalic viral inclusion involving endothelial, stromal, and/or epithelial cells on hematoxylin and eosin staining, and was subsequently confirmed by immunohistochemistry using specific antibody against CMV antigens. Immunocompromised patients were excluded. CMV EOD manifesting as colitis was diagnosed in 14 previously immunocompetent intensive care unit (ICU) patients. The mean age of the patients was 64 years. All had co-morbidities and developed shock before CMV EOD. The major manifestation was gastrointestinal bleeding. The in-hospital mortality rate was 71.4% despite specific treatment with ganciclovir. Despite being a rare condition, lower gastrointestinal bleeding in this profile of ICU patients could be the clinical manifestation of CMV colitis, and intensivists should be alert to this condition. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Dual-specific Chimeric Antigen Receptor T Cells and an Indirect Vaccine Eradicate a Variety of Large Solid Tumors in an Immunocompetent, Self-antigen Setting.

PubMed

Slaney, Clare Y; von Scheidt, Bianca; Davenport, Alexander J; Beavis, Paul A; Westwood, Jennifer A; Mardiana, Sherly; Tscharke, David C; Ellis, Sarah; Prince, H Miles; Trapani, Joseph A; Johnstone, Ricky W; Smyth, Mark J; Teng, Michele W; Ali, Aesha; Yu, Zhiya; Rosenberg, Steven A; Restifo, Nicholas P; Neeson, Paul; Darcy, Phillip K; Kershaw, Michael H

2017-05-15

Purpose: While adoptive transfer of T cells bearing a chimeric antigen receptor (CAR) can eliminate substantial burdens of some leukemias, the ultimate challenge remains the eradication of large solid tumors for most cancers. We aimed to develop an immunotherapy approach effective against large tumors in an immunocompetent, self-antigen preclinical mouse model. Experimental Design: In this study, we generated dual-specific T cells expressing both a CAR specific for Her2 and a TCR specific for the melanocyte protein (gp100). We used a regimen of adoptive cell transfer incorporating vaccination (ACTIV), with recombinant vaccinia virus expressing gp100, to treat a range of tumors including orthotopic breast tumors and large liver tumors. Results: ACTIV therapy induced durable complete remission of a variety of Her2 + tumors, some in excess of 150 mm 2 , in immunocompetent mice expressing Her2 in normal tissues, including the breast and brain. Vaccinia virus induced extensive proliferation of T cells, leading to massive infiltration of T cells into tumors. Durable tumor responses required the chemokine receptor CXCR3 and exogenous IL2, but were independent of IFNγ. Mice were resistant to tumor rechallenge, indicating immune memory involving epitope spreading. Evidence of limited neurologic toxicity was observed, associated with infiltration of cerebellum by T cells, but was only transient. Conclusions: This study supports a view that it is possible to design a highly effective combination immunotherapy for solid cancers, with acceptable transient toxicity, even when the target antigen is also expressed in vital tissues. Clin Cancer Res; 23(10); 2478-90. ©2016 AACR . ©2016 American Association for Cancer Research.

Scedosporium prolificans Osteomyelitis in an Immunocompetent Child Treated with Voriconazole and Caspofungin, as Well as Locally Applied Polyhexamethylene Biguanide

PubMed Central

Steinbach, William J.; Schell, Wiley A.; Miller, Jackie L.; Perfect, John R.

2003-01-01

Scedosporium species are increasingly isolated from immunocompromised and immunocompetent patients. Unfortunately, Scedosporium infections are generally resistant to amphotericin B, and Scedosporium prolificans strains are particularly resistant to the antifungal agents now in use. We report here on an immunocompetent child with S. prolificans-associated osteomyelitis successfully treated with debridement, local irrigation with polyhexamethylene biguanide, and the systemic administration of voriconazole and caspofungin despite poor in vitro activity of voriconazole alone against the isolate. We also review the treatments and outcomes of 28 reported cases of osteomyelitis or septic arthritis caused by Scedosporium species in immunocompetent patients. PMID:12904435

Disseminated folliculitis by Mycobacterium fortuitum in an immunocompetent woman*

PubMed Central

Macente, Sara; Helbel, Cesar; Souza, Simone Felizardo Rocha; Siqueira, Vera Lúcia Dias; Padua, Rubia Andreia Falleiros; Cardoso, Rosilene Fressatti

2013-01-01

Mycobacterium fortuitum is a non-tuberculous fast-growing mycobacterium which is frequently acquired from environmental sources such as soil and water. Since it is an opportunist pathogen, it is associated with trauma, surgery or immunodeficiency. The current report describes a case of Mycobacterium fortuitum-caused disseminated lesions on the skin of an immunocompetent patient. PMID:23539012

Acute social defeat stress increases the conditioned rewarding effects of cocaine in adult but not in adolescent mice.

PubMed

Montagud-Romero, S; Aguilar, M A; Maldonado, C; Manzanedo, C; Miñarro, J; Rodríguez-Arias, M

2015-08-01

Stressful experiences modify activity in areas of the brain involved in the rewarding effects of psychostimulants. In the present study we evaluated the influence of acute social defeat (ASD) on the conditioned rewarding effects of cocaine in adolescent (PND 29-32) and adult (PND 50-53) male mice in the conditioned place preference (CPP) paradigm. Experimental mice were exposed to social defeat in an agonistic encounter before each session of conditioning with 1mg/kg or 25mg/kg of cocaine. The effects of social defeat on corticosterone levels were also evaluated. Adult mice exposed to ASD showed an increase in the conditioned reinforcing effects of cocaine. Only these mice developed cocaine-induced CPP with the subthreshold dose of cocaine, and they needed a higher number of extinction sessions for the 25mg/kg cocaine-induced CPP to be extinguished. In adolescent mice, on the other hand, ASD reduced the conditioned reinforcing effects of cocaine, since CPP was not produced with the lower dose of cocaine and was extinguished faster when they were conditioned with 25mg/kg. Adult mice exposed to social defeat displayed higher levels of corticosterone than their controls and adolescent mice. Our results confirm that the effect of social defeat stress on the acquisition and reinstatement of the CPP induced by cocaine varies depending on the age at which this stress is experienced. Copyright © 2015 Elsevier Inc. All rights reserved.

Engraftment potential of dermal fibroblasts following in vivo myogenic conversion in immunocompetent dystrophic skeletal muscle

PubMed Central

Muir, Lindsey A; Nguyen, Quynh G; Hauschka, Stephen D; Chamberlain, Jeffrey S

2014-01-01

Autologous dermal fibroblasts (dFbs) are promising candidates for enhancing muscle regeneration in Duchenne muscular dystrophy (DMD) due to their ease of isolation, immunological compatibility, and greater proliferative potential than DMD satellite cells. We previously showed that mouse fibroblasts, after MyoD-mediated myogenic reprogramming in vivo, engraft in skeletal muscle and supply dystrophin. Assessing the therapeutic utility of this system requires optimization of conversion and transplantation conditions and quantitation of engraftment so that these parameters can be correlated with possible functional improvements. Here, we derived dFbs from transgenic mice carrying mini-dystrophin, transduced them by lentivirus carrying tamoxifen-inducible MyoD, and characterized their myogenic and engraftment potential. After cell transplantation into the muscles of immunocompetent dystrophic mdx4cv mice, tamoxifen treatment drove myogenic conversion and fusion into myofibers that expressed high levels of mini-dystrophin. Injecting 50,000 cells/µl (1 × 106 total cells) resulted in a peak of ~600 mini-dystrophin positive myofibers in tibialis anterior muscle single cross-sections. However, extensor digitorum longus muscles with up to 30% regional engraftment showed no functional improvements; similar limitations were obtained with whole muscle mononuclear cells. Despite the current lack of physiological improvement, this study suggests a viable initial strategy for using a patient-accessible dermal cell population to enhance skeletal muscle regeneration in DMD. PMID:25558461

Nestling immunocompetence and testosterone covary with brood size in a songbird.

PubMed Central

Naguib, Marc; Riebel, Katharina; Marzal, Alfonso; Gil, Diego

2004-01-01

The social and ecological conditions that individuals experience during early development have marked effects on their developmental trajectory. In songbirds, brood size is a key environmental factor affecting development, and experimental increases in brood size have been shown to have negative effects on growth, condition and fitness. Possible causes of decreased growth in chicks from enlarged broods are nutritional stress, crowding and increased social competition, i.e. environmental factors known to affect adult steroid levels (especially of testosterone and corticosteroids) in mammals and birds. Little, however, is known about environmental effects on steroid synthesis in nestlings. We addressed this question by following the development of zebra finch (Taeniopygia guttata) chicks that were cross-fostered and raised in different brood sizes. In line with previous findings, nestling growth and cell-mediated immunocompetence were negatively affected by brood size. Moreover, nestling testosterone levels covaried with treatment: plasma testosterone increased with experimental brood size. This result provides experimental evidence that levels of circulating testosterone in nestlings can be influenced by their physiological response to environmental conditions. PMID:15255102

Ectoparasite Burden, Clinical Disease, and Immune Responses throughout Fur Mite (Myocoptes musculinus) Infestation in C57BL/6 and Rag1–/– Mice

PubMed Central

Moats, Cassandra R; Baxter, Victoria K; Pate, Nathan M; Watson, Julie

2016-01-01

Immunocompetent weanling mice infested with Myocoptes musculinus harbor high mite loads, yet burdens decrease with age. The development of immunity to the parasite may explain this observation. In this study, we followed M. musculinus burdens in Rag1−/− mice and immunocompetent C57BL/6 controls from 4 to 36 wk of age and compared the clinical signs and body weights of noninfested and infested mice of both strains over time. In addition, histopathology of skin lesions and expression of cytokines and transcription factors associated with Th1- and Th2-type immune responses were assessed. Myocoptes burdens decreased and remained low in B6 mice over time, whereas Rag1−/− mice showed an initial decrease in burdens after 4 wk of age followed by an increase from 24 to 36 wk. In addition, Rag1−/− mice had higher burdens than B6 mice over time. Both strains of infested mice exhibited clinical signs of fur mite infestation—including alopecia, poor weight gain, mite-associated debris, and pruritus—and clinical signs positively correlated with the severity of the Myocoptes burden. Histopathology of skin from both strains of infested mice showed decreased lesion severity with age, likely a result of declining mite populations. Finally, compared with noninfested controls, infested B6 mice had increased expression of markers associated with the Th2-type immune response, which increased in magnitude with increasing age and duration of infestation. These results suggest that development of adaptive immunity plays a role in control of fur mite populations and that heavier infestations may result in more severe clinical signs and skin lesions. PMID:27298244

Pulmonary immune responses to Aspergillus fumigatus in an immunocompetent mouse model of repeated exposures

PubMed Central

Buskirk, Amanda D.; Templeton, Steven P.; Nayak, Ajay P.; Hettick, Justin M.; Law, Brandon F.; Green, Brett J.; Beezhold, Donald H.

2015-01-01

Aspergillus fumigatus is a filamentous fungus that produces abundant pigmented conidia. Several fungal components have been identified as virulence factors, including melanin; however, the impact of these factors in a repeated exposure model resembling natural environmental exposures remains unknown. This study examined the role of fungal melanin in the stimulation of pulmonary immune responses using immunocompetent BALB/c mice in a multiple exposure model. It compared conidia from wild-type A. fumigatus to two melanin mutants of the same strain, Δarp2 (tan) or Δalb1 (white). Mass spectrometry-based analysis of conidial extracts demonstrated that there was little difference in the protein fingerprint profiles between the three strains. Field emission scanning electron microscopy demonstrated that the immunologically inert Rodlet A layer remained intact in melanin-deficient conidia. Thus, the primary difference between the strains was the extent of melanization. Histopathology indicated that each A. fumigatus strain induced lung inflammation, regardless of the extent of melanization. In mice exposed to Δalb1 conidia, an increase in airway eosinophils and a decrease in neutrophils and CD8+ IL-17+ (Tc17) cells were observed. Additionally, it was shown that melanin mutant conidia were more rapidly cleared from the lungs than wild-type conidia. These data suggest that the presence of fungal melanin may modulate the pulmonary immune response in a mouse model of repeated exposures to A. fumigatus conidia. PMID:23919459

Adult Behavior in Male Mice Exposed to E-Cigarette Nicotine Vapors during Late Prenatal and Early Postnatal Life

PubMed Central

Smith, Dani; Aherrera, Angela; Lopez, Armando; Neptune, Enid; Winickoff, Jonathan P.; Klein, Jonathan D.; Chen, Gang; Lazarus, Philip; Collaco, Joseph M.; McGrath-Morrow, Sharon A.

2015-01-01

Nicotine exposure has been associated with an increased likelihood of developing attention deficit hyperactivity disorder (ADHD) in offspring of mothers who smoked during pregnancy. The goal of this study was to determine if exposure to E-cigarette nicotine vapors during late prenatal and early postnatal life altered behavior in adult mice. Methods Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG) or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains. Results Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not. Conclusion Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth. PMID:26372012

Molecular mechanisms mediating a deficit in recall of fear extinction in adult mice exposed to cocaine in utero.

PubMed

Kabir, Zeeba D; Katzman, Aaron C; Kosofsky, Barry E

2013-01-01

Prenatal cocaine exposure has been shown to alter cognitive processes of exposed individuals, presumed to be a result of long-lasting molecular alterations in the brain. In adult prenatal cocaine exposed (PCOC) mice we have identified a deficit in recall of fear extinction, a behavior that is dependent on the medial prefrontal cortex (mPFC) and the hippocampus. While we observed no change in the constitutive expression of brain derived neurotrophic factor (BDNF) protein and mRNA in the mPFC and hippocampus of adult PCOC mice, we observed blunted BDNF signaling in the mPFC of adult PCOC mice after fear extinction compared to the control animals. Specifically, during the consolidation phase of the extinction memory, we observed a decrease in BDNF protein and it's phospho-TrkB receptor expression. Interestingly, at this same time point there was a significant increase in total Bdnf mRNA levels in the mPFC of PCOC mice as compared with controls. In the Bdnf gene, we identified decreased constitutive binding of the transcription factors, MeCP2 and P-CREB at the promoters of Bdnf exons I and IV in the mPFC of PCOC mice, that unlike control mice remained unchanged when measured during the behavior. Finally, bilateral infusion of recombinant BDNF protein into the infralimbic subdivision of the mPFC during the consolidation phase of the extinction memory rescued the behavioral deficit in PCOC mice. In conclusion, these findings extend our knowledge of the neurobiologic impact of prenatal cocaine exposure on the mPFC of mice, which may lead to improved clinical recognition and treatment of exposed individuals.

Exposure to neonatal cigarette smoke causes durable lung changes but does not potentiate cigarette smoke–induced chronic obstructive pulmonary disease in adult mice

PubMed Central

McGrath-Morrow, Sharon; Malhotra, Deepti; Lauer, Thomas; Collaco, J. Michael; Mitzner, Wayne; Neptune, Enid; Wise, Robert; Biswal, Shyam

2016-01-01

The impact of early childhood cigarette smoke (CS) exposure on CS-induced chronic obstructive pulmonary disease (COPD) is unknown. This study was performed to evaluate the individual and combined effects of neonatal and adult CS exposure on lung structure, function, and gene expression in adult mice. To model a childhood CS exposure, neonatal C57/B6 mice were exposed to 14 days of CS (Neo CS). At 10 weeks of age, Neo CS and control mice were exposed to 4 months of CS. Pulmonary function tests, bronchoalveolar lavage, and lung morphometry were measured and gene expression profiling was performed on lung tissue. Mean chord lengths and lung volumes were increased in neonatal and/or adult CS-exposed mice. Differences in immune, cornified envelope protein, muscle, and erythrocyte genes were found in CS-exposed lung. Neonatal CS exposure caused durable structural and functional changes in the adult lung but did not potentiate CS-induced COPD changes. Cornified envelope protein gene expression was decreased in all CS-exposed mice, whereas myosin and erythrocyte gene expression was increased in mice exposed to both neonatal and adult CS, suggesting an adaptive response. Additional studies may be warranted to determine the utility of these genes as biomarkers of respiratory outcomes. PMID:21649527

A case of infective endocarditis along with a ruptured valve caused by Streptococcus agalactiae in an immunocompetent man.

PubMed

Suzuki, Kiyozumi; Hirai, Yuji; Morita, Fujiko; Uehara, Yuki; Oshima, Hiroko; Mitsuhashi, Kazunori; Amano, Atsushi; Naito, Toshio

2016-01-01

Streptococcus agalactiae ( S. agalactiae ) is a major cause of invasive disease in neonates and pregnant women, but has also recently been observed among non-pregnant adults, especially elderly persons or persons with underlying chronic disease. S. agalactiae is also a rare cause of infective endocarditis, and most cases require early surgery. We report the case of a 43-year-old previously healthy man who experienced rapid progressive culture-negative infective endocarditis with aortic valve vegetation and severe aortic regurgitation, which was complicated by lumbar spondylodiscitis. Emergency aortic valve replacement was performed on the day of his admission, which revealed a congenital bicuspid aortic valve was ruptured by the vegetation. The resected aortic valve specimen was submitted for 16S ribosomal RNA gene sequencing, which revealed that the pathogen was S. agalactiae . Therefore, S. agalactiae should be considered a potentially causative pathogen in cases of rapid progressive infective endocarditis, even if it occurs in a non-pregnant immunocompetent adult.

Prenatal ethanol weakens the efficacy of reinforcers for adult mice.

PubMed

Gentry, G D; Middaugh, L D

1988-02-01

Pregnant C57BL/6cr mice were fed a liquid diet containing 20% of the total calories from either ethanol (E) or sucrose (S) for gestation days 5-17. Adult male and female (six of each from both prenatal-treatment groups) offspring were tested under various schedules of food reinforcement. The first phase was a test of fixed-ratio (FR) acquisition in which the required number of responses per unit of reinforcement was increased from 1 to 20 to 100. Prenatal ethanol exposure interacted with other factors to produce an acquisition deficit. The second phase involved responding under extinction (Ext). Under standard Ext procedures there were no prenatal-ethanol effects; however, when a conditioned reinforcer was superimposed on an FR 5, the E males did not increase their rates as much as the S males. Finally, under a multiple FR 5 DRO 15-sec (differential-reinforcement-of-other-behavior) arrangement, prenatal-ethanol effects were found in each component. For the FR 5 component, prenatal ethanol eliminated the sex differences found in the S subjects. For the DRO 15-sec component, prenatal ethanol elevated response rates. The results indicate a general decreased efficacy of positive reinforcement in adult mice following prenatal ethanol exposure.

Aspergillus vertebral osteomyelitis in immunocompetent patients.

PubMed

Sethi, Somika; Siraj, Fouzia; Kalra, Kl; Chopra, P

2012-03-01

Fungal infections are one of the important cause of morbidity and mortality in immunocompromised patients. Aspergillus vertebral osteomyelitis is extremely rare. We report two cases of aspergillus vertebral osteomyelitis in immunocompetent men in the absence of an underlying disorder. The clinical and radiological findings were suggestive of Pott's spine. The absolute CD4, CD8 counts and their ratio were normal. The HIV status was negative in both patients. Both patients underwent surgical decompression. The histopathology of tissue obtained were suggestive of aspergillus osteomyelitis. One patient had antifungal treatment for 3 months and was doing well at 1 year followup, whereas other patient did not turnup after 2 months.

Aspergillus vertebral osteomyelitis in immunocompetent patients

PubMed Central

Sethi, Somika; Siraj, Fouzia; Kalra, KL; Chopra, P

2012-01-01

Fungal infections are one of the important cause of morbidity and mortality in immunocompromised patients. Aspergillus vertebral osteomyelitis is extremely rare. We report two cases of aspergillus vertebral osteomyelitis in immunocompetent men in the absence of an underlying disorder. The clinical and radiological findings were suggestive of Pott's spine. The absolute CD4, CD8 counts and their ratio were normal. The HIV status was negative in both patients. Both patients underwent surgical decompression. The histopathology of tissue obtained were suggestive of aspergillus osteomyelitis. One patient had antifungal treatment for 3 months and was doing well at 1 year followup, whereas other patient did not turnup after 2 months. PMID:22448068

Aspergillus spondylodiscitis in an immunocompetent paraplegic patient.

PubMed

Schubert, M; Schär, G; Curt, A; Dietz, V

1998-11-01

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.

Effects of ethanol on immune response in the brain: region-specific changes in adolescent versus adult mice.

PubMed

Kane, Cynthia J M; Phelan, Kevin D; Douglas, James C; Wagoner, Gail; Johnson, Jennifer W; Xu, Jihong; Phelan, Patrick S; Drew, Paul D

2014-02-01

Alcohol use occurs across the life span beginning in adolescence and continuing through adulthood. Ethanol (EtOH)-induced pathology varies with age and includes changes in neurogenesis, neurodegeneration, and glial cell activation. EtOH-induced changes in glial activation and immune activity are believed to contribute to EtOH-induced neuropathology. Recent studies indicate an emerging role of glial-derived neuroimmune molecules in alcohol abuse and addiction. Adolescent and adult C57BL/6 mice were treated via gavage with 6 g/kg EtOH for 10 days, and tissue was harvested 1 day post treatment. We compared the effects of EtOH on chemokine and cytokine expression and astrocyte glial fibrillary acidic protein (GFAP) immunostaining and morphology in the hippocampus, cerebellum, and cerebral cortex. EtOH increased mRNA levels of the chemokine CCL2/MCP-1 in all 3 regions of adult mice relative to controls. The cytokine interleukin-6 (IL-6) was selectively increased only in the adult cerebellum. EtOH did not affect mRNA levels of the cytokine tumor necrosis factor-alpha (TNF-α) in any of these brain regions in adult animals. Interestingly, CCL2, IL-6, and TNF-α mRNA levels were not increased in the hippocampus, cerebellum, or cortex of adolescent mice. EtOH treatment of adult and adolescent mice resulted in increased GFAP immunostaining. Collectively, these data indicate an age- and region-specific susceptibility to EtOH regulation of neuroinflammatory and addiction-related molecules as well as astrocyte phenotype. These studies may have important implications concerning differential alcohol-induced neuropathology and alcohol addiction across the life span. Copyright © 2013 by the Research Society on Alcoholism.

Early postnatal motor experience shapes the motor properties of C57BL/6J adult mice.

PubMed

Serradj, Nadjet; Picquet, Florence; Jamon, Marc

2013-11-01

This study aimed to evaluate the long-term consequences of early motor training on the muscle phenotype and motor output of middle-aged C57BL/6J mice. Neonatal mice were subjected to a variety of motor training procedures, for 3 weeks during the period of acquisition of locomotion. These procedures are widely used for motor training in adults; they include enriched environment, forced treadmill, chronic centrifugation, and hindlimb suspension. At 9 months, the mice reared in the enriched environment showed a slower type of fibre in slow muscles and a faster type in fast muscles, improved performance in motor tests, and a modified gait and body posture while walking. The proportion of fibres in the postural muscles of centrifuged mice did not change, but these mice showed improved resistance to fatigue. The suspended mice showed increased persistence of immature hybrid fibres in the tibialis, with a slower shift in the load-bearing soleus, without any behavioural changes. The forced treadmill was very stressful for the mice, but had limited effects on motor output, although a slower profile was observed in the tibialis. These results support the hypothesis that motor experience during a critical period of motor development shapes muscle phenotype and motor output. The different impacts of the various training procedures suggest that motor performance in adults can be optimized by appropriate training during a defined period of motor development. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Herpes zoster duplex bilateralis in an immunocompetent adolescent boy: a case report and literature review.

PubMed

Yan, Chen; Laguna, Benjamin A; Marlowe, Lauren E; Keller, Michael D; Treat, James R

2014-01-01

Simultaneous involvement of herpes zoster in multiple dermatomes is uncommon, and even more so in immunocompetent individuals. We report a case wherein a healthy adolescent boy presented with herpes zoster in two distinct dermatomes, raising concern for immunodeficiency, but he was found to be immunocompetent on further testing. A 14-year-old boy with no significant past medical history developed painless vesicular eruptions in two distinct distributions. Varicella zoster virus polymerase chain reaction was positive from unroofed vesicles in both regions. Initial laboratory studies disclosed abnormalities of unknown significance in natural killer (NK) cell percentage and function. The patient was treated with appropriate antiviral therapy. Repeat studies while healthy were not suggestive of an underlying NK cell defect. There are few case reports describing herpes zoster in two or more dermatomes in children. Previously described presentations most commonly occurred in the context of primary immunodeficiency, acquired immunodeficiency, or immunosuppressive medications. Because of the rarity of this presentation in immunocompetent patients, the authors recommend a thorough immune evaluation of all children presenting with isolated multidermatomal zoster. © 2014 Wiley Periodicals, Inc.

Development and Preclinical Application of an Immunocompetent Transplant Model of Basal Breast Cancer with Lung, Liver and Brain Metastases

PubMed Central

Hoenerhoff, Mark; Hixon, Julie A.; Durum, Scott K.; Qiu, Ting-hu; He, Siping; Burkett, Sandra; Liu, Zi-Yao; Swanson, Steven M.; Green, Jeffrey E.

2016-01-01

Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is associated with a poor prognosis and for which no targeted therapies currently exist. In order to improve preclinical testing for TNBC that relies primarily on using human xenografts in immunodeficient mice, we have developed a novel immunocompetent syngeneic murine tumor transplant model for basal-like triple-negative breast cancer. The C3(1)/SV40-T/t-antigen (C3(1)/Tag) mouse mammary tumor model in the FVB/N background shares important similarities with human basal-like TNBC. However, these tumors or derived cell lines are rejected when transplanted into wt FVB/N mice, likely due to the expression of SV40 T-antigen. We have developed a sub-line of mice (designated REAR mice) that carry only one copy of the C3(1)/Tag-antigen transgene resulting from a spontaneous transgene rearrangement in the original founder line. Unlike the original C3(1)/Tag mice, REAR mice do not develop mammary tumors or other phenotypes observed in the original C3(1)/Tag transgenic mice. REAR mice are more immunologically tolerant to SV40 T-antigen driven tumors and cell lines in an FVB/N background (including prostate tumors from TRAMP mice), but are otherwise immunologically intact. This transplant model system offers the ability to synchronously implant the C3(1)/Tag tumor-derived M6 cell line or individual C3(1)/Tag tumors from various stages of tumor development into the mammary fat pads or tail veins of REAR mice. C3(1)/Tag tumors or M6 cells implanted into the mammary fat pads spontaneously metastasize at a high frequency to the lung and liver. M6 cells injected by tail vein can form brain metastases. We demonstrate that irradiated M6 tumor cells or the same cells expressing GM-CSF can act as a vaccine to retard tumor growth of implanted tumor cells in the REAR model. Preclinical studies performed in animals with an intact immune system should more authentically replicate treatment responses in

Pityrosporum folliculitis in an immunocompetent patient: clinical case description.

PubMed

Viana de Andrade, Ana Carolina Dias; Pithon, Matheus Melo; Oiticica, Olga Maria

2013-08-15

The present report concerns Malassezia-related pityrosporum folliculitis in a patient without any predisposing factor. Once the diagnosis had been confirmed by histopathologic exam, the patient was treated with oral ketoconazole and selenium sulfide shampoo; complete remission of the clinical condition was obtained. Thus it could be concluded that in spite of being routinely associated with immunosuppression, this condition may be present in an immunocompetent patient.

Studies on immunocompetence status in two turkey varieties in India.

PubMed

Singh, N S; Kumar, S; Majumdar, S; Sivaraman, G K; Shivakumar, B M

2004-10-01

(1) Two hundred and twenty-seven adult turkeys of both sexes, of two varieties (104 Black and 123 White) were used to evaluate their immunocompetence status and body weights. (2) Response to sheep red blood cells (SRBC) (humoral immunity) was measured by Haemagglutination (HA) test 5 days post immunisation (dpi) and expressed as log2 values. Mercaptoethanol resistant (MER) antibodies representing IgG were determined by Mercaptoethanol HA test and Mercaptoethanol sensitive (MES) antibodies, representing IgM as the difference in total HA titre and IgG. Serum lysozyme concentrations were estimated by 'Lysoplate assay' and expressed in log2 values. (3) Least squares analysis of variance revealed that the White variety had higher adult body weight (4.788 +/- 0.040 kg) than the Black (3.774 +/- 0.044 kg). Sexual dimorphism was apparent and meals were heavier than females in both varieties. The interaction effect of variety and sex on body weight was also significant. (4) Least squares means for immunological traits, namely, total anti-SRBC antibodies, MER, MES titres and serum lysozyme were 7.161 +/- 0.189, 0.801 +/- 0.071, 6.362 +/- 0.160 and 1.766 +/- 0.043 microg/ml, respectively. The Black variety had a higher MES antibody titre than the White. (5) Sex had an effect on all the immunological traits except on MER titres. Females generally had higher anti-SRBC, MER and MES titres and serum lysozyme. The variety x sex interaction effect was significant for MES titres and serum lysozyme. White males had the lowest MES titres.

Overweight and metabolic and hormonal parameter disruption are induced in adult male mice by manipulations during lactation period.

PubMed

Loizzo, Alberto; Loizzo, Stefano; Galietta, Gabriella; Caiola, Stefania; Spampinato, Santi; Campana, Gabriele; Seghieri, Giuseppe; Ghirlanda, Giovanni; Franconi, Flavia

2006-01-01

Neonatal manipulations (10 min of maternal separation plus s.c. sham injection, daily for the first 21 d of life) determine overweight in male adult mice. In this work, we investigated the mechanisms underlying mild obesity and the alteration of caloric balance. Neonatally manipulated mice become overweight after onset of maturity, showing increased fat tissue and hypertrophic epididymal adipocytes. Increase in body weight occurs in the presence of a small increase in daily food intake (significant only in the adult period) and the absence of a decrease in spontaneous locomotor activity, while the calculated caloric efficiency is higher in manipulated mice, especially in adulthood. Fasting adult animals show hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and hyperleptinemia. Soon after weaning and in the adulthood, plasma corticosterone and adrenocorticotropin (ACTH) are also significantly increased. Thus, neonatal manipulations in nongenetically susceptible male mice program mild obesity, with metabolic and hormonal alterations that are similar to those found in experimental models of diabetes mellitus, suggesting that this metabolic derangement may have at least part of its roots early on in life and, more interestingly, that psychological and nociceptive stimuli induce these features.

Cystoisospora belli Infection of the Gallbladder in Immunocompetent Patients: A Clinicopathologic Review of 18 Cases.

PubMed

Lai, Keith K; Goyne, Hannah E; Hernandez-Gonzalo, David; Miller, Kennon A; Tuohy, Marion; Procop, Gary W; Lamps, Laura W; Patil, Deepa T

2016-08-01

Cystoisospora belli, previously known as Isospora belli, is an obligate intracellular coccidian parasite that is most often associated with gastrointestinal disease in immunocompromised patients. In this study, we detail the clinicopathologic features of 18 cases of Cystoisospora infection affecting the gallbladder in immunocompetent individuals and compare them with a control group. Each case was reviewed for cholecystitis (none, acute, chronic), epithelial disarray, presence of intraepithelial lymphocytes (none, rare [≤5 per 20 epithelial cells], present [>5 per 20 epithelial cells]), architectural distortion, intramucosal eosinophilia, and mural thickening/serositis. The mean age of patients with Cystoisospora infection was 33 years and the male to female ratio 1:4.3. Cholecystectomy was performed for biliary dyskinesia (n=7), abdominal pain (n=7), suspected cholelithiasis (n=5), and cholecystitis (n=3). In 2 cases, Cystoisospora was found in donor gallbladders resected at the time of liver transplantation. Each case was characterized by eosinophilic, oval or banana-shaped intraepithelial parasites within perinuclear parasitophorous vacuoles. Most cases showed epithelial disarray and minimal intraepithelial lymphocytosis. Of the 11 cases with an average follow-up of 15 months, none had evidence of disease related to Cystoisospora infection within the biliary tract or elsewhere in the gastrointestinal tract. We present the largest series of gallbladder cystoisosporiasis in immunocompetent patients to date. Cystoisospora infection is underrecognized in the gallbladders of immunocompetent patients, in part due to the subtle findings in routine cholecystectomy specimens. On the basis of the clinical follow-up, gallbladder cystoisosporiasis in immunocompetent individuals appears to be a self-limited infection.

Crimean-Congo hemorrhagic fever virus infection is lethal for adult type I interferon receptor-knockout mice.

PubMed

Bereczky, Sándor; Lindegren, Gunnel; Karlberg, Helen; Akerström, Sara; Klingström, Jonas; Mirazimi, Ali

2010-06-01

Crimean-Congo hemorrhagic fever virus (CCHFV) poses a great threat to public health due to its high mortality, transmission and geographical distribution. To date, there is no vaccine or specific treatment available and the knowledge regarding its pathogenesis is highly limited. Using a small-animal model system, this study showed that adult mice missing the type I interferon (IFN) receptor (IFNAR(-/-)) were susceptible to CCHFV and developed an acute disease with fatal outcome. In contrast, infection of wild-type mice (129 Sv/Ew) was asymptomatic. Viral RNA was found in all analysed organs of the infected mice, but the amount of CCHFV RNA was significantly higher in the IFNAR(-/-) mice than in the wild-type mice. Furthermore, the liver of IFNAR(-/-) mice was enlarged significantly, showing that IFN is important for limiting virus spread and protecting against liver damage in mice.

Repeatability and consistency of individual behaviour in juvenile and adult Eurasian harvest mice

NASA Astrophysics Data System (ADS)

Schuster, Andrea C.; Carl, Teresa; Foerster, Katharina

2017-04-01

Knowledge on animal personality has provided new insights into evolutionary biology and animal ecology, as behavioural types have been shown to affect fitness. Animal personality is characterized by repeatable and consistent between-individual behavioural differences throughout time and across different situations. Behavioural repeatability within life history stages and consistency between life history stages should be checked for the independence of sex and age, as recent data have shown that males and females in some species may differ in the repeatability of behavioural traits, as well as in their consistency. We measured the repeatability and consistency of three behavioural and one cognitive traits in juvenile and adult Eurasian harvest mice ( Micromys minutus). We found that exploration, activity and boldness were repeatable in juveniles and adults. Spatial recognition measured in a Y Maze was only repeatable in adult mice. Exploration, activity and boldness were consistent before and after maturation, as well as before and after first sexual contact. Data on spatial recognition provided little evidence for consistency. Further, we found some evidence for a litter effect on behaviours by comparing different linear mixed models. We concluded that harvest mice express animal personality traits as behaviours were repeatable across sexes and consistent across life history stages. The tested cognitive trait showed low repeatability and was less consistent across life history stages. Given the rising interest in individual variation in cognitive performance, and in its relationship to animal personality, we suggest that it is important to gather more data on the repeatability and consistency of cognitive traits.

Impaired long-term memory retention: common denominator for acutely or genetically reduced hippocampal neurogenesis in adult mice.

PubMed

Ben Abdallah, Nada M-B; Filipkowski, Robert K; Pruschy, Martin; Jaholkowski, Piotr; Winkler, Juergen; Kaczmarek, Leszek; Lipp, Hans-Peter

2013-09-01

In adult rodents, decreasing hippocampal neurogenesis experimentally using different approaches often impairs performance in hippocampus-dependent processes. Nonetheless, functional relevance of adult neurogenesis is far from being unraveled, and deficits so far described in animal models often lack reproducibility. One hypothesis is that such differences might be the consequence of the extent of the methodological specificity used to alter neurogenesis rather than the extent to which adult neurogenesis is altered. To address this, we focused on cranial irradiation, the most widely used technique to impair hippocampal neurogenesis and consequentially induce hippocampus-dependent behavioral deficits. To investigate the specificity of the technique, we thus exposed 4-5 months old female cyclin D2 knockout mice, a model lacking physiological levels of olfactory and hippocampal neurogenesis, to an X-ray dose of 10 Gy, reported to specifically affect transiently amplifying precursors. After a recovery period of 1.5 months, behavioral tests were performed and probed for locomotor activity, habituation, anxiety, and spatial learning and memory. Spatial learning in the Morris water maze was intact in all experimental groups. Although spatial memory retention assessed 24h following acquisition was also intact in all mice, irradiated wild type and cyclin D2 knockout mice displayed memory deficits one week after acquisition. In addition, we observed significant differences in tests addressing anxiety and locomotor activity dependent on the technique used to alter neurogenesis. Whereas irradiated mice were hyperactive regardless of their genotype, cyclin D2 knockout mice were hypoactive in most of the tests and displayed altered habituation. The present study emphasizes that different approaches aimed at decreasing adult hippocampal neurogenesis may result in distinct behavioral impairments related to locomotion and anxiety. In contrast, spatial long-term memory retention is

Apolipoprotein E4 reduces evoked hippocampal acetylcholine release in adult mice.

PubMed

Dolejší, Eva; Liraz, Ori; Rudajev, Vladimír; Zimčík, Pavel; Doležal, Vladimír; Michaelson, Daniel M

2016-02-01

Apolipoprotein E4 (apoE4) is the most prevalent genetic risk factor for Alzheimer's disease. We utilized apoE4-targeted replacement mice (approved by the Tel Aviv University Animal Care Committee) to investigate whether cholinergic dysfunction, which increases during aging and is a hallmark of Alzheimer's disease, is accentuated by apoE4. This revealed that levels of the pre-synaptic cholinergic marker, vesicular acetylcholine transporter in the hippocampus and the corresponding electrically evoked release of acetylcholine, are similar in 4-month-old apoE4 and apolipoprotein E3 (apoE3) mice. Both parameters decrease with age. This decrease is, however, significantly more pronounced in the apoE4 mice. The levels of cholinacetyltransferase (ChAT), acetylcholinesterase (AChE), and butyrylcholinesterase (BuChE) were similar in the hippocampus of young apoE4 and apoE3 mice and decreased during aging. For ChAT, this decrease was similar in the apoE4 and apoE3 mice, whereas it was more pronounced in the apoE4 mice, regarding their corresponding AChE and BuChE levels. The level of muscarinic receptors was higher in the apoE4 than in the apoE3 mice at 4 months and increased to similar levels with age. However, the relative representation of the M1 receptor subtype decreased during aging in apoE4 mice. These results demonstrate impairment of the evoked release of acetylcholine in hippocampus by apoE4 in 12-month-old mice but not in 4-month-old mice. The levels of ChAT and the extent of the M2 receptor-mediated autoregulation of ACh release were similar in the adult mice, suggesting that the apoE4-related inhibition of hippocampal ACh release in these mice is not driven by these parameters. Evoked ACh release from hippocampal and cortical slices is similar in 4-month-old apoE4 and apoE3 mice but is specifically and significantly reduced in hippocampus, but not cortex, of 12-month-old apoE4 mice. This effect is accompanied by decreased VAChT levels. These findings show that

Antibody-directed myostatin inhibition improves diaphragm pathology in young but not adult dystrophic mdx mice.

PubMed

Murphy, Kate T; Ryall, James G; Snell, Sarah M; Nair, Lawrence; Koopman, René; Krasney, Philip A; Ibebunjo, Chikwendu; Holden, Kathryn S; Loria, Paula M; Salatto, Christopher T; Lynch, Gordon S

2010-05-01

Duchenne muscular dystrophy (DMD) is characterized by progressive skeletal muscle wasting and weakness, leading to premature death from respiratory and/or cardiac failure. A clinically relevant question is whether myostatin inhibition can improve function of the diaphragm, which exhibits a severe and progressive pathology comparable with that in DMD. We hypothesized that antibody-directed myostatin inhibition would improve the pathophysiology of diaphragm muscle strips from young mdx mice (when the pathology is mild) and adult mdx mice (when the pathology is quite marked). Five weeks treatment with a mouse chimera of anti-human myostatin antibody (PF-354, 10 mg/kg/week) increased muscle mass (P < 0.05) and increased diaphragm median fiber cross-sectional area (CSA, P < 0.05) in young C57BL/10 and mdx mice, compared with saline-treated controls. PF-354 had no effect on specific force (sPo, maximum force normalized to muscle CSA) of diaphragm muscle strips from young C57BL/10 mice, but increased sPo by 84% (P < 0.05) in young mdx mice. In contrast, 8 weeks of PF-354 treatment did not improve muscle mass, median fiber CSA, collagen infiltration, or sPo of diaphragm muscle strips from adult mdx mice. PF-354 antibody-directed myostatin inhibition completely restored the functional capacity of diaphragm strips to control levels when treatment was initiated early, but not in the later stages of disease progression, suggesting that such therapies may only have a limited window of efficacy for DMD and related conditions.

Adult Behavior in Male Mice Exposed to E-Cigarette Nicotine Vapors during Late Prenatal and Early Postnatal Life.

PubMed

Smith, Dani; Aherrera, Angela; Lopez, Armando; Neptune, Enid; Winickoff, Jonathan P; Klein, Jonathan D; Chen, Gang; Lazarus, Philip; Collaco, Joseph M; McGrath-Morrow, Sharon A

2015-01-01

Timed-pregnant C57BL/6J mice were exposed to 2.4% nicotine in propylene glycol (PG) or 0% nicotine /PG once a day from gestational day 15 until delivery. After delivery, offspring and mothers were exposed to E-cigarette vapors for an additional 14 days from postnatal day 2 through 16. Following their last exposure serum cotinine levels were measured in female juvenile mice. Male mice underwent behavioral testing at 14 weeks of age to assess sensorimotor, affective, and cognitive functional domains. Adult male mice exposed to 2.4% nicotine/PG E-cigarette vapors had significantly more head dips in the zero maze test and higher levels of rearing activity in the open field test compared to 0% nicotine/PG exposed mice and untreated controls. In the water maze test after reversal training, the 2.4% nicotine/PG mice spent more than 25% of time in the new location whereas the other groups did not. Adult male mice exhibited increased levels of activity in the zero maze and open field tests when exposed to E-cigarette vapor containing nicotine during late prenatal and early postnatal life. These findings indicate that nicotine exposure from E-cigarettes may cause persistent behavioral changes when exposure occurs during a period of rapid brain growth.

Molecular detection and species identification of Enterocytozoon bieneusi isolated from immunocompetent Orang Asli in Malaysia.

PubMed

Ashikin, Azah; Al-Mekhlafi, Hesham M; Moktar, Norhayati; Anuar, Tengku Shahrul

2017-04-01

Most studies of opportunistic infections focus on immunocompromised patients. However, there is a lack of information on microsporidiosis in healthy people (immunocompetent) worldwide. This study aimed to detect and identify microsporidia species in immunocompetent Orang Asli living in Pahang, Malaysia. Orang Asli is a collective term for a group of indigenous people that usually reside in the interior regions of Peninsular Malaysia. They comprise about 0.7% of the total population in Malaysia and 76% of them lived below the poverty line i.e., poor housing conditions with the lack of access to safe drinking water and adequate sanitation, contaminated environment, high illiteracy rate and unhygienic practices by these people. Stool samples were collected from 209 Orang Asli and analyzed for detecting the presence of Enterocytozoon bieneusi and Encephalitozoon intestinalis by polymerase chain reaction assay targeting small subunit ribosomal RNA gene. E. bieneusi was detected in 8 individuals (3.83%). This infection was commonly found in males than females (5.2% vs. 2.7%). All infected Orang Asli were adults, with a mean age of 44years. Diarrhea and other gastrointestinal symptoms were reported in one case (12.5%) among individuals infected with this species. These findings clearly show that exposure to E. bieneusi may actually be common than reported. The accurate detection and identification of microsporidian species by molecular technique will improve therapy, clinical manifestations and prognosis of this infection, as no antiparasitic therapy has been approved for E. bieneusi. It is hoped that these findings will allow the formulation of better health management and disease prevention advisories, and improvement in the standards of health in similar communities. Copyright © 2017 Elsevier B.V. All rights reserved.

Short-Term Treatment with Bisphenol-A Leads to Metabolic Abnormalities in Adult Male Mice

PubMed Central

Batista, Thiago M.; Alonso-Magdalena, Paloma; Vieira, Elaine; Amaral, Maria Esmeria C.; Cederroth, Christopher R.; Nef, Serge; Quesada, Ivan; Carneiro, Everardo M.; Nadal, Angel

2012-01-01

Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals (EDC) used as the base compound in the manufacture of polycarbonate plastics. Although evidence points to consider exposure to BPA as a risk factor for insulin resistance, its actions on whole body metabolism and on insulin-sensitive tissues are still unclear. The aim of the present work was to study the effects of low doses of BPA in insulin-sensitive peripheral tissues and whole body metabolism in adult mice. Adult mice were treated with subcutaneous injection of 100 µg/kg BPA or vehicle for 8 days. Whole body energy homeostasis was assessed with in vivo indirect calorimetry. Insulin signaling assays were conducted by western blot analysis. Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. BPA-treated mice had decreased food intake, lower body temperature and locomotor activity compared to control. In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit was impaired in BPA-treated mice. This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr308 residue. Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. The mitogen-activated protein kinase (MAPK) signaling pathway was also impaired in the skeletal muscle from BPA-treated mice. In the liver, BPA effects were of lesser intensity with decreased insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit. In conclusion, short-term treatment with low doses of BPA slows down whole body energy metabolism and disrupts insulin signaling in peripheral tissues. Thus, our findings support the notion that BPA can be considered a risk factor for the development of type 2 diabetes. PMID:22470480

Nutritional and supranutritional levels of selenate differentially suppress prostate tumor growth in adult but not young nude mice.

PubMed

Holmstrom, Alexandra; Wu, Ryan T Y; Zeng, Huawei; Lei, K Y; Cheng, Wen-Hsing

2012-09-01

The inhibitory effect of oral methylseleninic acid or methylselenocysteine administration on cancer cell xenograft development in nude mice is well characterized; however, less is known about the efficacy of selenate and age on selenium chemoprevention. In this study, we tested whether selenate and duration on diets would regulate prostate cancer xenograft in nude mice. Thirty-nine homozygous NU/J nude mice were fed a selenium-deficient, Torula yeast basal diet alone (Se-) or supplemented with 0.15 (Se) or 1.0 (Se+) mg selenium/kg (as Na₂SeO₄) for 6 months in Experiment 1 and for 4 weeks in Experiment 2, followed by a 47-day PC-3 prostate cancer cell xenograft on the designated diet. In Experiment 1, the Se- diet enhanced the initial tumor development on days 11-17, whereas the Se+ diet suppressed tumor growth on days 35-47 in adult nude mice. Tumors grown in Se- mice were loosely packed and showed increased necrosis and inflammation as compared to those in Se and Se+ mice. In Experiment 2, dietary selenium did not affect tumor development or histopathology throughout the time course. In both experiments, postmortem plasma selenium concentrations in Se and Se+ mice were comparable and were twofold greater than those in Se- mice. Taken together, dietary selenate at nutritional and supranutritional levels differentially inhibit tumor development in adult, but not young, nude mice engrafted with PC-3 prostate cancer cells. Copyright © 2012 Elsevier Inc. All rights reserved.

The role of juvenile hormone in immune function and pheromone production trade-offs: a test of the immunocompetence handicap principle.

PubMed Central

Rantala, Markus J; Vainikka, Anssi; Kortet, Raine

2003-01-01

The immunocompetence handicap hypothesis postulates that secondary sexual traits are honest signals of mate quality because the hormones (e.g. testosterone) needed to develop secondary sexual traits have immunosuppressive effects. The best support for predictions arising from the immunocompetence handicap hypothesis so far comes from studies of insects, although they lack male-specific hormones such as testosterone. In our previous studies, we found that female mealworm beetles prefer pheromones of immunocompetent males. Here, we tested how juvenile hormone (JH) affects male investment in secondary sexual characteristics and immune functions in the mealworm beetle, Tenebrio molitor. We injected male mealworm beetles with JH (type III) and found that injection increased the attractiveness of male pheromones but simultaneously suppressed immune functions (phenoloxidase activity and encapsulation). Our results suggest that JH, which is involved in the control of reproduction and morphogenesis, also plays a central role in the regulation of a trade-off between the immune system and sexual advertisement in insects. Thus, the results reflect a general mechanism by which the immunocompetence handicap hypothesis may work in insects. PMID:14613612

Effect of nerve injury on the number of dorsal root ganglion neurons and autotomy behavior in adult Bax-deficient mice.

PubMed

Lyu, Chuang; Lyu, Gong-Wei; Martinez, Aurora; Shi, Tie-Jun Sten

2017-01-01

The proapoptotic molecule BAX, plays an important role in mitochondrial apoptotic pathway. Dorsal root ganglion (DRG) neurons depend on neurotrophic factors for survival at early developmental stages. Withdrawal of neurotrophic factors will induce apoptosis in DRG neurons, but this type of cell death can be delayed or prevented in neonatal Bax knockout (KO) mice. In adult animals, evidence also shows that DRG neurons are less dependent upon neurotrophic factors for survival. However, little is known about the effect of Bax deletion on the survival of normal and denervated DRG neurons in adult mice. A unilateral sciatic nerve transection was performed in adult Bax KO mice and wild-type (WT) littermates. Stereological method was employed to quantify the number of lumbar-5 DRG neurons 1 month post-surgery. Nerve injury-induced autotomy behavior was also examined on days 1, 3, and 7 post-surgery. There were significantly more neurons in contralateral DRGs of KO mice as compared with WT mice. The number of neurons was reduced in ipsilateral DRGs in both KO and WT mice. No changes in size distributions of DRG neuron profiles were detected before or after nerve injury. Injury-induced autotomy behavior developed much earlier and was more serious in KO mice. Although postnatal death or loss of DRG neurons is partially prevented by Bax deletion, this effect cannot interfere with long-term nerve injury-induced neuronal loss. The exaggerated self-amputation behavior observed in the mutant mice indicates that Bax deficiency may enhance the development of spontaneous pain following nerve injury.

Early postnatal GFAP-expressing cells produce multilineage progeny in cerebrum and astrocytes in cerebellum of adult mice.

PubMed

Guo, Zhibao; Wang, Xijuan; Xiao, Jun; Wang, Yihui; Lu, Hong; Teng, Junfang; Wang, Wei

2013-09-26

Early postnatal GFAP-expressing cells are thought to be immature astrocytes. However, it is not clear if they possess multilineage capacity and if they can generate different lineages (astrocytes, neurons and oligodendrocytes) in the brain of adult mice. In order to identify the fate of astroglial cells in the postnatal brain, hGFAP-Cre-ER(T2) transgenic mice were crossed with the R26R Cre reporter mouse strains which exhibit constitutive expression of β-galactosidase (β-gal). Mice carrying the hGFAP-Cre-ER(T2)/R26R transgene were treated with Tamoxifen to induce Cre recombination in astroglial cells at postnatal (P) day 6 and Cre recombinase-expressing cells were identified by X-gal staining. Immunohistochemical staining was used to identify the type(s) of these reporter-tagged cells. Sixty days after recombination, X-gal-positive cells in different cerebral regions of the adult mice expressed the astroglial markers Blbp and GFAP, the neuronal marker NeuN, the oligodendrocyte precursor cell marker NG2 and the mature oligodendrocyte marker CC1. X-gal-positive cells in the cerebellum coexpressed the astroglial marker Blbp, but not the granule cell marker NeuN, Purkinje cell marker Calbindin or oligodendrocyte precursor cell marker NG2. Our genetic fate mapping data demonstrated that early postnatal GFAP-positive cells possessed multilineage potential and eventually differentiated into neurons, astrocytes, and oligodendrocyte precursor cells in the cerebrum and into astrocytes (including Bergmann glia) in the cerebellum of adult mice. © 2013 Elsevier B.V. All rights reserved.

Metabolic costs of mounting an antigen-stimulated immune response in adult and aged C57BL/6J mice.

PubMed

Demas, G E; Chefer, V; Talan, M I; Nelson, R J

1997-11-01

Animals must balance their energy budget despite seasonal changes in both energy availability and physiological expenditures. Immunity, in addition to growth, thermoregulation, and cellular maintenance, requires substantial energy to maintain function, although few studies have directly tested the energetic cost of immunity. The present study assessed the metabolic costs of an antibody response. Adult and aged male C5BL/6J mice were implanted with either empty Silastic capsules or capsules filled with melatonin and injected with either saline or keyhole limpet hemocyanin (KLH). O2 consumption was monitored periodically throughout antibody production using indirect calorimetry. KLH-injected mice mounted significant immunoglobulin G (IgG) responses and consumed more O2 compared with animals injected with saline. Melatonin treatment increased O2 consumption in mice injected with saline but suppressed the increased metabolic rate associated with an immune response in KLH-injected animals. Melatonin had no effect on immune response to KLH. Adult and aged mice did not differ in antibody response or metabolic activity. Aged mice appear unable to maintain sufficient heat production despite comparable O2 production to adult mice. These results suggest that mounting an immune response requires significant energy and therefore requires using resources that could otherwise be allocated to other physiological processes. Energetic trade-offs are likely when energy demands are high (e.g., during winter, pregnancy, or lactation). Melatonin appears to play an adaptive role in coordinating reproductive, immunologic, and energetic processes.

Membrane potential dye imaging of ventromedial hypothalamus neurons from adult mice to study glucose sensing.

PubMed

Vazirani, Reema P; Fioramonti, Xavier; Routh, Vanessa H

2013-11-27

Studies of neuronal activity are often performed using neurons from rodents less than 2 months of age due to the technical difficulties associated with increasing connective tissue and decreased neuronal viability that occur with age. Here, we describe a methodology for the dissociation of healthy hypothalamic neurons from adult-aged mice. The ability to study neurons from adult-aged mice allows the use of disease models that manifest at a later age and might be more developmentally accurate for certain studies. Fluorescence imaging of dissociated neurons can be used to study the activity of a population of neurons, as opposed to using electrophysiology to study a single neuron. This is particularly useful when studying a heterogeneous neuronal population in which the desired neuronal type is rare such as for hypothalamic glucose sensing neurons. We utilized membrane potential dye imaging of adult ventromedial hypothalamic neurons to study their responses to changes in extracellular glucose. Glucose sensing neurons are believed to play a role in central regulation of energy balance. The ability to study glucose sensing in adult rodents is particularly useful since the predominance of diseases related to dysfunctional energy balance (e.g. obesity) increase with age.

AAV-Mediated Administration of Myostatin Pro-Peptide Mutant in Adult Ldlr Null Mice Reduces Diet-Induced Hepatosteatosis and Arteriosclerosis

PubMed Central

Guo, Wen; Wong, Siu; Bhasin, Shalender

2013-01-01

Genetic disruption of myostatin or its related signaling is known to cause strong protection against diet-induced metabolic disorders. The translational value of these prior findings, however, is dependent on whether such metabolically favorable phenotype can be reproduced when myostatin blockade begins at an adult age. Here, we reported that AAV-mediated delivery of a myostatin pro-peptide D76A mutant in adult mice attenuates the development of hepatic steatosis and arteriosclerosis, two common diet-induced metabolic diseases. A single dose of AAV-D76A in adult Ldlr null mice resulted in sustained expression of myostatin pro-peptide in the liver. Compared to vehicle-treated mice, D76A-treated mice gained similar amount of lean and fat mass when fed a high fat diet. However, D76A-treated mice displayed significantly reduced aortic lesions and liver fat, in association with a reduction in hepatic expression of lipogenic genes and improvement in liver insulin sensitivity. This suggests that muscle and fat may not be the primary targets of treatment under our experimental condition. In support to this argument, we show that myostatin directly up-regulated lipogenic genes and increased fat accumulation in cultured liver cells. We also show that both myostatin and its receptor were abundantly expressed in mouse aorta. Cultured aortic endothelial cells responded to myostatin with a reduction in eNOS phosphorylation and an increase in ICAM-1 and VCAM-1 expression. Conclusions: AAV-mediated expression of myostatin pro-peptide D76A mutant in adult Ldlr null mice sustained metabolic protection without remarkable impacts on body lean and fat mass. Further investigations are needed to determine whether direct impact of myostatin on liver and aortic endothelium may contribute to the related metabolic phenotypes. PMID:23936482

Developmental and Adult GAP-43 Deficiency in Mice Dynamically Alters Hippocampal Neurogenesis and Mossy Fiber Volume

PubMed Central

Latchney, Sarah E.; Masiulis, Irene; Zaccaria, Kimberly J.; Lagace, Diane C.; Powell, Craig M.; McCasland, James S.; Eisch, Amelia J.

2014-01-01

Growth Associated Protein-43 (GAP-43) is a pre-synaptic protein that plays key roles in axonal growth and guidance and in modulating synapse formation. Previous work has demonstrated that mice lacking one allele of this gene [GAP-43(+/-) mice] exhibit hippocampal structural abnormalities and impaired spatial learning and stress-induced behavioral withdrawal and anxiety (Zaccaria et al., 2010), behaviors that are dependent on proper hippocampal circuitry and function. Given the correlation between hippocampal function, synaptic connectivity, and neurogenesis, we tested if behaviorally-naïve GAP-43(+/-) mice had alterations in either neurogenesis or synaptic connectivity in the hippocampus during early postnatal development and young adulthood, and following behavior testing in older adults. To test our hypothesis, we examined hippocampal cell proliferation (Ki67), number of immature neuroblasts (DCX), and mossy fiber volume (synaptoporin) in behaviorally-naïve postnatal (P) day 9 (P9), P26, and behaviorally-experienced 5-7 month old GAP-43(+/-) and (+/+) littermate mice. P9 GAP-43(+/-) mice had fewer Ki67+ and DCX+ cells compared to (+/+) mice, particularly in the posterior dentate gyrus, and smaller mossy fiber volume in the same region. In young adulthood, however, male GAP-43(+/-) mice had more Ki67+ and DCX+ cells and greater mossy fiber volume in the posterior dentate gyrus relative to male (+/+). These increases were not seen in females. In 5-7 month old GAP-43(+/-) mice whose behaviors were the focus of our prior publication (Zaccaria et al., 2010), there was no global change in number of proliferating or immature neurons relative to (+/+) mice. However, more detailed analysis revealed fewer proliferative DCX+ cells in the anterior dentate gyrus of male GAP-43(+/-) mice compared to male (+/+) mice. This reduction was not observed in females. These results suggest that young GAP-43(+/-) mice have decreased hippocampal neurogenesis and synaptic connectivity

Flt3 Ligand Regulates the Development of Innate Lymphoid Cells in Fetal and Adult Mice.

PubMed

Baerenwaldt, Anne; von Burg, Nicole; Kreuzaler, Matthias; Sitte, Selina; Horvath, Edit; Peter, Annick; Voehringer, David; Rolink, Antonius G; Finke, Daniela

2016-03-15

Flt3 ligand (Flt3L) promotes survival of lymphoid progenitors in the bone marrow and differentiation of dendritic cells (DCs), but its role in regulating innate lymphoid cells (ILCs) during fetal and adult life is not understood. By using Flt3L knockout and transgenic mice, we demonstrate that Flt3L controls ILC numbers by regulating the pool of α4β7(-) and α4β7(+) lymphoid tissue inducer cell progenitors in the fetal liver and common lymphoid progenitors in the bone marrow. Deletion of flt3l severely reduced the number of fetal liver progenitors and lymphoid tissue inducer cells in the neonatal intestine, resulting in impaired development of Peyer's patches. In the adult intestine, NK cells and group 2 and 3 ILCs were severely reduced. This effect occurred independently of DCs as ILC numbers were normal in mice in which DCs were constitutively deleted. Finally, we could show that administration of Flt3L increased the number of NKp46(-) group 3 ILCs in wild-type and even in Il7(-/-) mice, which generally have reduced numbers of ILCs. Taken together, Flt3L significantly contributes to ILC and Peyer's patches development by targeting lymphoid progenitor cells during fetal and adult life. Copyright © 2016 by The American Association of Immunologists, Inc.

Dietary enrichment with alpha-linolenic acid during pregnancy attenuates insulin resistance in adult offspring in mice.

PubMed

Hollander, K S; Tempel Brami, C; Konikoff, F M; Fainaru, M; Leikin-Frenkel, A

2014-07-01

Our objective was to test the contribution of dietary enrichment in essential or saturated fatty acids, in normocaloric diets, on the lipid accumulation and insulin resistance in the adult offspring in a C57Bl6/J mice model. Pregnant mothers were fed normocaloric diets containing 6% fat enriched in essential fatty acids (EFA): alpha-linolenic (ALA-18:3, n-3), linoleic (LA-18:2, n-6), or saturated fatty acids (SFA). After a washing-out period with regular diet, the offspring received a high-fat diet before euthanization. Adult mice fed maternal ALA showed lower body weight gain and lower liver fat accumulation, lower HOMA index and lower stearoyl-CoA desaturase (SCD1) activity than those fed maternal SFA. The results observed using this novel model suggest that ALA in maternal diet may have the potential to inhibit insulin resistance in adult offspring.

Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice.

PubMed

Mustroph, M L; Merritt, J R; Holloway, A L; Pinardo, H; Miller, D S; Kilby, C N; Bucko, P; Wyer, A; Rhodes, J S

2015-01-01

Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin-thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Transient postnatal fluoxetine decreases brain concentrations of 20-HETE and 15-epi-LXA4, arachidonic acid metabolites in adult mice.

PubMed

Yuan, Zhi-Xin; Rapoport, Stanley I

2015-10-01

Transient postnatal exposure of rodents to the selective serotonin (5-HT) reuptake inhibitor (SSRI) fluoxetine alters behavior and brain 5-HT neurotransmission during adulthood, and also reduces brain arachidonic (ARA) metabolic consumption and protein level of the ARA metabolizing enzyme, cytochrome P4504A (CYP4A). Brain 20-hydroxyeicosatetraenoic acid (20-HETE), converted by CYP4A from ARA, will be reduced in adult mice treated transiently and postnatally with fluoxetine. Male mice pups were injected i.p. daily with fluoxetine (10mg/kg) or saline during P4-P21. At P90 their brain was high-energy microwaved and analyzed for 20-HETE and six other ARA metabolites by enzyme immunoassay. Postnatal fluoxetine vs. saline significantly decreased brain concentrations of 20-HETE (-70.3%) and 15-epi-lipoxin A4 (-60%) in adult mice, but did not change other eicosanoid concentrations. Behavioral changes in adult mice treated postnatally with fluoxetine may be related to reduced brain ARA metabolism involving CYP4A and 20-HETE formation. Published by Elsevier Ltd.

Epileptogenesis following Kainic Acid-Induced Status Epilepticus in Cyclin D2 Knock-Out Mice with Diminished Adult Neurogenesis

PubMed Central

Kondratiuk, Ilona; Plucinska, Gabriela; Miszczuk, Diana; Wozniak, Grazyna; Szydlowska, Kinga; Kaczmarek, Leszek; Filipkowski, Robert K.; Lukasiuk, Katarzyna

2015-01-01

The goal of this study was to determine whether a substantial decrease in adult neurogenesis influences epileptogenesis evoked by the intra-amygdala injection of kainic acid (KA). Cyclin D2 knockout (cD2 KO) mice, which lack adult neurogenesis almost entirely, were used as a model. First, we examined whether status epilepticus (SE) evoked by an intra-amygdala injection of KA induces cell proliferation in cD2 KO mice. On the day after SE, we injected BrdU into mice for 5 days and evaluated the number of DCX- and DCX/BrdU-immunopositive cells 3 days later. In cD2 KO control animals, only a small number of DCX+ cells was observed. The number of DCX+ and DCX/BrdU+ cells/mm of subgranular layer in cD2 KO mice increased significantly following SE (p<0.05). However, the number of newly born cells was very low and was significantly lower than in KA-treated wild type (wt) mice. To evaluate the impact of diminished neurogenesis on epileptogenesis and early epilepsy, we performed video-EEG monitoring of wt and cD2 KO mice for 16 days following SE. The number of animals with seizures did not differ between wt (11 out of 15) and cD2 KO (9 out of 12) mice. The median latency to the first spontaneous seizure was 4 days (range 2 – 10 days) in wt mice and 8 days (range 2 – 16 days) in cD2 KO mice and did not differ significantly between groups. Similarly, no differences were observed in median seizure frequency (wt: 1.23, range 0.1 – 3.4; cD2 KO: 0.57, range 0.1 – 2.0 seizures/day) or median seizure duration (wt: 51 s, range 23 – 103; cD2 KO: 51 s, range 23 – 103). Our results indicate that SE-induced epileptogenesis is not disrupted in mice with markedly reduced adult neurogenesis. However, we cannot exclude the contribution of reduced neurogenesis to the chronic epileptic state. PMID:26020770

Early Exposure to Intermediate-Frequency Magnetic Fields Alters Brain Biomarkers without Histopathological Changes in Adult Mice

PubMed Central

Win-Shwe, Tin-Tin; Ohtani, Shin; Ushiyama, Akira; Kunugita, Naoki

2015-01-01

Recently we have reported that intermediate-frequency magnetic field (IF-MF) exposure transiently altered the mRNA expression levels of memory function-related genes in the hippocampi of adult male mice. However, the effects of IF-MF exposure during brain development on neurological biomarkers have not yet been clarified. In the present study, we investigated the effect of IF-MF exposure during development on neurological and immunological markers in the mouse hippocampus in 3- and 7-week-old male mice. Pregnant C57BL/6J mice were exposed to IF-MF (21 kHz, 3.8 mT) for one hour per day from organogenesis period day 7 to 17. At adolescence, some IF-MF-exposed mice were further divided into exposure, recovery, and sham-exposure groups. The adolescent-exposure groups were exposed again to IF-MF from postnatal day 27 to 48. The expression of mRNA in the hippocampi was examined using a real-time RT-PCR method, and microglia activation was examined by immunohistochemical analysis. The expression levels of NR1 and NR2B as well as transcription factors (CaMKIV, CREB1), inflammatory mediators (COX2, IL-1 β,TNF-α), and the oxidative stress marker heme-oxygenase (HO)-1 were significantly increased in the IF-MF-exposed mice, compared with the control group, in the 7-week-old mice, but not in the 3-week-old mice. Microglia activation was not different between the control and other groups. This study provides the first evidence that early exposure to IF-MF reversibly affects the NMDA receptor, its related signaling pathways, and inflammatory mediators in the hippocampus of young adult mice; these changes are transient and recover after termination of exposure without histopathological changes. PMID:25913185

A rare case of spontaneous Aspergillus spondylodiscitis with epidural abscess in a 45-year-old immunocompetent female.

PubMed

Raj, K Ambedkar; Srinivasamurthy, Banushree C; Nagarajan, Krishnan; Sinduja, M G Ilavarasi

2013-07-01

Vertebral osteomyelitis and discitis are mainly due to bacterial infections though fungal infections are one of the important causes of morbidity and mortality in immunocompromised patients. Aspergillus involving intervertebral disc space is extremely rare. We report a case of aspergillosis of intervertebral L5-S1 disc space with spinal epidural abscess in an immunocompetent 45-year-old female which can add on to a few case reports described in literature as well as an insight for clinicians regarding this rare spontaneous infection in an immunocompetent patient.

Structural and functional cardiac cholinergic deficits in adult neurturin knockout mice.

PubMed

Mabe, Abigail M; Hoover, Donald B

2009-04-01

Previous work provided indirect evidence that the neurotrophic factor neurturin (NRTN) is required for normal cholinergic innervation of the heart. This study used nrtn knockout (KO) and wild-type (WT) mice to determine the effect of nrtn deletion on cardiac cholinergic innervation and function in the adult heart. Immunohistochemistry, confocal microscopy, and quantitative image analysis were used to directly evaluate intrinsic cardiac neuronal development. Atrial acetylcholine (ACh) levels were determined as an indirect index of cholinergic innervation. Cholinergic function was evaluated by measuring negative chronotropic responses to right vagal nerve stimulation in anaesthetized mice and responses of isolated atria to muscarinic agonists. KO hearts contained only 35% the normal number of cholinergic neurons, and the residual cholinergic neurons were 15% smaller than in WT. Cholinergic nerve density at the sinoatrial node was reduced by 87% in KOs, but noradrenergic nerve density was unaffected. Atrial ACh levels were substantially lower in KO mice (0.013 +/- 0.004 vs. 0.050 +/- 0.011 pmol/microg protein; P < 0.02) as expected from cholinergic neuron and nerve fibre deficits. Maximum bradycardia evoked by vagal stimulation was reduced in KO mice (38 +/- 6% vs. 69 +/- 3% decrease at 20 Hz; P < 0.001), and chronotropic responses took longer to develop and fade. In contrast to these deficits, isolated atria from KO mice had normal post-junctional sensitivity to carbachol and bethanechol. These findings demonstrate that NRTN is essential for normal cardiac cholinergic innervation and cholinergic control of heart rate. The presence of residual cardiac cholinergic neurons and vagal bradycardia in KO mice suggests that additional neurotrophic factors may influence this system.

Postnatal proteasome inhibition induces neurodegeneration and cognitive deficiencies in adult mice: a new model of neurodevelopment syndrome.

PubMed

Romero-Granados, Rocío; Fontán-Lozano, Ángela; Aguilar-Montilla, Francisco Javier; Carrión, Ángel Manuel

2011-01-01

Defects in the ubiquitin-proteasome system have been related to aging and the development of neurodegenerative disease, although the effects of deficient proteasome activity during early postnatal development are poorly understood. Accordingly, we have assessed how proteasome dysfunction during early postnatal development, induced by administering proteasome inhibitors daily during the first 10 days of life, affects the behaviour of adult mice. We found that this regime of exposure to the proteasome inhibitors MG132 or lactacystin did not produce significant behavioural or morphological changes in the first 15 days of life. However, towards the end of the treatment with proteasome inhibitors, there was a loss of mitochondrial markers and activity, and an increase in DNA oxidation. On reaching adulthood, the memory of mice that were injected with proteasome inhibitors postnatally was impaired in hippocampal and amygdala-dependent tasks, and they suffered motor dysfunction and imbalance. These behavioural deficiencies were correlated with neuronal loss in the hippocampus, amygdala and brainstem, and with diminished adult neurogenesis. Accordingly, impairing proteasome activity at early postnatal ages appears to cause morphological and behavioural alterations in adult mice that resemble those associated with certain neurodegenerative diseases and/or syndromes of mental retardation.

Rhinovirus exacerbates house-dust-mite induced lung disease in adult mice.

PubMed

Phan, Jennifer A; Kicic, Anthony; Berry, Luke J; Fernandes, Lynette B; Zosky, Graeme R; Sly, Peter D; Larcombe, Alexander N

2014-01-01

Human rhinovirus is a key viral trigger for asthma exacerbations. To date, murine studies investigating rhinovirus-induced exacerbation of allergic airways disease have employed systemic sensitisation/intranasal challenge with ovalbumin. In this study, we combined human-rhinovirus infection with a clinically relevant mouse model of aero-allergen exposure using house-dust-mite in an attempt to more accurately understand the links between human-rhinovirus infection and exacerbations of asthma. Adult BALB/c mice were intranasally exposed to low-dose house-dust-mite (or vehicle) daily for 10 days. On day 9, mice were inoculated with human-rhinovirus-1B (or UV-inactivated human-rhinovirus-1B). Forty-eight hours after inoculation, we assessed bronchoalveolar cellular inflammation, levels of relevant cytokines/serum antibodies, lung function and responsiveness/sensitivity to methacholine. House-dust-mite exposure did not result in a classical TH2-driven response, but was more representative of noneosinophilic asthma. However, there were significant effects of house-dust-mite exposure on most of the parameters measured including increased cellular inflammation (primarily macrophages and neutrophils), increased total IgE and house-dust-mite-specific IgG1 and increased responsiveness/sensitivity to methacholine. There were limited effects of human-rhinovirus-1B infection alone, and the combination of the two insults resulted in additive increases in neutrophil levels and lung parenchymal responses to methacholine (tissue elastance). We conclude that acute rhinovirus infection exacerbates house-dust-mite-induced lung disease in adult mice. The similarity of our results using the naturally occurring allergen house-dust-mite, to previous studies using ovalbumin, suggests that the exacerbation of allergic airways disease by rhinovirus infection could act via multiple or conserved mechanisms.

Perinatal programming of depressive-like behavior by inflammation in adult offspring mice whose mothers were fed polluted eels: Gender selective effects.

PubMed

Soualeh, Nidhal; Dridi, Imen; Eppe, Gauthier; Némos, Christophe; Soulimani, Rachid; Bouayed, Jaouad

2017-07-01

Several lines of evidence indicate that early-life inflammation may predispose to mental illness, including depression, in later-life. We investigated the impact of perinatal exposure to polluted eels on neonatal, postnatal, and adult brain inflammation, and on the resignation behavior of male and female adult offspring mice. The effects of maternal standard diet (laboratory food) were compared to the same diet enriched with low, intermediate, or highly polluted eels. Brain inflammatory markers including cytokines were assessed in offspring mice on the day of birth (i.e., on the postnatal day-PND 1), upon weaning (PND 21) and at adulthood (PND 100). Plasma myeloperoxidase and corticosterone levels were evaluated at PND 100. Immobility behavior of offspring was assessed in adulthood (i.e., at PNDs 95-100), using the tail suspension and forced swimming tests. Chronic brain inflammation was found in male and female offspring mice compared to controls, as assessed at PNDs 1, 21, and 100. The level of myeloperoxidase was found to be significantly higher in both adult males and females vs. control offspring. However, high corticosterone levels were only found in male offspring mice that were perinatally exposed to eels, suggesting a gender-selective dysregulation of the adult hypothalamic-pituitaryadrenal (HPA) axis. Gender-specific differences were also detected in adulthood in regard to offspring resignation behavior. Thus, compared to controls, males, but not females, whose mothers were fed eels during pregnancy and lactation exhibited a depressive-like behavior in adult age in both behavioral models of depression. Depressive symptoms were more pronounced in male mice perinatally exposed to either intermediate or highly polluted eels than those exposed to only lowly polluted eels. Our results indicate that early-life inflammatory insult is a plausible causative factor that induces the depressive phenotype exhibited by male adult offspring mice, most likely through a

In Vivo Efficacy of Plazomicin Alone or in Combination with Meropenem or Tigecycline against Enterobacteriaceae Isolates Exhibiting Various Resistance Mechanisms in an Immunocompetent Murine Septicemia Model.

PubMed

Abdelraouf, Kamilia; Kim, Aryun; Krause, Kevin M; Nicolau, David P

2018-06-04

Background : Plazomicin is a next-generation aminoglycoside with potent in vitro activity against multidrug- and carbapenem-resistant Enterobacteriaceae. The objective of this study was to assess the efficacy of plazomicin exposure, alone and in combination with meropenem or tigecycline, against Enterobacteriaceae in the immunocompetent murine septicemia model. Methods : ICR mice were inoculated intraperitoneally with bacterial suspensions. Eight Enterobacteriaceae isolates with wide ranges of plazomicin, meropenem and tigecycline MICs were utilized. Treatment mice were administered plazomicin, meropenem or tigecycline human-equivalent doses alone or in combinations of plazomicin/meropenem and plazomicin/tigecycline. Treatments were initiated 1h post-infection and continued for 24h. Efficacy was assessed by survival through 96h. Results : Compared with controls, plazomicin monotherapy produced significant improvement in survival for all isolates (P<0.05) and resulted in overall survival of 86% (n=50) and 53.3% (n=30) for isolates with plazomicin MIC ≤4 and ≥8 mg/L, respectively (P<0.05). Survival of meropenem and tigecycline groups correlated well with their respective susceptibilities, with incremental increase in survival observed at lower MIC values. For isolate KP 561 (plazomicin, meropenem and tigecycline MICs of 8, >32 and 2 mg/L, respectively), combination therapies showed significant reduction in mortality compared with any monotherapy (P<0.05). Conclusion : Plazomicin monotherapy resulted in improved survival in the immunocompetent murine septicemia model, notably for isolates with plazomicin MIC ≤4 mg/L. As evidenced by our current data, co-administration of meropenem or tigecycline could potentially lead to further improvement in survival. These data support a role for plazomicin in the management of septicemia due to Enterobacteriaceae with plazomicin MIC ≤4 mg/L, including carbapenem-resistant isolates. Copyright © 2018 American Society for

Effects of Early-Life Stress on Social and Anxiety-Like Behaviors in Adult Mice: Sex-Specific Effects

PubMed Central

Lepeshko, Arina A.; Reshetnikov, Vasiliy V.

2018-01-01

Stressful events in an early postnatal period have critical implications for the individual's life and can increase later risk for psychiatric disorders. The aim of this study was to investigate the influence of early-life stress on the social behavior of adult male and female mice. C57Bl/6 mice were exposed to maternal separation (MS, 3 h once a day) or handling (HD, 15 min once a day) on postnatal day 2 through 14. Adult male and female mice were tested for social behavior in the social interaction test and for individual behavior in the plus-maze and open-field tests. Female mice exposed to maternal separation had increased social behavior and increased anxiety. MS male mice had no changes in social behavior but had significantly disrupted individual behavior, including locomotor and exploratory activity. Handling had positive effects on social behavior in males and females and decreased anxiety in males. Our results support the hypothesis that brief separation of pups from their mothers (handling), which can be considered as moderate stress, may result in future positive changes in behavior. Maternal separation has deleterious effects on individual behavior and significant sex-specific effects on social behavior. PMID:29619126

Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice.

PubMed

Scheving, Lawrence A; Zhang, Xiuqi; Garcia, Oscar A; Wang, Rebecca F; Stevenson, Mary C; Threadgill, David W; Russell, William E

2014-03-01

Dsk5 mice have a gain of function in the epidermal growth factor receptor (EGFR), caused by a point mutation in the kinase domain. We analyzed the effect of this mutation on liver size, histology, and composition. We found that the livers of 12-wk-old male Dsk5 heterozygotes (+/Dsk5) were 62% heavier compared with those of wild-type controls (+/+). The livers of the +/Dsk5 mice compared with +/+ mice had larger hepatocytes with prominent, polyploid nuclei and showed modestly increased cell proliferation indices in both hepatocytes and nonparenchymal cells. An analysis of total protein, DNA, and RNA (expressed relative to liver weight) revealed no differences between the mutant and wild-type mice. However, the livers of the +/Dsk5 mice had more cholesterol but less phospholipid and fatty acid. Circulating cholesterol levels were twice as high in adult male +/Dsk5 mice but not in postweaned young male or female mice. The elevated total plasma cholesterol resulted mainly from an increase in low-density lipoprotein (LDL). The +/Dsk5 adult mouse liver expressed markedly reduced protein levels of LDL receptor, no change in proprotein convertase subtilisin/kexin type 9, and a markedly increased fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-CoA reductase. Increased expression of transcription factors associated with enhanced cholesterol synthesis was also observed. Together, these findings suggest that the EGFR may play a regulatory role in hepatocyte proliferation and lipid metabolism in adult male mice, explaining why elevated levels of EGF or EGF-like peptides have been positively correlated to increased cholesterol levels in human studies.

Molecular subtype-specific immunocompetent models of high-grade urothelial carcinoma reveal differential neoantigen expression and response to immunotherapy.

PubMed

Saito, Ryoichi; Smith, Christof C; Utsumi, Takanobu; Bixby, Lisa M; Kardos, Jordan; Wobker, Sara E; Stewart, Kyle G; Chai, Shengjie; Manocha, Ujjawal; Byrd, Kevin Matthew; Damrauer, Jeffrey S; Williams, Scott E; Vincent, Benjamin G; Kim, William Y

2018-05-21

High-grade urothelial cancer contains intrinsic molecular subtypes that exhibit differences in underlying tumor biology and can be divided into luminal-like and basal-like subtypes. We describe here the first subtype-specific murine models of bladder cancer and show that Upk3a-CreERT2; Trp53L/L; PtenL/L; Rosa26LSL-Luc (UPPL: luminal-like) and BBN (basal-like) tumors are more faithful to human bladder cancer than the widely-used MB49 cells. Following engraftment into immunocompetent C57BL/6 mice, BBN tumors were more responsive to PD-1 inhibition than UPPL tumors. Responding tumors within the BBN model showed differences in immune microenvironment composition, including increased ratios of CD8+:CD4+ and memory:regulatory T cells. Finally, we predicted and confirmed immunogenicity of tumor neoantigens in each model. These UPPL and BBN models will be a valuable resource for future studies examining bladder cancer biology and immunotherapy. Copyright ©2018, American Association for Cancer Research.

Enterococcus faecium small colony variant endocarditis in an immunocompetent patient

PubMed Central

Egido, S. Hernández; Ruiz, M. Siller; Inés Revuelta, S.; García, I. García; Bellido, J.L. Muñoz

2015-01-01

Small colony variants (SCV) are slow-growing subpopulations of bacteria usually associated with auxotrophism, causing persistent or recurrent infections. Enterococcus faecalis SCV have been seldom described, and only one case of Enterococcus faecium SCV has been reported, associated with sepsis in a leukaemia patient. Here we report the first case described of bacteraemia and endocarditis by SCV E. faecium in an immunocompetent patient. PMID:26862434

Enterococcus faecium small colony variant endocarditis in an immunocompetent patient.

PubMed

Egido, S Hernández; Ruiz, M Siller; Inés Revuelta, S; García, I García; Bellido, J L Muñoz

2016-01-01

Small colony variants (SCV) are slow-growing subpopulations of bacteria usually associated with auxotrophism, causing persistent or recurrent infections. Enterococcus faecalis SCV have been seldom described, and only one case of Enterococcus faecium SCV has been reported, associated with sepsis in a leukaemia patient. Here we report the first case described of bacteraemia and endocarditis by SCV E. faecium in an immunocompetent patient.

Chimeric Mice with Competent Hematopoietic Immunity Reproduce Key Features of Severe Lassa Fever.

PubMed

Oestereich, Lisa; Lüdtke, Anja; Ruibal, Paula; Pallasch, Elisa; Kerber, Romy; Rieger, Toni; Wurr, Stephanie; Bockholt, Sabrina; Pérez-Girón, José V; Krasemann, Susanne; Günther, Stephan; Muñoz-Fontela, César

2016-05-01

Lassa fever (LASF) is a highly severe viral syndrome endemic to West African countries. Despite the annual high morbidity and mortality caused by LASF, very little is known about the pathophysiology of the disease. Basic research on LASF has been precluded due to the lack of relevant small animal models that reproduce the human disease. Immunocompetent laboratory mice are resistant to infection with Lassa virus (LASV) and, to date, only immunodeficient mice, or mice expressing human HLA, have shown some degree of susceptibility to experimental infection. Here, transplantation of wild-type bone marrow cells into irradiated type I interferon receptor knockout mice (IFNAR-/-) was used to generate chimeric mice that reproduced important features of severe LASF in humans. This included high lethality, liver damage, vascular leakage and systemic virus dissemination. In addition, this model indicated that T cell-mediated immunopathology was an important component of LASF pathogenesis that was directly correlated with vascular leakage. Our strategy allows easy generation of a suitable small animal model to test new vaccines and antivirals and to dissect the basic components of LASF pathophysiology.

A rare case of spontaneous Aspergillus spondylodiscitis with epidural abscess in a 45-year-old immunocompetent female

PubMed Central

Raj, K. Ambedkar; Srinivasamurthy, Banushree C.; Nagarajan, Krishnan; Sinduja, M. G. Ilavarasi

2013-01-01

Vertebral osteomyelitis and discitis are mainly due to bacterial infections though fungal infections are one of the important causes of morbidity and mortality in immunocompromised patients. Aspergillus involving intervertebral disc space is extremely rare. We report a case of aspergillosis of intervertebral L5-S1 disc space with spinal epidural abscess in an immunocompetent 45-year-old female which can add on to a few case reports described in literature as well as an insight for clinicians regarding this rare spontaneous infection in an immunocompetent patient. PMID:24744568

Nontuberculous mycobacterial infection of the musculoskeletal system in immunocompetent hosts.

PubMed

Gundavda, Manit K; Patil, Hitendra G; Agashe, Vikas M; Soman, Rajeev; Rodriques, Camilla; Deshpande, Ramesh B

2017-01-01

Nontuberculous mycobacteria (NTM) were considered saprophytic organisms for many years but now are recognized as human pathogens. Although humans are routinely exposed to NTM, the rate of clinical infection is low. Such infections usually occur in the elderly and in patients who are immunocompromised. However, there has been an increasing incidence in recent years of infections in immunocompetent hosts. NTM infections in immunocompetent individuals are secondary to direct inoculation either contamination from surgical procedures or penetrating injuries rather than hematogenous dissemination. Clinically and on histopathology, musculoskeletal infections caused by NTM resemble those caused by Mycobacterium tuberculosis but are mostly resistant to routine antituberculosis medicines. Six cases of NTM infection in immunocompetent hosts presenting to the department from 2004 to 2015 were included in study. Of which two cases (one patella and one humerus) of infection were following an open wound due to trauma while two cases (one hip and one shoulder) of infection were by inoculation following an intraarticular injection for arthrogram of the joint, one case was infection following arthroscopy of knee joint and one case (calcaneum) was infection following local injection for the treatment of plantar fasciitis. All patients underwent inaging and tissue diagnosis with samples being sent for culture, staining, and histopathology. Clinical suspicion of NTM inoculation led to the correct diagnosis (four cases with culture positive and two cases with histopathological diagnosis). There treatment protocol for extrapulmonary NTM infection was radical surgical debridement and medical management based on drug sensitivity testing in culture positive cases. At a mean follow up of 3 years (range1-9 years) all patients had total remission and excellent results. Whenever a case of chronic granulomatous infection is encountered that does not respond to standard anti-tuberculous treatment

Testicular toxoplasmosis in a 26-year-old immunocompetent man.

PubMed

Wong, Vincent; Amarasekera, Channa; Kundu, Shilajit

2018-06-04

Testicular toxoplasmosis is a very rare presentation of Toxoplasma gondii A 26-year-old immunocompetent man presented to us with right testicular pain and a right epididymal mass. Ultrasound was concerning for malignancy and a radical orchiectomy was performed. Surgical pathology revealed chronic granulomatous inflammation which stained positive for T. gondii . © BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CD1 Mice

EPA Science Inventory

Developmental exposure to inorganic arsenic is carcinogenic in humans and mice, and adult offspring of mice exposed to inorganic arsenic can develop tumors of the lung, liver, adrenal, uterus, and ovary. It has been suggested that methylarsonous acid (MMA3+), a product of the bi...

Tumor necrosis factor-alpha during neonatal brain development affects anxiety- and depression-related behaviors in adult male and female mice.

PubMed

Babri, Shirin; Doosti, Mohammad-Hossein; Salari, Ali-Akbar

2014-03-15

A nascent literature suggests that neonatal infection is a risk factor for the development of brain, behavior and hypothalamic-pituitary-adrenal axis which can affect anxiety- and depression-related behaviors in later life. It has been documented that neonatal infection raises the concentrations of tumor necrosis factor-alpha (TNF-α) in neonate rodents and such infections may result in neonatal brain injury, at least in part, through pro-inflammatory cytokines. In addition, previous studies have shown that TNF-α is involved in cellular differentiation, neurogenesis and programmed cell death during the development of the central nervous system. We investigated for the first time whether neonatal exposure to TNF-α can affect body weight, stress-induced corticosterone (COR), anxiety- and depression-related behaviors in adult mice. In the present study, neonatal mice were treated to recombinant mouse TNF-α (0.2, 0.4, 0.7 and 1 μg/kg) or saline on postnatal days 3 and 5, then adult male and female mice were exposed to different behavioral tests. The results indicated that neonatal TNF-α treatment reduced body weight in neonatal period in both sexes. In addition, this study presents findings indicating that high doses of TNF- increase stress-induced COR levels, anxiety- and depression-related behaviors in adult males, but increase levels of anxiety without significantly influencing depression in adult female mice [corrected]. Our findings suggest that TNF-α exposure during neonatal period can alter brain and behavior development in a dose and sex-dependent manner in mice. Copyright © 2014 Elsevier B.V. All rights reserved.

Cytomegalovirus infection in immunocompetent wheezy infants: the diagnostic value of CMV PCR in bronchoalveolar lavage fluid.

PubMed

Cinel, G; Pekcan, S; Ozçelik, U; Alp, A; Yalçın, E; Doğru Ersöz, D; Kiper, N

2014-08-01

Cytomegalovirus (CMV) pneumonitis in immunocompetent hosts is uncommon but is being recognized more frequently, particularly when presenting as severe viral pneumonia. The objective of this study was to examine lower respiratory tract CMV infection in immunocompetent wheezy infants, based on polymerase chain reaction (PCR) in bronchoalveolar lavage (BAL) fluid, to compare CMV PCR results in BAL and in blood samples and to evaluate the benefits of antiviral ganciclovir therapy in these patients. Retrospective review of the records of patients referred to our tertiary care hospital between January 2000 and July 2010 who had unexplained persistent wheezing and underwent fibreoptic flexible bronchoscopy (FFB). Fibreoptic flexible bronchoscopy was applied to 102 infants with persistent wheezing and diffuse interstitial infiltration on radiological investigations; so CMV PCR in BAL fluid was performed. CMV PCR in BAL fluid was positive in 51 patients. Retrospectively, we had access to the files of 25 of these patients. The mean CMV PCR in BAL fluid was 334 840 copies/mL. Only eight patients had CMV PCR positivity in their blood samples (mean: 2026·3 copies/mL). There was not a relationship between BAL and blood CMV PCR values based on Spearman's correlation analysis (r = -0·008). Fourteen patients had severe respiratory symptoms and received ganciclovir therapy. Twelve of them fully recovered. Bronchoalveolar lavage fluid CMV PCR was superior to blood CMV PCR in diagnosing lower respiratory tract infections caused by CMV in immunocompetent infants. Ganciclovir therapy may be effective in selected immunocompetent wheezy infants with CMV PCR positivity in BAL fluid. © 2014 John Wiley & Sons Ltd.

Thin-section computed tomography findings in 104 immunocompetent patients with adenovirus pneumonia.

PubMed

Park, Chan Kue; Kwon, Hoon; Park, Ji Young

2017-08-01

Background To date, there has been no computed tomography (CT) evaluation of adenovirus pneumonia in a large number of immunocompetent patients. Purpose To describe the thin-section CT findings of immunocompetent patients with adenovirus pneumonia. Material and Methods We prospectively enrolled 104 patients with adenovirus pneumonia from a military hospital. CT scans of each patient were retrospectively and independently assessed by two radiologists for the presence of abnormalities, laterality and zonal predominance of the parenchymal abnormalities, and dominant imaging patterns and their anatomic distributions. Results CT findings included consolidation (n = 92), ground-glass opacity (GGO; n = 82), septal thickening (n = 34), nodules (n = 46), bronchial wall thickening (n = 32), pleural effusion (n = 16), and lymphadenopathy (n = 3). Eighty-four patients (81%) exhibited unilateral parenchymal abnormalities and 57 (57%) exhibited lower lung zone abnormalities. The most frequently dominant CT pattern was consolidation with surrounding GGO (n = 50), with subpleural (70%) and peribronchovascular (94%) distributions. Consolidation-the second-most common pattern (n = 33)-also exhibited subpleural (79%) and peribronchovascular (97%) distributions. The dominant nodule pattern (n = 14) exhibited mixed (64%) and peribronchovascular (100%) distributions. A dominant GGO pattern was only observed in four patients; none had central distribution. Conclusion Although the manifestations of adenovirus pneumonia on CT are varied, we found the most frequent pattern was consolidation with or without surrounding GGO, with subpleural and peribronchovascular distributions. Parenchymal abnormalities were predominantly unilateral and located in the lower lung zone. If dominant consolidation findings are present in immunocompetent patients during the early stages, adenovirus pneumonia should be considered.

Valomaciclovir versus valacyclovir for the treatment of acute herpes zoster in immunocompetent adults: a randomized, double-blind, active-controlled trial.

PubMed

Tyring, Stephen K; Plunkett, Stephanie; Scribner, Anita R; Broker, Robert E; Herrod, John N; Handke, Lane T; Wise, John M; Martin, Paul A

2012-08-01

Herpes zoster is a common infectious disease that can result in significant acute and chronic morbidity. The safety and efficacy of once-daily oral valomaciclovir (EPB-348) was evaluated for non-inferiority to 3-times daily valacyclovir, an approved therapy. In this study, 373 immunocompetent adults with onset of a herpes zoster rash within the preceding 72 hr were randomly assigned to receive one of four treatments for 7 days: (1) EPB-348 1,000 mg once-daily; (2) EPB-348 2,000 mg once-daily; (3) EPB-348 3,000 mg once-daily; or (4) valacyclovir 1,000 mg 3-times daily. A 20% margin was the reference for non-inferiority assessment. For the primary efficacy measure of time to complete crusting of the zoster rash by Day 28, non-inferiority criteria were met for once-daily EPB-348 2,000 mg and once-daily EPB-348 3,000 mg compared to 3-times daily valacyclovir. Additionally, EPB-348 3,000 mg significantly shortened the time to complete rash crusting by Day 28 compared to valacyclovir. For secondary efficacy measures, non-inferiority was achieved for the EPB-348 1,000 and 2,000 mg groups compared to the valacyclovir group for time to rash resolution by Day 28. No EPB-348 group was non-inferior to valacyclovir for time to cessation of new lesion formation or time to cessation of pain by Day 120, though no significant differences occurred between treatment groups. Nausea, headache, and vomiting were the most common adverse events. Based on these results, additional studies are warranted to define further EPB-348's potential as an effective and safe therapy for acute herpes zoster. Copyright © 2012 Wiley Periodicals, Inc.

Wnt5a is essential for hippocampal dendritic maintenance and spatial learning and memory in adult mice

PubMed Central

Chen, Chih-Ming; Orefice, Lauren L.; Chiu, Shu-Ling; LeGates, Tara A.; Huganir, Richard L.; Zhao, Haiqing; Xu, Baoji; Kuruvilla, Rejji

2017-01-01

Stability of neuronal connectivity is critical for brain functions, and morphological perturbations are associated with neurodegenerative disorders. However, how neuronal morphology is maintained in the adult brain remains poorly understood. Here, we identify Wnt5a, a member of the Wnt family of secreted morphogens, as an essential factor in maintaining dendritic architecture in the adult hippocampus and for related cognitive functions in mice. Wnt5a expression in hippocampal neurons begins postnatally, and its deletion attenuated CaMKII and Rac1 activity, reduced GluN1 glutamate receptor expression, and impaired synaptic plasticity and spatial learning and memory in 3-mo-old mice. With increased age, Wnt5a loss caused progressive attrition of dendrite arbors and spines in Cornu Ammonis (CA)1 pyramidal neurons and exacerbated behavioral defects. Wnt5a functions cell-autonomously to maintain CA1 dendrites, and exogenous Wnt5a expression corrected structural anomalies even at late-adult stages. These findings reveal a maintenance factor in the adult brain, and highlight a trophic pathway that can be targeted to ameliorate dendrite loss in pathological conditions. PMID:28069946

Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

PubMed

Castilla-Ortega, Estela; Blanco, Eduardo; Serrano, Antonia; Ladrón de Guevara-Miranda, David; Pedraz, María; Estivill-Torrús, Guillermo; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Santín, Luis J

2016-05-01

We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model. © 2015 Society for the Study of Addiction.

BALB/c mice resistant to Toxoplasma gondii infection proved to be highly susceptible when previously infected with Myocoptes musculinus fur mites

PubMed Central

Welter, Áurea; Mineo, José Roberto; de Oliveira Silva, Deise Aparecida; Lourenço, Elaine Vicente; Ferro, Eloísa Amália Vieira; Roque-Barreira, Maria Cristina; da Silva, Neide Maria

2007-01-01

Summary The immune response induced by Toxoplasma gondii is characterized by Th1 immune mechanisms. We previously demonstrated that C57BL/6 mice infested with Myocoptes musculinus and infected with T. gondii by intraperitoneal route undergo accelerated mortality according to Th2 immune mechanisms induced by the acarian. To evaluate whether infection with M. musculinus influences T. gondii-induced Th1 response in a resistant mouse lineage, BALB/c, which develops latent chronic toxoplasmosis in a way similar to that observed in immunocompetent humans, this study was done. The animals were infected with T. gondii ME-49 strain 1 month after M. musculinus infestation, being the survival and the immune response monitored. The double-infected displayed higher mortality rate if compared with the mono-infected mice. In addition, infection with M. musculinus changed the T. gondii-specific immune response, converting BALB/c host to a susceptible phenotype. Spleen cells had increased the levels of IL-4 in double-infected mice. This alteration was associated with severe pneumonia, encephalitis and wasting condition. In addition, a higher tissue parasitism was observed in double-infected animals. It can be concluded that infection with these two contrasting parasites, M. musculinus and T. gondii, may convert an immunocompetent host into a susceptible one, and such a host will develop severe toxoplasmosis. PMID:17877534

Identification of an Astrovirus Commonly Infecting Laboratory Mice in the US and Japan

PubMed Central

Ng, Terry Fei Fan; Kondov, Nikola O.; Hayashimoto, Nobuhito; Uchida, Ritsuki; Cha, Yunhee; Beyer, Ashley I.; Wong, Walt; Pesavento, Patricia A.; Suemizu, Hiroshi; Muench, Marcus O.; Delwart, Eric

2013-01-01

Mice (Mus musculus) are the most commonly used laboratory animals. Viral metagenomics on tissues of immunodeficient mice revealed sequences of a novel mammalian astrovirus. Using PCR, we screened mice from 4 breeders, 4 pharmaceutical companies, 14 research institutes and 30 universities in the US and Japan. Mice from one US breeder tested positive while none from Japanese breeders were positive for MuAstV. Mice in over half of the universities (19/30), institutes (7/14) and pharmaceutical animal facilities (2/4) investigated revealed the presence of MuAstV. Nine mice strains tested positive including both immunodeficient strains (NSG, NOD-SCID, NSG-3GS, C57BL6-Timp-3 −/−, and uPA-NOG) and immunocompetent strains (B6J, ICR, Bash2, BALB/c). Our data indicates that MuAstV has a wide geographical, institutional and host strain distribution. Comparison of the MuAstV RdRp sequences showed numerous mutations indicating ongoing viral divergence in different facilities. This study demonstrates the need for metagenomic screening of laboratory animals to identify adventitious infections that may affect experimental outcomes. PMID:23825590

Transient postnatal fluoxetine leads to decreased brain arachidonic acid metabolism and cytochrome P450 4A in adult mice.

PubMed

Ramadan, Epolia; Blanchard, Helene; Cheon, Yewon; Fox, Meredith A; Chang, Lisa; Chen, Mei; Ma, Kaizong; Rapoport, Stanley I; Basselin, Mireille

2014-05-01

Fetal and perinatal exposure to selective serotonin (5-HT) reuptake inhibitors (SSRIs) has been reported to alter childhood behavior, while transient early exposure in rodents is reported to alter their behavior and decrease brain extracellular 5-HT in adulthood. Since 5-HT2A/2C receptor-mediated neurotransmission can involve G-protein coupled activation of cytosolic phospholipase A2 (cPLA2), releasing arachidonic acid (ARA) from synaptic membrane phospholipid, we hypothesized that transient postnatal exposure to fluoxetine would alter brain ARA metabolism in adult mice. Brain ARA incorporation coefficients k* and rates Jin were quantitatively imaged following intravenous [1-(14)C]ARA infusion of unanesthetized adult mice that had been injected daily with fluoxetine (10mg/kg i.p.) or saline during postnatal days P4-P21. Expression of brain ARA metabolic enzymes and other relevant markers also was measured. On neuroimaging, k* and Jin was decreased widely in early fluoxetine- compared to saline-treated adult mice. Of the enzymes measured, cPLA2 activity was unchanged, while Ca(2+)-independent iPLA2 activity was increased. There was a significant 74% reduced protein level of cytochrome P450 (CYP) 4A, which can convert ARA to 20-HETE. Reduced brain ARA metabolism in adult mice transiently exposed to postnatal fluoxetine, and a 74% reduction in CYP4A protein, suggest long-term effects independent of drug presence in brain ARA metabolism, and in CYP4A metabolites. These changes might contribute to reported altered behavior following early SSRI in rodents. Published by Elsevier Ltd.

Expression of genes involved in carbohydrate-lipid metabolism in muscle and fat tissues in the initial stage of adult-age obesity in fed and fasted mice.

PubMed

Bazhan, Nadezhda M; Baklanov, Alexandr V; Piskunova, Julia V; Kazantseva, Antonina J; Makarova, Elena N

2017-10-01

C57Bl mice exhibit impaired glucose metabolism by the late adult age under standard living conditions. The aim of this study was to evaluate white adipose tissue (WAT), brown adipose tissue (BAT), and skeletal muscle expression of genes involved in carbohydrate-lipid metabolism at postpubertal stages preceding the late adult age in C57Bl mice. Muscle mRNA levels of uncoupling protein 3 ( Ucp3 ) and carnitine palmitoyltransferase 1 ( Cpt1 ) (indicators of FFA oxidation), WAT mRNA levels of hormone-sensitive lipase ( Lipe ) and lipoprotein lipase ( Lpl ) (indicators of lipolysis and lipogenesis), muscle and WAT mRNA levels of the type 4 glucose transporter Slc2a4 (indicators of insulin-dependent glucose uptake), and BAT mRNA levels of uncoupling protein 1 ( Ucp1 ) (indicator of thermogenesis) were measured in fed and 16 h-fasted mice in three age groups: 10-week-old (young), 15-week-old (early adult), and 30-week-old (late adult). Weight gain from young to early adult age was not accompanied by changes in WAT and BAT indexes and biochemical blood parameters. Weight gain from early to late adult age was accompanied by increased WAT and BAT indexes and decreased glucose tolerance. Muscle Ucp3 and Cpt1 mRNA levels and WAT Lipe and Slc2a4 mRNA levels increased from young to early adult age and then sharply decreased by the late adult age. Moreover, BAT Ucp1 mRNA level decreased in the late adult age. Fasting failed to increase muscle Cpt1 mRNA levels in late adult mice. These transcriptional changes could contribute to impaired glucose metabolism and the onset of obesity in late adult mice during normal development. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Cellular immunocompetence in melanoma: effect of extent of disease and immunotherapy.

PubMed Central

Lui, V. K.; Karpuchas, J.; Dent, P. B.; McCulloch, P. B.; Blajchman, M. A.

1975-01-01

Cell mediated immunocompetence was measured serially in 35 patients with malignant melanoma in order to determine the effect of extent of disease and prognosis as well as the influence of BCG immunotherapy on immune reactivity. Compared with normal adult controls, statistically significant lymphopenia occurred only in patients with widespread disease. Seventeen of 21 patients with negative pre-therapy PPD skin test converted to skin test positivity. PHA blastogenesis was depressed only in patients in the pre-terminal stages of their disease using optimal mitogen concentrations for stimulation. Threshold concentrations of this mitogen more clearly demonstrated a depressed responsiveness which correlated in severity with extent of disease. PPD induced blastogenesis was normal or increased in the majority of patients; however, the degree of stimulation by PPD was less in the BCG induced convertors than in those patients who were skin test positive before BCG treatment. Comparison of the pre- and post BCG assessments reveals no significant differences except in relation to PPD conversion. We conclude that using threshold concentrations of PHA, impaired responses are regularly associated with disease beyond the regional lymph nodes. Routine assessment of lymphocyte function by these parameters did not provide information that was not available from clinical evaluation. PMID:1233077

Conversion of adult endothelium to immunocompetent haematopoietic stem cells.

PubMed

Lis, Raphael; Karrasch, Charles C; Poulos, Michael G; Kunar, Balvir; Redmond, David; Duran, Jose G Barcia; Badwe, Chaitanya R; Schachterle, William; Ginsberg, Michael; Xiang, Jenny; Tabrizi, Arash Rafii; Shido, Koji; Rosenwaks, Zev; Elemento, Olivier; Speck, Nancy A; Butler, Jason M; Scandura, Joseph M; Rafii, Shahin

2017-05-25

Developmental pathways that orchestrate the fleeting transition of endothelial cells into haematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully reprogramming adult mouse endothelial cells to haematopoietic stem cells (rEC-HSCs) through transient expression of the transcription-factor-encoding genes Fosb, Gfi1, Runx1, and Spi1 (collectively denoted hereafter as FGRS) and vascular-niche-derived angiocrine factors. The induction phase (days 0-8) of conversion is initiated by expression of FGRS in mature endothelial cells, which results in endogenous Runx1 expression. During the specification phase (days 8-20), RUNX1 + FGRS-transduced endothelial cells commit to a haematopoietic fate, yielding rEC-HSCs that no longer require FGRS expression. The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (days 20-28). rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to those of adult haematopoietic stem cells, and can be used for clonal engraftment and serial primary and secondary multi-lineage reconstitution, including antigen-dependent adaptive immune function. Inhibition of TGFβ and CXCR7 or activation of BMP and CXCR4 signalling enhanced generation of rEC-HSCs. Pluripotency-independent conversion of endothelial cells into autologous authentic engraftable haematopoietic stem cells could aid treatment of haematological disorders.

Variable phenotypic penetrance of thrombosis in adult mice after tissue-selective and temporally controlled Thbd gene inactivation

PubMed Central

van Mens, Thijs E.; Liang, Hai-Po H.; Basu, Sreemanti; Hernandez, Irene; Zogg, Mark; May, Jennifer; Zhan, Min; Yang, Qiuhui; Foeckler, Jamie; Kalloway, Shawn; Sood, Rashmi; Karlson, Caren Sue

2017-01-01

Thrombomodulin (Thbd) exerts pleiotropic effects on blood coagulation, fibrinolysis, and complement system activity by facilitating the thrombin-mediated activation of protein C and thrombin-activatable fibrinolysis inhibitor and may have additional thrombin- and protein C (pC)-independent functions. In mice, complete Thbd deficiency causes embryonic death due to defective placental development. In this study, we used tissue-selective and temporally controlled Thbd gene ablation to examine the function of Thbd in adult mice. Selective preservation of Thbd function in the extraembryonic ectoderm and primitive endoderm via the Meox2Cre-transgene enabled normal intrauterine development of Thbd-deficient (Thbd−/−) mice to term. Half of the Thbd−/− offspring expired perinatally due to thrombohemorrhagic lesions. Surviving Thbd−/− animals only rarely developed overt thrombotic lesions, exhibited low-grade compensated consumptive coagulopathy, and yet exhibited marked, sudden-onset mortality. A corresponding pathology was seen in mice in which the Thbd gene was ablated after reaching adulthood. Supplementation of activated PC by transgenic expression of a partially Thbd-independent murine pC zymogen prevented the pathologies of Thbd−/− mice. However, Thbd−/− females expressing the PC transgene exhibited pregnancy-induced morbidity and mortality with near-complete penetrance. These findings suggest that Thbd function in nonendothelial embryonic tissues of the placenta and yolk sac affects through as-yet-unknown mechanisms the penetrance and severity of thrombosis after birth and provide novel opportunities to study the role of the natural Thbd-pC pathway in adult mice and during pregnancy. PMID:28920104

Environmental enrichment and social interaction improve cognitive function and decrease reactive oxidative species in normal adult mice.

PubMed

Doulames, Vanessa; Lee, Sangmook; Shea, Thomas B

2014-05-01

Environmental stimulation and increased social interactions stimulate cognitive performance, while decrease in these parameters can exacerbate cognitive decline as a function of illness, injury, or age. We examined the impact of environmental stimulation and social interactions on cognitive performance in healthy adult C57B1/6J mice. Mice were housed for 1 month individually or in groups of three (to prevent or allow social interaction) in either a standard environment (SE) or an enlarged cage containing nesting material and items classically utilized to stimulate exploration and activity ("enriched environment"; EE). Cognitive performance was tested by Y maze navigation and Novel Object Recognition (NOR; which compares the relative amount of time mice spent investigating a novel vs. a familiar object). Mice maintained for 1 month under isolated conditions in the SE statistically declined in performance versus baseline in the Y maze (p < 0.02; ANOVA). Performance under all other conditions did not change from baseline. Maintenance in groups in the SE statistically improved NOR (p < 0.01), whereas maintenance in isolation in the SE did not alter performance from baseline. Maintenance in the EE statistically improved performance in NOR for mice housed in groups and individually (p < 0.01). Maintenance under isolated conditions slightly increased reactive oxygen/nitrogen species (ROS/RNS) in brain. Environmental enrichment did not influence ROS/RNS. These findings indicate that environmental and social enrichment can positively influence cognitive performance in healthy adult mice, and support the notion that proactive approaches may delay age-related cognitive decline.

Herpes zoster-associated acute urinary retention in immunocompetent patient*

PubMed Central

Marques, Silvio Alencar; Hortense, Juliana

2014-01-01

Herpes zoster-associated urinary retention is an uncommon event related to virus infection of the S2-S4 dermatome. The possible major reasons are ipsilateral hemicystitis, neuritis-induced or myelitis-associated virus infection. We report a case of a 65-year-old immunocompetent female patient who presented an acute urinary retention after four days under treatment with valacyclovir for gluteal herpes zoster. The patient had to use a vesical catheter, was treated with antibiotics and corticosteroids and fully recovered after eight weeks. PMID:25387508

Nondermatophytic onychomycosis by Fusarium oxysporum in an immunocompetent host.

PubMed

Shah, S R; Dalal, B D; Modak, M S

2016-03-01

Fusarium onychomycosis is not uncommon in tropical countries but is worth reporting. We report a case of nondermatophytic onychomycosis by Fusarium oxysporum in an immunocompetent woman from Buldhana district of Maharashtra (India). Bilateral involvement of great toe nail, chronic duration and acquisition of infection due to peculiar practice of daily pasting floors with mud and dung, is interesting. The case was successfully treated with topical and oral terbinafine with a dose of 250 mg daily for 3 weeks. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

Current treatment of ocular toxoplasmosis in immunocompetent patients: A network meta-analysis.

PubMed

Zhang, Yanxia; Lin, Xiao; Lu, Fangli

2018-04-25

Ocular toxoplasmosis (OT) is the most frequent form of infectious posterior uveitis caused by the protozoan parasite Toxoplasma gondii. To evaluate the available evidence in peer-reviewed publications about the most effective therapy for OT in immunocompetent patients, herein a systematic literature search was conducted using Embase, PubMed, Google Scholar, and the Cochrane Central Register of Controlled Trials (CENTRAL) database from January 1987 to October 2017, with search terms "OT", "retinochoroiditis", "treatment", and "immunocompetent"; search filters "controlled clinical trial", "randomized clinical trial", and "clinical trial". The included studies were performed to evaluate the various treatment modalities of OT. Different treatment regimens were compared with regard to the improvement of visual acuity, the resolution of vitreous inflammation, recurrence, and side-effects. We independently extracted data and assessed eligibility and risk of bias using the preferred reporting items for systematic reviews and meta-analysis, and resolved any disagreement through discussion. A Bayesian network meta-analysis model was used to evaluate the interesting outcomes of all the interventions. Total 10 trials of treatments for OT were found to meet the inclusion criteria. Six trials of treatments including clindamycin, azithromycin, and trimethoprim-sulfamethoxazole (TMP-SMX) were compared with conventional therapy (the combination of pyrimethamine, sulfadiazine, and prednisone) for evaluation of the effect on visual acuity, vitreous inflammation, recurrence of OT, and side-effects. Two trials were compared TMP-SMX with placebo. One trial was compared azithromycin with TMP-SMX. And another trial was compared among treatments with clindamycin, P-S, TMP-SMX, and placebo. Based on our network meta-analysis, therapy with TMP-SMX seems to be an alternative treatment of OT in immunocompetent patients. Copyright © 2018 Elsevier B.V. All rights reserved.

Genetic diversity predicts pathogen resistance and cell-mediated immunocompetence in house finches

PubMed Central

Hawley, Dana M; Sydenstricker, Keila V; Kollias, George V; Dhondt, André A

2005-01-01

Evidence is accumulating that genetic variation within individual hosts can influence their susceptibility to pathogens. However, there have been few opportunities to experimentally test this relationship, particularly within outbred populations of non-domestic vertebrates. We performed a standardized pathogen challenge in house finches (Carpodacus mexicanus) to test whether multilocus heterozygosity across 12 microsatellite loci predicts resistance to a recently emerged strain of the bacterial pathogen, Mycoplasma gallisepticum (MG). We simultaneously tested whether the relationship between heterozygosity and pathogen susceptibility is mediated by differences in cell-mediated or humoral immunocompetence. We inoculated 40 house finches with MG under identical conditions and assayed both humoral and cell-mediated components of the immune response. Heterozygous house finches developed less severe disease when infected with MG, and they mounted stronger cell-mediated immune responses to phytohaemagglutinin. Differences in cell-mediated immunocompetence may, therefore, partly explain why more heterozygous house finches show greater resistance to MG. Overall, our results underscore the importance of multilocus heterozygosity for individual pathogen resistance and immunity. PMID:17148199

A virtual tissue bank for primary central nervous system lymphomas in immunocompetent individuals.

PubMed

Ponzoni, Maurilio; Kwee, Ivo; Mazzucchelli, Luca; Ferreri, Andrés J M; Zucca, Emanuele; Doglioni, Claudio; Cavalli, Franco; Bertoni, Francesco

2007-01-01

Primary central nervous system lymphoma (PCNSL) is a rare form of extranodal non-Hodgkin's lymphoma with continuously increasing incidence in both immunosuppressed and immunocompetent individuals. PCNSL is a very aggressive tumor with a poor outcome, and its clinical outcome is much worse than for nodal lymphomas. Differently from lymphomas arising in lymph nodes or in other extranodal sites, the treatment of PCNSL remains very unsatisfactory. Current biologic knowledge of PCNSL is still limited and several fundamental questions remain to be answered. This is mainly due to the paucity of PCNSL material for adequate translational research. With the aim of providing biologic material to investigators interested in PCNSL, we have implemented a virtual tissue bank (VTB) for PCNSL in immunocompetent patients. After registration, the VTB is accessible via any web browser at www.ielsg.org. Only anonymous data are centralized at the website of the International Extranodal Lymphoma Study Group, whilst the pathologic material is maintained at the local pathology institutes. (c) 2007 S. Karger AG, Basel.

Characteristics of Multi-Organ Lymphangiectasia Resulting from Temporal Deletion of Calcitonin Receptor-Like Receptor in Adult Mice

PubMed Central

Hoopes, Samantha L.; Willcockson, Helen H.; Caron, Kathleen M.

2012-01-01

Adrenomedullin (AM) and its receptor complexes, calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2/3, are highly expressed in lymphatic endothelial cells and are required for embryonic lymphatic development. To determine the role of Calcrl in adulthood, we used an inducible Cre-loxP system to temporally and ubiquitously delete Calcrl in adult mice. Following tamoxifen injection, Calcrlfl/fl/CAGGCre-ER™ mice rapidly developed corneal edema and inflammation that was preceded by and persistently associated with dilated corneoscleral lymphatics. Lacteals and submucosal lymphatic capillaries of the intestine were also dilated, while mesenteric collecting lymphatics failed to properly transport chyle after an acute Western Diet, culminating in chronic failure of Calcrlfl/fl/CAGGCre-ER™ mice to gain weight. Dermal lymphatic capillaries were also dilated and chronic edema challenge confirmed significant and prolonged dermal lymphatic insufficiency. In vivo and in vitro imaging of lymphatics with either genetic or pharmacologic inhibition of AM signaling revealed markedly disorganized lymphatic junctional proteins ZO-1 and VE-cadherin. The maintenance of AM signaling during adulthood is required for preserving normal lymphatic permeability and function. Collectively, these studies reveal a spectrum of lymphatic defects in adult Calcrlfl/fl/CAGGCre-ER™ mice that closely recapitulate the clinical symptoms of patients with corneal, intestinal and peripheral lymphangiectasia. PMID:23028890

Characteristics of multi-organ lymphangiectasia resulting from temporal deletion of calcitonin receptor-like receptor in adult mice.

PubMed

Hoopes, Samantha L; Willcockson, Helen H; Caron, Kathleen M

2012-01-01

Adrenomedullin (AM) and its receptor complexes, calcitonin receptor-like receptor (Calcrl) and receptor activity modifying protein 2/3, are highly expressed in lymphatic endothelial cells and are required for embryonic lymphatic development. To determine the role of Calcrl in adulthood, we used an inducible Cre-loxP system to temporally and ubiquitously delete Calcrl in adult mice. Following tamoxifen injection, Calcrl(fl/fl)/CAGGCre-ER™ mice rapidly developed corneal edema and inflammation that was preceded by and persistently associated with dilated corneoscleral lymphatics. Lacteals and submucosal lymphatic capillaries of the intestine were also dilated, while mesenteric collecting lymphatics failed to properly transport chyle after an acute Western Diet, culminating in chronic failure of Calcrl(fl/fl)/CAGGCre-ER™ mice to gain weight. Dermal lymphatic capillaries were also dilated and chronic edema challenge confirmed significant and prolonged dermal lymphatic insufficiency. In vivo and in vitro imaging of lymphatics with either genetic or pharmacologic inhibition of AM signaling revealed markedly disorganized lymphatic junctional proteins ZO-1 and VE-cadherin. The maintenance of AM signaling during adulthood is required for preserving normal lymphatic permeability and function. Collectively, these studies reveal a spectrum of lymphatic defects in adult Calcrl(fl/fl)/CAGGCre-ER™ mice that closely recapitulate the clinical symptoms of patients with corneal, intestinal and peripheral lymphangiectasia.

[Investigation of Pneumocystis jirovecii pneumonia and colonization in iatrogenically immunosuppressed and immunocompetent patients].

PubMed

Özkoç, Soykan; Bayram Delibaş, Songül

2015-04-01

Pneumocystis pneumonia (PCP) is a potentially life-threatening infection for the immunocompromized patients. However, Pneumocystis jirovecii colonization can also be detected in healthy individuals and in patients with various underlying lung diseases. The aim of this study was to evaluate the immunocompetent and iatrogenically immunosuppressed patients in terms of PCP and P.jirovecii colonization. A total of 92 patients (66 male, 26 female; age range: 18-93 years, median: 58.5) who underwent bronchoscopy due to various pulmonary symptoms between January 2011-April 2014, were included in the study. Of these patients, 65 were under immunosuppressive therapy (38 were treated with anti-cancer drugs, 15 with anti-rejection/immunomodulatory drugs and 12 with corticosteroids), while 27 were immunocompetent. Bronchoalveolar lavage (BAL) fluids were evaluated for the presence of P.jirovecii mitochondrial gene coding ribosomal large subunit (mtLSUrRNA) with nested PCR (nPCR) method. All of the samples were also examined by Giemsa and Gomori's methenamine silver (GMG) staining methods. P.jirovecii DNA was detected in 31 (33.7%) out of 92 BAL samples by nPCR. Although six immunosuppressed patients were positive in the first round of amplification, 26 of 65 (40%) immunosuppressed and five of 27 (18.5%) immunocompetent patients were positive with nPCR. P.jirovecii cysts and trophozoites were detected in only five (16.1%) of the 31 nPCR positive samples. The probability of being immunosuppressive among nPCR positive cases was statistically higher than nPCR negative cases (χ²= 3.940; p= 0.047). This difference was more significant in organ transplant recipients and patients under anti-rejection/immunomodulatory treatment (χ²= 6.715, p= 0.01; χ²= 5.550, p= 0.018, respectively). When clinical, laboratory and radiological findings of nPCR positive patients were considered, five patients (2 kidney transplant, 1 bone marrow transplant, 1 interstitial lung disease and 1 lung

Parasitemia in an immunocompetent horse experimentally challenged with Sarcocystis neurona sporocysts.

PubMed

Rossano, M G; Schott, H C; Murphy, A J; Kaneene, J B; Sellon, D C; Hines, M T; Hochstatter, T; Bell, J A; Mansfield, L S

2005-01-04

Equine protozoal myeloencephalitis (EPM) is a serious neurological disease of horses in Americans. Most cases are attributed to infection of the central nervous system with Sarcocystis neurona. Parasitemia has not been demonstrated in immunocompetent horses, but has been documented in one immunocompromised foal. The objective of this study was to isolate viable S. neurona from the blood of immunocompetent horses. Horses used in this study received orally administered S. neurona sporocysts (strain SN 37-R) daily for 112 days at the following doses: 100/day for 28 days, followed by 500/day for 28 days, followed by 1000/day for 56 days. On day 98 of the study, six yearling colts were selected for attempted culture of S. neurona from blood, two testing positive, two testing suspect and two testing negative for antibodies against S. neurona on day 84 of the study. Two 10 ml tubes with EDTA were filled from each horse by jugular venipuncture and the plasma fraction rich in mononuclear cells was pipetted onto confluent equine dermal cell cultures. The cultures were monitored weekly for parasite growth for 12 weeks. Merozoites grown from cultures were harvested and tested using S. neurona-specific PCR with RFLP to confirm species identity. PCR products were sequenced and compared to known strains of S. neurona. After 38 days of in vitro incubation, one cell culture from a horse testing positive for antibodies against S. neurona was positive for parasite growth while the five remaining cultures remained negative for parasite growth for all 12 weeks. The Sarcocystis isolate recovered from cell culture was confirmed to be S. neurona by PCR with RFLP. Gene sequence analysis revealed that the isolate was identical to the challenge strain SN-37R and differed from two known strains UCD1 and MIH1. To our knowledge this is the first report of parasitemia with S. neurona in an immunocompetent horse.

Conversion of adult endothelium to immunocompetent haematopoietic stem cells

PubMed Central

Lis, Raphael; Karrasch, Charles C.; Poulos, Michael G.; Kunar, Balvir; Redmond, David; Barcia Duran, Jose G.; Badwe, Chaitanya R.; Schachterle, Will; Ginsberg, Michael; Xiang, Jenny; Tabrizi, Arash Rafii; Shido, Koji; Rosenwaks, Zev; Elemento, Olivier; Speck, Nancy; Butler, Jason M.; Scandura, Joseph M.; Rafii, Shahin

2018-01-01

Developmental pathways that orchestrate the fleeting transition of endothelial cells into haematopoietic stem cells remain undefined. Here we demonstrate a tractable approach for fully converting adult mouse endothelial cells to haematopoietic stem cells (rEC-HSCs) through transient expression of genes encoding the transcription factors Fosb, Gfi1, Runx1, and Spi1 (also known as Fgrs) and vascular-niche-derived angiocrine factors. The induction phase (day 0–8) of conversion is initiated by expression of Fgrs in mature endothelial cells, which results in endogenous Runx1 expression. During the specification phase (day 8–20), Runx1+ Fgrs-transduced endothelial cells commit to a haematopoietic fate yielding rEC-HSCs that no longer require Fgrs expression. The vascular niche drives a robust self-renewal and expansion phase of rEC-HSCs (at day 20–28). rEC-HSCs have a transcriptome and long-term self-renewal capacity similar to those of adult haematopoietic stem cells, are competent for clonal engraftment and serial primary and secondary multi-lineage reconstituting potential, including antigen-dependent adaptive immune function. Inhibition of TGF-β and CXCR7 or activation of BMP and CXCR4 signalling enhanced generation of rEC-HSCs. Conversion of endothelial cells into autologous authentic engraftable haematopoietic stem cells could aid treatment of haematological disorders. PMID:28514438

Brevibacterium casei as a cause of brain abscess in an immunocompetent patient.

PubMed

Kumar, V Anil; Augustine, Deepthi; Panikar, Dilip; Nandakumar, Aswathy; Dinesh, Kavitha R; Karim, Shamsul; Philip, Rosamma

2011-12-01

Coryneform bacteria belonging to the genus Brevibacterium have emerged as opportunistic pathogens. Of the nine known species of Brevibacterium isolated from human clinical samples, Brevibacterium casei is the most frequently reported species from clinical specimens. We report the first case of B. casei brain abscess in an immunocompetent patient successfully treated by surgery and antimicrobial therapy.

A travel misadventure--visceral leishmaniasis in an immunocompetent patient.

PubMed

Delacour, H; Roche, C; Roche, B; Morand, C; Koeck, J L

2010-09-01

Visceral leishmaniasis is one of the world's most neglected diseases. Over 90% of the 500,000 annual new cases occur in only five countries: India, Nepal, Bangladesh, Sudan and North-Eastern Brazil, but the disease remains endemic in Southern Europe. We report a case of visceral leishmaniasis in an immunocompetent serviceman after a seven-day stay in the Marseilles region of South-Eastern France. This case is intended to alert clinicians to the possibility of visceral leishmaniasis in patients who develop a febrile illness after returning from travel in Southern European countries.

Angiogenic inhibitors delivered by the type III secretion system of tumor-targeting Salmonella typhimurium safely shrink tumors in mice.

PubMed

Shi, Lei; Yu, Bin; Cai, Chun-Hui; Huang, Jian-Dong

2016-12-01

Despite of a growing number of bacterial species that apparently exhibit intrinsic tumor-targeting properties, no bacterium is able to inhibit tumor growth completely in the immunocompetent hosts, due to its poor dissemination inside the tumors. Oxygen and inflammatory reaction form two barriers and restrain the spread of the bacteria inside the tumors. Here, we engineered a Salmonella typhimurium strain named ST8 which is safe and has limited ability to spread beyond the anaerobic regions of tumors. When injected systemically to tumor-bearing immunocompetent mice, ST8 accumulated in tumors at levels at least 100-fold greater than parental obligate anaerobic strain ST4. ST8/pSEndo harboring therapeutic plasmids encoding Endostatin fused with a secreted protein SopA could target vasculature at the tumor periphery, can stably maintain and safely deliver a therapeutic vector, release angiogenic inhibitors through a type III secretion system (T3SS) to interfere with the pro-angiogenic action of growth factors in tumors. Mice with murine CT26 colon cancer that had been injected with ST8/pSEndo showed efficient tumor suppression by inducing more severe necrosis and inhibiting blooding vessel density within tumors. Our findings provide a therapeutic platform for indirectly acting therapeutic strategies such as anti-angiogenesis and immune therapy.

Antagonistic effect of Lepidium meyenii (red maca) on prostatic hyperplasia in adult mice.

PubMed

Gonzales, G F; Gasco, M; Malheiros-Pereira, A; Gonzales-Castañeda, C

2008-06-01

The plants from the Lepidium gender have demonstrated to have effect on the size of the prostate. Lepidium meyenii (Maca) is a Peruvian plant that grows exclusively over 4000 m above sea level. The present study was designed to determine the effect of red maca (RM) in the prostate hyperplasia induced with testosterone enanthate (TE) in adult mice. Prostate hyperplasia was induced by administering TE, and then these animals (n = 6, each group) were treated with RM or Finasteride (positive control) for 21 days. There was an additional group without prostate hyperplasia (vehicle). Mice were killed on days 7, 14 and 21 after treatment with RM. Testosterone and oestradiol levels were measured on the last day of treatment. Prostatic stroma, epithelium and acini were measured histologically. RM reduced prostate weight at 21 days of treatment. Weights of seminal vesicles, testis and epididymis were not affected by RM treatment. The reduction in prostate size by RM was 1.59 times. Histological analysis showed that TE increased 2-fold the acinar area, effect prevented in the groups receiving TE + RM for 14 (P < 0.05) and 21 (P < 0.05) days and the group receiving TE + Finasteride for 21 days (P < 0.05). TE increased prostatic stroma area and this effect was prevented by treatment with RM since 7 days of treatment or Finasteride. The reduction in prostatic stroma area by RM was 1.42 times. RM has an anti-hyperplastic effect on the prostate of adult mice when hyperplasia was induced with TE acting first at prostatic stromal level.

Characterization of adult ghrelin and ghrelin receptor knockout mice under positive and negative energy balance

USDA-ARS?s Scientific Manuscript database

Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R) are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin(-/-) and Ghsr(-/-) mice under conditions of both positive (high-fat diet) and nega...

THE EFFECTS OF HYPERTHERMIA ON SPERMATOGENESIS, APOPTOSIS, GENE EXPRESSION AND FERTILITY IN ADULT MALE MICE

EPA Science Inventory

The effects of hyperthermia on spermatogenesis, apoptosis, gene expression and fertility in adult male mice
John C. Rockett1, Faye L. Mapp1, J. Brian Garges1, J. Christopher Luft1, Chisato Mori2 and David J. Dix1.
1Reproductive Toxicology Division, National Health and Envir...

Disseminated cutaneous sporotrichosis associated with ocular lesion in an immunocompetent patient.

PubMed

Medeiros, Karina Bittencourt; Landeiro, Luana Gomes; Diniz, Lucia Martins; Falqueto, Aloísio

2016-01-01

A 59-year-old female patient, previously healthy, immunocompetent, presented left bulbar conjunctiva lesions and nodular-ulcerated lesions on the arms and cervical region, besides left cervical and retroauricular lymphadenopathy. She had previous contact with domestic cats that excoriated her face. The diagnosis was conclusive of disseminated sporotrichosis through clinical and epidemiological history and cultures of skin and ocular secretions. It evolved with good response to oral antifungal therapy.

Disseminated cutaneous sporotrichosis associated with ocular lesion in an immunocompetent patient*

PubMed Central

Medeiros, Karina Bittencourt; Landeiro, Luana Gomes; Diniz, Lucia Martins; Falqueto, Aloísio

2016-01-01

A 59-year-old female patient, previously healthy, immunocompetent, presented left bulbar conjunctiva lesions and nodular-ulcerated lesions on the arms and cervical region, besides left cervical and retroauricular lymphadenopathy. She had previous contact with domestic cats that excoriated her face. The diagnosis was conclusive of disseminated sporotrichosis through clinical and epidemiological history and cultures of skin and ocular secretions. It evolved with good response to oral antifungal therapy. PMID:27579758

Long-Term Intermittent Hypoxia Elevates Cobalt Levels in the Brain and Injures White Matter in Adult Mice

PubMed Central

Veasey, Sigrid C.; Lear, Jessica; Zhu, Yan; Grinspan, Judith B.; Hare, Dominic J.; Wang, SiHe; Bunch, Dustin; Doble, Philip A.; Robinson, Stephen R.

2013-01-01

Study Objectives: Exposure to the variable oxygenation patterns in obstructive sleep apnea (OSA) causes oxidative stress within the brain. We hypothesized that this stress is associated with increased levels of redox-active metals and white matter injury. Design: Participants were randomly allocated to a control or experimental group (single independent variable). Setting: University animal house. Participants: Adult male C57BL/6J mice. Interventions: To model OSA, mice were exposed to long-term intermittent hypoxia (LTIH) for 10 hours/day for 8 weeks or sham intermittent hypoxia (SIH). Measurements and Results: Laser ablation-inductively coupled plasma-mass spectrometry was used to quantitatively map the distribution of the trace elements cobalt, copper, iron, and zinc in forebrain sections. Control mice contained 62 ± 7 ng cobalt/g wet weight, whereas LTIH mice contained 5600 ± 600 ng cobalt/g wet weight (P < 0.0001). Other elements were unchanged between conditions. Cobalt was concentrated within white matter regions of the brain, including the corpus callosum. Compared to that of control mice, the corpus callosum of LTIH mice had significantly more endoplasmic reticulum stress, fewer myelin-associated proteins, disorganized myelin sheaths, and more degenerated axon profiles. Because cobalt is an essential component of vitamin B12, serum methylmalonic acid (MMA) levels were measured. LTIH mice had low MMA levels (P < 0.0001), indicative of increased B12 activity. Conclusions: Long-term intermittent hypoxia increases brain cobalt, predominantly in the white matter. The increased cobalt is associated with endoplasmic reticulum stress, myelin loss, and axonal injury. Low plasma methylmalonic acid levels are associated with white matter injury in long-term intermittent hypoxia and possibly in obstructive sleep apnea. Citation: Veasey SC; Lear J; Zhu Y; Grinspan JB; Hare DJ; Wang S; Bunch D; Doble PA; Robinson SR. Long-term intermittent hypoxia elevates cobalt

Round and Round and Round We Go: Behavior of Adult Female Mice on the ISS

NASA Technical Reports Server (NTRS)

Ronca, April E.

2016-01-01

The NASA Decadal Survey (2011) emphasized the importance of long duration rodent experiments on the International Space Station (ISS). To accomplish this objective, flight hardware and science capabilities supporting mouse studies in space were developed at Ames Research Center. Here we present a video-based behavioral analysis of ten C57BL6 female adult mice exposed to a total of 37 days in space compared with identically housed Ground Controls. Flight and Control mice exhibited the same range of behaviors, including feeding, drinking, exploratory behavior, grooming, and social interactions. Mice propelled themselves freely and actively throughout the Habitat using their forelimbs to push off or by floating from one cage area to another. Overall activity was greater in Flt as compared to GC mice. Spontaneous, organized circling or race-tracking behavior emerged within the first few days of flight and encompassed the primary dark cycle activity for the remainder of the experiment. I will summarize qualitative observations and quantitative comparisons of mice in microgravity and 1g conditions. Behavioral phenotyping revealed important insights into the overall health and adaptation of mice to the space environment, and identified unique behaviors that can guide future habitat development and research on rodents in space.

Long-Term Visual Training Increases Visual Acuity and Long-Term Monocular Deprivation Promotes Ocular Dominance Plasticity in Adult Standard Cage-Raised Mice

PubMed Central

Yusifov, Rashad

2018-01-01

Abstract For routine behavioral tasks, mice predominantly rely on olfactory cues and tactile information. In contrast, their visual capabilities appear rather restricted, raising the question whether they can improve if vision gets more behaviorally relevant. We therefore performed long-term training using the visual water task (VWT): adult standard cage (SC)-raised mice were trained to swim toward a rewarded grating stimulus so that using visual information avoided excessive swimming toward nonrewarded stimuli. Indeed, and in contrast to old mice raised in a generally enriched environment (Greifzu et al., 2016), long-term VWT training increased visual acuity (VA) on average by more than 30% to 0.82 cycles per degree (cyc/deg). In an individual animal, VA even increased to 1.49 cyc/deg, i.e., beyond the rat range of VAs. Since visual experience enhances the spatial frequency threshold of the optomotor (OPT) reflex of the open eye after monocular deprivation (MD), we also quantified monocular vision after VWT training. Monocular VA did not increase reliably, and eye reopening did not initiate a decline to pre-MD values as observed by optomotry; VA values rather increased by continued VWT training. Thus, optomotry and VWT measure different parameters of mouse spatial vision. Finally, we tested whether long-term MD induced ocular dominance (OD) plasticity in the visual cortex of adult [postnatal day (P)162–P182] SC-raised mice. This was indeed the case: 40–50 days of MD induced OD shifts toward the open eye in both VWT-trained and, surprisingly, also in age-matched mice without VWT training. These data indicate that (1) long-term VWT training increases adult mouse VA, and (2) long-term MD induces OD shifts also in adult SC-raised mice. PMID:29379877

Long-Term Visual Training Increases Visual Acuity and Long-Term Monocular Deprivation Promotes Ocular Dominance Plasticity in Adult Standard Cage-Raised Mice.

PubMed

Hosang, Leon; Yusifov, Rashad; Löwel, Siegrid

2018-01-01

For routine behavioral tasks, mice predominantly rely on olfactory cues and tactile information. In contrast, their visual capabilities appear rather restricted, raising the question whether they can improve if vision gets more behaviorally relevant. We therefore performed long-term training using the visual water task (VWT): adult standard cage (SC)-raised mice were trained to swim toward a rewarded grating stimulus so that using visual information avoided excessive swimming toward nonrewarded stimuli. Indeed, and in contrast to old mice raised in a generally enriched environment (Greifzu et al., 2016), long-term VWT training increased visual acuity (VA) on average by more than 30% to 0.82 cycles per degree (cyc/deg). In an individual animal, VA even increased to 1.49 cyc/deg, i.e., beyond the rat range of VAs. Since visual experience enhances the spatial frequency threshold of the optomotor (OPT) reflex of the open eye after monocular deprivation (MD), we also quantified monocular vision after VWT training. Monocular VA did not increase reliably, and eye reopening did not initiate a decline to pre-MD values as observed by optomotry; VA values rather increased by continued VWT training. Thus, optomotry and VWT measure different parameters of mouse spatial vision. Finally, we tested whether long-term MD induced ocular dominance (OD) plasticity in the visual cortex of adult [postnatal day (P)162-P182] SC-raised mice. This was indeed the case: 40-50 days of MD induced OD shifts toward the open eye in both VWT-trained and, surprisingly, also in age-matched mice without VWT training. These data indicate that (1) long-term VWT training increases adult mouse VA, and (2) long-term MD induces OD shifts also in adult SC-raised mice.

Altered gene expression and spine density in nucleus accumbens of adolescent and adult male mice exposed to emotional and physical stress

PubMed Central

Warren, Brandon L; Sial, Omar K.; Alcantara, Lyonna F.; Greenwood, Maria A.; Brewer, Jacob S.; Rozofsky, John P.; Parise, Eric M.; Bolaños-Guzmán, Carlos A.

2014-01-01

Stressful early life experiences are implicated in lifelong health. However, little is known about the consequences of emotional or physical stress on neurobiology. Therefore, the following set of experiments was designed to assess changes in transcription and translation of key proteins within the nucleus accumbens (NAc). Male adolescent (postnatal day [PD] 35) or adult (eight-week old) mice were exposed to emotional (ES) or physical stress (PS) using a vicarious social defeat paradigm. Twenty-four hours after the last stress session, we measured levels of specific mRNAs and proteins within the NAc. Spine density was also assessed in separate groups of mice. Exposure to ES or PS disrupted ERK2, reduced transcription of ΔFosB, and had no effect on CREB mRNA. Western blots revealed that exposure to ES or PS decreased ERK2 phosphorylation in adolescents, whereas the same stress regimen increased ERK2 phosphorylation in adults. Exposure to ES or PS had no effect on ΔFosB or CREB phosphorylation. ES and PS increased spine density in the NAc of adolescent-exposed mice, but only exposure to PS increased spine density in adults. Together, these findings demonstrate that exposure to ES or PS is a potent stressor in adolescent and adult mice, and can disturb the integrity of the NAc by altering transcription and translation of important signaling molecules in an age-dependent manner. Furthermore, exposure to ES and PS induces substantial synaptic plasticity of the NAc. PMID:24943326

Intestinal coccidian parasites as an underestimated cause of travellers' diarrhoea in Polish immunocompetent patients.

PubMed

Kłudkowska, Matylda; Pielok, Łukasz; Frąckowiak, Krystyna; Paul, Małgorzata

2017-09-26

Intestinal coccidian parasites are intracellular protozoa most frequently transmitted during food-borne and water-borne infections. This group of parasites is responsible for acute diarrhoeal illnesses especially among immunocompromised patients. However, they are more frequently detected in immunocompetent individuals including travellers, and they should also be considered as important etiologic factors of travellers' diarrhoea. We examined 221 immunocompetent patients hospitalized due to acute or chronic diarrhoea and other gastrointestinal symptoms after returning from international journeys to hot climates. A basic microscopical examination and acid - fast staining of stool samples was performed. Each patient was also a part of the epidemiological investigation to define potential risk factors of tropical gastrointestinal infections. Intestinal coccidiosis was confirmed in 12 out of 221 successively hospitalized patients (5.4%). The most common coccidian parasite was Cryptosporidium spp., detected in nine Polish travellers (4.1%). Cyclospora spp. was diagnosed in three cases (1.4%), including two mixed infections with Cryptosporidium spp., and Cystoisospora spp. in two other cases (0.9%). The study has revealed that intestinal coccidian parasites are a significant threat to immunocompetent travellers and should be always considered in the differential diagnosis of gastrointestinal disorders. Therefore, it is necessary to perform specialized diagnostic methods for the detection of Cryptosporidium spp., Cystoisospora spp., and Cyclospora spp. oocysts in reference parasitology laboratories. Clinical observations demonstrated simultaneously an insufficient level of knowledge in Polish tourists concerning the main risk factors of intestinal parasitic diseases during international travels, particularly to developing countries with lower economic and sanitary conditions.

Repeated social defeat and the rewarding effects of cocaine in adult and adolescent mice: dopamine transcription factors, proBDNF signaling pathways, and the TrkB receptor in the mesolimbic system.

PubMed

Montagud-Romero, Sandra; Nuñez, Cristina; Blanco-Gandia, M Carmen; Martínez-Laorden, Elena; Aguilar, María A; Navarro-Zaragoza, Javier; Almela, Pilar; Milanés, Maria-Victoria; Laorden, María-Luisa; Miñarro, José; Rodríguez-Arias, Marta

2017-07-01

Repeated social defeat (RSD) increases the rewarding effects of cocaine in adolescent and adult rodents. The aim of the present study was to compare the long-term effects of RSD on the conditioned rewarding effects of cocaine and levels of the transcription factors Pitx3 and Nurr1 in the ventral tegmental area (VTA), the dopamine transporter (DAT), the D2 dopamine receptor (D2DR) and precursor of brain-derived neurotrophic factor (proBDNF) signaling pathways, and the tropomyosin-related kinase B (TrkB) receptor in the nucleus accumbens (NAc) in adult and adolescent mice. Male adolescent and young adult OF1 mice were exposed to four episodes of social defeat and were conditioned 3 weeks later with 1 mg/kg of cocaine. In a second set of mice, the expressions of the abovementioned dopaminergic and proBDNF and TrkB receptor were measured in VTA and NAc, respectively. Adolescent mice experienced social defeats less intensely than their adult counterparts and produced lower levels of corticosterone. However, both adult and adolescent defeated mice developed conditioned place preference for the compartment associated with this low dose of cocaine. Furthermore, only adolescent defeated mice displayed diminished levels of the transcription factors Pitx3 in the VTA, without changes in the expression of DAT and D2DR in the NAc. In addition, stressed adult mice showed a decreased expression of proBDNF and the TrkB receptor, while stressed adolescent mice exhibited increased expression of latter without changes in the former. Our findings suggest that dopaminergic pathways and proBDNF signaling and TrkB receptors play different roles in social defeat-stressed mice exposed to cocaine.

Strain dependent effects of conditioned fear in adult C57Bl/6 and Balb/C mice following postnatal exposure to chlorpyrifos: relation to expression of brain acetylcholinesterase mRNA

PubMed Central

Oriel, Sarit; Kofman, Ora

2015-01-01

Following reports of emotional psychopathology in children and adults exposed to organophosphates, the effects of postnatal chlorpyrifos (CPF) on fear-conditioning and depression-like behaviors were tested in adult mice. Concomitant changes in expression of mRNA for synaptic and soluble splice variants of acetylcholinesterase (AChE) were examined in mouse pups and adults of the Balb/C and C57Bl/6 (B6) strains, which differ in their behavioral and hormonal stress response. Mice were injected subcutaneously with 1 mg/kg CPF on postnatal days 4–10 and tested as adults for conditioned fear, sucrose preference, and forced swim. Acetylcholinesterase activity was assessed in the brains of pups on the first and last day of treatment. Expression of soluble and synaptic AChE mRNA was assessed in brains of treated pups and fear-conditioned adults using real-time PCR. Adult Balb/C mice exposed postnatally to CPF showed exacerbated fear-conditioning and impaired active avoidance. Adult B6 mice exposed postnatally to CPF showed a more specific fear response to tones and less freezing in the inter-tone intervals, in contrast to the vehicle-pretreated mice. Chlorpyrifos also attenuated sweet preference and enhanced climbing in the forced swim test. Chlorpyrifos-treated mice had increased expression of both synaptic and readthrough AChE transcripts in the hippocampus of Balb/C mice and decreased expression in the amygdala following fear-conditioning. In conclusion, postnatal CPF had long-term effects on fear and depression, as well as on expression of AChE mRNA. These changes may be related to alteration in the interaction between hippocampus and amygdala in regulating negative emotions. PMID:25972795

Long-term effects of chronic nicotine on emotional and cognitive behaviors and hippocampus cell morphology in mice: comparisons of adult and adolescent nicotine exposure.

PubMed

Holliday, Erica D; Nucero, Paul; Kutlu, Munir G; Oliver, Chicora; Connelly, Krista L; Gould, Thomas J; Unterwald, Ellen M

2016-11-01

Nicotine dependence is associated with increased risk for emotional, cognitive and neurological impairments later in life. This study investigated the long-term effects of nicotine exposure during adolescence and adulthood on measures of depression, anxiety, learning and hippocampal pyramidal cell morphology. Mice (C57BL/6J) received saline or nicotine for 12 days via pumps implanted on postnatal day 32 (adolescent) or 54 (adults). Thirty days after cessation of nicotine/saline, mice were tested for learning using contextual fear conditioning, depression-like behaviors using the forced swim test or anxiety-like behaviors with the elevated plus maze. Brains from nicotine- or saline-exposed mice were processed with Golgi stain for whole neuron reconstruction in the CA1 and CA3 regions of the hippocampus. Results demonstrate higher depression-like responses in both adolescent and adult mice when tested during acute nicotine withdrawal. Heightened depression-like behaviors persisted when tested after 30 days of nicotine abstinence in mice exposed as adolescents, but not adults. Adult, but not adolescent, exposure to nicotine resulted in increased open-arm time when tested after 30 days of abstinence. Nicotine exposure during adolescence caused deficits in contextual fear learning indicated by lower levels of freezing to the context as compared with controls when tested 30 days later. In addition, reduced dendritic length and complexity in the apical CA1 branches in adult mice exposed to nicotine during adolescence were found. These results demonstrate that nicotine exposure and withdrawal can have long-term effects on emotional and cognitive functioning, particularly when nicotine exposure occurs during the critical period of adolescence. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Administration of midazolam in infancy does not affect learning and memory of adult mice.

PubMed

Xu, Hua; Liu, Zhi-Qiang; Liu, Yi; Zhang, Wei-Shi; Xu, Bo; Xiong, Yuan-Chang; Deng, Xiao-Ming

2009-12-01

1. Midazolam is a common fast-acting GABA(A) receptor agonist. Recent data suggest that exposure to midazolam in early life may cause long-term effects on brain function through stable epigenetic reprogramming. The aim of the present study was to determine whether the administration of midazolam to infant mice would affect their learning and memory in adulthood. 2. An open-field test was conducted before and then 3, 24, 48 and 72 h after administration of midazolam (50 mg/kg, i.p.) to infant mice. Saline control mice received an equal volume of saline i.p. 3 h before the open-field test. Total movements, total movement time, total movement distance and velocity were analysed. Novel object recognition (NOR), Morris water-maze and passive avoidance tests were performed when the treated mice grew to adulthood (105 days of age). 3. The results of open-field test showed that midazolam significantly reduced locomotor activity (total movements, total movement time, total movement distance and velocity) in infant mice 3 and 24 h after drug administration and that these effects had disappeared by 72 h after drug administration. The results of the water-maze, NOR and passive avoidance tests in adulthood (at 105 days of age) indicated that administration of midazolam in infancy had no long-term effects on the learning and memory behaviours of adult mice compared with the saline control. 4. Acute midazolam administration to infant mice affected spontaneous locomotor activity for approximately 2 days, but did not seem to have any significant impact on cognitive functioning that lasted into adulthood.

Effect of Anti-Sclerostin Therapy and Osteogenesis Imperfecta on Tissue-level Properties in Growing and Adult Mice While Controlling for Tissue Age

PubMed Central

Sinder, Benjamin P.; Lloyd, William R.; Salemi, Joseph D.; Marini, Joan C.; Caird, Michelle S.; Morris, Michael D.; Kozloff, Kenneth M.

2016-01-01

Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as Osteogenesis Imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly→Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5 weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2–4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages >3wk) and rapidly growing Brtl/+ (at tissue ages > 4wk) mice compared to WT. At identical tissue ages defined by fluorescent labels adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age

Effect of anti-sclerostin therapy and osteogenesis imperfecta on tissue-level properties in growing and adult mice while controlling for tissue age.

PubMed

Sinder, Benjamin P; Lloyd, William R; Salemi, Joseph D; Marini, Joan C; Caird, Michelle S; Morris, Michael D; Kozloff, Kenneth M

2016-03-01

Bone composition and biomechanics at the tissue-level are important contributors to whole bone strength. Sclerostin antibody (Scl-Ab) is a candidate anabolic therapy for the treatment of osteoporosis that increases bone formation, bone mass, and bone strength in animal studies, but its effect on bone quality at the tissue-level has received little attention. Pre-clinical studies of Scl-Ab have recently expanded to include diseases with altered collagen and material properties such as osteogenesis imperfecta (OI). The purpose of this study was to investigate the role of Scl-Ab on bone quality by determining bone material composition and tissue-level mechanical properties in normal wild type (WT) tissue, as well as mice with a typical OI Gly➔Cys mutation (Brtl/+) in type I collagen. Rapidly growing (3-week-old) and adult (6-month-old) WT and Brtl/+ mice were treated for 5weeks with Scl-Ab. Fluorescent guided tissue-level bone composition analysis (Raman spectroscopy) and biomechanical testing (nanoindentation) were performed at multiple tissue ages. Scl-Ab increased mineral to matrix in adult WT and Brtl/+ at tissue ages of 2-4wks. However, no treatment related changes were observed in mineral to matrix levels at mid-cortex, and elastic modulus was not altered by Scl-Ab at any tissue age. Increased mineral-to-matrix was phenotypically observed in adult Brtl/+ OI mice (at tissue ages>3wks) and rapidly growing Brtl/+ (at tissue ages>4wks) mice compared to WT. At identical tissue ages defined by fluorescent labels, adult mice had generally lower mineral to matrix ratios and a greater elastic modulus than rapidly growing mice, demonstrating that bone matrix quality can be influenced by animal age and tissue age alike. In summary, these data suggest that Scl-Ab alters the matrix chemistry of newly formed bone while not affecting the elastic modulus, induces similar changes between Brtl/+ and WT mice, and provides new insight into the interaction between tissue age and

Congenitally athymic nude (nu/nu) mice have Thy-1-bearing immunocompetent helper T cells in their peritoneal cavity

PubMed Central

1980-01-01

Heavily irradiated peritoneal cells (PC) from congenitally athymic nude (nu/nu) mice markedly restored the impaired in vitro antibody response of nu/nu spleen cells to sheep erythrocyte antigens (T-dependent antigen), whereas irradiated spleen or lymph node cells from nu/nu mice had no effect on the response. This activity of the irradiated PC of nu/nu mice was completely abolished by treatment with anti-Thy-1.2 antiserum plus normal guinea pig serum (C') and is, therefore, attributable to a function of matured T cells. PMID:6966314

Effects of Postchallenge Administration of ST-246 on Dissemination of IHD-J-Luc Vaccinia Virus in Normal Mice and in Immune-Deficient Mice Reconstituted with T Cells

PubMed Central

Shotwell, Elisabeth; Scott, John; Cruz, Stephanie; King, Lisa R.; Manischewitz, Jody; Diaz, Claudia G.; Jordan, Robert A.; Grosenbach, Douglas W.; Golding, Hana

2013-01-01

Whole-body bioimaging was used to study dissemination of vaccinia virus (VACV) in normal and in immune deficient (nu−/nu−) mice protected from lethality by postchallenge administration of ST-246. Total fluxes were recorded in the liver, spleen, lungs, and nasal cavities of live mice after intranasal infection with a recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve were calculated for individual mice to assess viral loads. Treatment for 2 to 5 days of normal BALB/c mice with ST-246 at 100 mg/kg starting 24 h postchallenge conferred 100% protection and reduced viral loads in four organs compared to control mice. Mice also survived after 5 days of treatment with ST-246 at 30 mg/kg, and yet the viral loads and poxes were higher in these mice compared to 100-mg/kg treatment group. Nude mice were not protected by ST-246 alone or by 10 million adoptively transferred T cells. In contrast, nude mice that received T cells and 7-day treatment with ST-246 survived infection and exhibited reduced viral loads compared to nonreconstituted and ST-246-treated mice after ST-246 was stopped. Similar protection of nude mice was achieved using adoptively transferred 1.0 and 0.1 million, but not 0.01 million, purified T cells or CD4+ or CD8+ T cells in conjunction with ST-246 treatment. These data suggest that ST-246 protects immunocompetent mice from lethality and reduces viral dissemination in internal organs and poxvirus lesions. Furthermore, immune-deficient animals with partial T cell reconstitution can control virus replication after a course of ST-246 and survive lethal vaccinia virus challenge. PMID:23468500

Maternal influence on susceptibility of offspring to Brugia malayi infection in a murine model of filariasis.

PubMed

Rajan, T V; Bailis, J M; Yates, J A; Shultz, L D; Greiner, D L; Nelson, F K

1994-12-01

We have used the severe combined immunodeficient C.B-17-scid/scid mouse to investigate the influences of maternal immune status and parasite burden on the susceptibility (or resistance) of offspring to infection with the human filarial parasite, Brugia malayi. C.B-17-scid/scid mice are permissive for infection while immunocompetent C.B-17(-)+/+ mice are uniformly resistant. Reciprocal matings of C.B-17-scid/scid and C.B-17(-)+/+ mice were performed. The C.B-17-scid/scid females were either naive or infected with Brugia malayi. The resulting immunocompetent C.B-17-scid/+ and C.B-17(-)+/scid progeny were challenged at weaning with an intraperitoneal injection of Brugia malayi third stage larvae known to produce patent infection in > 95% of C.B-17-scid/scid mice. We observed that 40.0%l (34/85) of the immunocompetent offspring of C.B-17-scid/scid females x C.B-17(-)+/+ males were permissive for the growth and development of Brugia malayi larvae to adults. No difference was observed in susceptibility to infection between the progeny of infected or uninfected C.B-17-scid/scid mothers mated with C.B-17(-)+/+ fathers, arguing against acquired immunological tolerance to the parasite in the former. In marked contrast, only 4.8% (2/42) of the heterozygous progeny of wild type C.B-17(-)+/+ females mated with C.B-17-scid/scid males were permissive. These observations document conversion of a 'resistant' phenotype to a 'susceptible' phenotype by manipulation of maternal immune status and provide clear evidence of maternal influence on offspring susceptibility to infection with Brugia malayi.

Immunosuppression in Early Postnatal Days Induces Persistent and Allergen-Specific Immune Tolerance to Asthma in Adult Mice

PubMed Central

Chen, Yan; Zhang, Jin; Lu, Yong; Wang, Libo

2015-01-01

Bronchial asthma is a chronic airway inflammatory condition with high morbidity, and effective treatments for asthma are limited. Allergen-specific immunotherapy can only induce peripheral immune tolerance and is not sustainable. Exploring new therapeutic strategies is of great clinical importance. Recombinant adenovirus (rAdV) was used as a vector to make cells expressing cytotoxic T lymphocyte-associated antigen-4-immunoglobulin (CTLA4Ig) a soluble CTLA4 immunoglobulin fusion protein. Dendritic cells (DCs) were modified using the rAdVs together with allergens. Then these modified DCs were transplanted to mice before allergen sensitization. The persistence and specificity of immune tolerance were evaluated in mice challenged with asthma allergens at 3 and 7 months. DCs modified by CTLA4Ig showed increased IL-10 secretion, decreased IL-12 secretion, and T cell stimulation in vitro. Mice treated with these DCs in the early neonatal period developed tolerance against the allergens that were used to induce asthma in the adult stage. Asthma symptoms, lung damage, airway reactivity, and inflammatory response all improved. Humoral immunity indices showed that this therapeutic strategy strongly suppressed mice immune responses and was maintained for as long as 7 months. Furthermore, allergen cross-sensitization and challenge experiments demonstrated that this immune tolerance was allergen-specific. Treatment with CTLA4Ig modified DCs in the early neonatal period, inducing persistent and allergen-specific immune tolerance to asthma in adult mice. Our results suggest that it may be possible to develop a vaccine for asthma. PMID:25860995

Immunization with a Novel Human type 5 Adenovirus-Vectored Vaccine Expressing the Premembrane and Envelope Proteins of Zika Virus Provides Consistent and Sterilizing Protection in Multiple Immunocompetent and Immunocompromised Animal Models.

PubMed

Guo, Qiang; Chan, Jasper Fuk-Woo; Poon, Vincent Kwok-Man; Wu, Shipo; Chan, Chris Chung-Sing; Hou, Lihua; Yip, Cyril Chik-Yan; Ren, Changpeng; Cai, Jian-Piao; Zhao, Mengsu; Zhang, Anna Jinxia; Song, Xiaohong; Chan, Kwok-Hung; Wang, Busen; Kok, Kin-Hang; Wen, Yanbo; Yuen, Kwok-Yung; Chen, Wei

2018-03-29

Zika virus (ZIKV) infection may be associated with severe complications and disseminated via both vector-borne and non-vector-borne routes. Adenovirus-vectored vaccines represent a favorable controlling measure for the ZIKV epidemic as they have been shown to be safe, immunogenic, and rapidly generable for other emerging viral infections. Evaluations of two previously reported adenovirus-vectored ZIKV vaccines were performed using non-lethal animal models and/or non-epidemic ZIKV strain. We constructed and evaluated two human adenovirus-5-vectored vaccines containing the ZIKV premembrane-envelope(Ad5-Sig-prM-Env) and envelope(Ad5-Env) proteins, respectively, in multiple non-lethal and lethal animal models using epidemic ZIKV strains. Both vaccines elicited robust humoral and cellular immune responses in immunocompetent BALB/c mice. Dexamethasone-immunosuppressed mice vaccinated with either vaccine demonstrated robust and durable antibody responses and significantly lower blood/tissue viral loads than controls(P<0.05). Similar findings were also observed in interferon-α/β-receptor-deficient A129 mice. In both these immunocompromised animal models, Ad5-Sig-prM-Env-vaccinated mice had significantly(P<0.05) higher titers of anti-ZIKV-specific neutralizing antibody titers and lower(undetectable) viral loads than Ad5-Env-vaccinated mice. The close correlation between the neutralizing antibody titer and viral load helped to explain the better protective effect of Ad5-Sig-prM-Env than Ad5-Env. Anamnestic response was absent in Ad5-Sig-prM-Env-vaccinated A129 mice. Ad5-Sig-prM-Env provided sterilizing protection against ZIKV infection in mice.

Clinical features of viral meningitis in adults: significant differences in cerebrospinal fluid findings among herpes simplex virus, varicella zoster virus, and enterovirus infections.

PubMed

Ihekwaba, Ugo K; Kudesia, Goura; McKendrick, Michael W

2008-09-15

In this retrospective study, our objective was to review the epidemiology of viral meningitis and to compare clinical features associated with enterovirus, herpes simplex virus (HSV), and varicella zoster virus (VZV) infections in immunocompetent adults. Data on cerebrospinal fluid (CSF) samples submitted to the Trust Virology Laboratory (Sheffield, UK) from April 2004 through April 2007 were reviewed. Notes on immunocompetent adults who were polymerase chain reaction (PCR) positive for enterovirus, HSV type 2, or VZV and who had presented to local clinical departments were scrutinized (4 patients were positive for HSV type 1 and did not meet the inclusion criteria). A total of 2045 samples were analyzed for viral pathogens during the 3-year period. Of the 109 PCR-positive samples, 38 (35%) were from immunocompetent adults, of whom 22 were infected with enterovirus, 8 were infected with HSV type 2, and 8 were infected with VZV. The median ages were 32 years (range, 16-39 years), 39 years (range, 22-53 years), and 47.5 years (range, 26-80 years), respectively. Rash occurred after the meningitis symptoms in 5 patients infected with VZV (median time from meningitis symptoms to rash, 6 days). Protein levels were significantly higher in CSF samples from patients infected with HSV type 2 (median, 1205 mg/L) and in samples from those infected with VZV (median, 974 mg/L) than in samples from those infected with enterovirus (median, 640 mg/L; P = .001 and P = .01, respectively). White blood cell counts were significantly higher in CSF samples from patients infected with HSV type 2 (median, 240 x 10(6) cells/L) than in samples from those infected with enterovirus (median, 51 x 10(6) cells/L; P = .01). Enterovirus infection was the most common cause of viral meningitis in immunocompetent adults in this study. White blood cell counts and protein levels were significantly higher in CSF samples from patients infected with HSV type 2 than in samples from patients with enterovirus

Vaccine Protection of Leukopenic Mice against Staphylococcus aureus Bloodstream Infection

PubMed Central

Rauch, Sabine; Gough, Portia; Kim, Hwan Keun; Schneewind, Olaf

2014-01-01

The risk for Staphylococcus aureus bloodstream infection (BSI) is increased in immunocompromised individuals, including patients with hematologic malignancy and/or chemotherapy. Due to the emergence of antibiotic-resistant strains, designated methicillin-resistant S. aureus (MRSA), staphylococcal BSI in cancer patients is associated with high mortality; however, neither a protective vaccine nor pathogen-specific immunotherapy is currently available. Here, we modeled staphylococcal BSI in leukopenic CD-1 mice that had been treated with cyclophosphamide, a drug for leukemia and lymphoma patients. Cyclophosphamide-treated mice were highly sensitive to S. aureus BSI and developed infectious lesions lacking immune cell infiltrates. Virulence factors of S. aureus that are key for disease establishment in immunocompetent hosts—α-hemolysin (Hla), iron-regulated surface determinants (IsdA and IsdB), coagulase (Coa), and von Willebrand factor binding protein (vWbp)—are dispensable for the pathogenesis of BSI in leukopenic mice. In contrast, sortase A mutants, which cannot assemble surface proteins, display delayed time to death and increased survival in this model. A vaccine with four surface antigens (ClfA, FnBPB, SdrD, and SpAKKAA), which was identified by genetic vaccinology using sortase A mutants, raised antigen-specific immune responses that protected leukopenic mice against staphylococcal BSI. PMID:25183728

Asbestos-Induced Cellular and Molecular Alteration of Immunocompetent Cells and Their Relationship with Chronic Inflammation and Carcinogenesis

PubMed Central

Matsuzaki, Hidenori; Maeda, Megumi; Lee, Suni; Nishimura, Yasumitsu; Kumagai-Takei, Naoko; Hayashi, Hiroaki; Yamamoto, Shoko; Hatayama, Tamayo; Kojima, Yoko; Tabata, Rika; Kishimoto, Takumi; Hiratsuka, Junichi; Otsuki, Takemi

2012-01-01

Asbestos causes lung fibrosis known as asbestosis as well as cancers such as malignant mesothelioma and lung cancer. Asbestos is a mineral silicate containing iron, magnesium, and calcium with a core of SiO2. The immunological effect of silica, SiO2, involves the dysregulation of autoimmunity because of the complications of autoimmune diseases found in silicosis. Asbestos can therefore cause alteration of immunocompetent cells to result in a decline of tumor immunity. Additionally, due to its physical characteristics, asbestos fibers remain in the lung, regional lymph nodes, and the pleural cavity, particularly at the opening sites of lymphatic vessels. Asbestos can induce chronic inflammation in these areas due to the production of reactive oxygen/nitrogen species. As a consequence, immunocompetent cells can have their cellular and molecular features altered by chronic and recurrent encounters with asbestos fibers, and there may be modification by the surrounding inflammation, all of which eventually lead to decreased tumor immunity. In this paper, the brief results of our investigation regarding reduction of tumor immunity of immunocompetent cells exposed to asbestos in vitro are discussed, as are our findings concerned with an investigation of chronic inflammation and analyses of peripheral blood samples derived from patients with pleural plaque and mesothelioma that have been exposed to asbestos. PMID:22500091

Prenatal exposure to psychostimulants increases impulsivity, compulsivity, and motivation for rewards in adult mice.

PubMed

Lloyd, S A; Oltean, C; Pass, H; Phillips, B; Staton, K; Robertson, C L; Shanks, R A

2013-07-02

Given the widespread use and misuse of methamphetamine (METH) and methylphenidate (MPD), especially in relation to women of childbearing age, it is important to consider the long-lasting effects of these drugs on the brain of the developing fetus. Male and female C57Bl/6J mice were prenatally exposed to METH (5mg/kg), MPD (10mg/kg), or saline. Following a 3-month washout, behavioral analysis using the 5-Choice Serial Reaction Time Task (5CSRTT) was performed on adult mice. After reaching training criteria, performance on a pseudo-random intertrial interval test session revealed decrements in 5CSRTT behavior. Prenatally-treated METH and MPD mice demonstrated significant increases in impulsivity, compulsivity, and motivation for reward compared to their saline controls. There were sex by drug interactions indicating a possible sexually dimorphic response to these prenatal drug exposures. Of particular clinical interest, we find that mice prenatally exposed to METH or MPD express characteristics of both inhibitory control decrements and heightened motivation for rewards, which represent core symptoms of addiction and other impulse control disorders. Copyright © 2013 Elsevier Inc. All rights reserved.

[Severe Legionnaire's disease revealing an invasive aspergillosis in an apparently immunocompetent patient].

PubMed

Vergne, S; Lathuile, D; Bénosa, B; Fragnier, F; Destrac, S; Avedan, M; Alzieu, M; Campistron, J

2003-10-18

Invasive aspergillosis, a sever disease, usually occurs in immuno-depressed patients. However, it may also develop in presumably immuno-competent patients. A 54-year-old man, smoker, was hospitalised for hypoxemia of the right lung and septic shock, rapidly requiring mechanical ventilation combined with administration of vasopressors, and followed by dialysis because of the rapid worsening of an acute kidney failure. The diagnosis of pulmonary Legionnaire's disease was made on the second day in view of the positivity of the urinary legionella antigen. The progression of the disease was marked by the discovery of a histologically documented gastric aspergillosis and three abscessed intracerebral lesions within the context of a strongly positive aspergillus antigenemia. The disease worsened and the patient died on D 17, despite the antibiotic and anti-aspergillus treatments, haemodynamic support and dialysis. To our knowledge, the association of invasive aspergillosis and severe Legionnaire's disease has never been described in an presumably immunocompetent patient. This clinical case suggests the existence, other than the usual risk factors of invasive aspergillosis that characterise profound states of immunodepression, of more subtle alterations in the immune system that may enhance this type of infection.

Gardening can induce pulmonary failure: Aspergillus ARDS in an immunocompetent patient, a case report.

PubMed

Jung, Nina; Mronga, Silke; Schroth, Susanne; Vassiliou, Timon; Sommer, Frank; Walthers, Eduard; Aepinus, Christian; Jerrentrup, Andreas; Vogelmeier, Claus; Holland, Angelique; Koczulla, Rembert

2014-11-26

Acute Aspergillus fumigatus infection in immunocompetent patients is rare. This is the first known case of a patient who survived Aspergillus sepsis after being treated early with veno-venous extracorporeal membrane (ECMO) and antifungal therapy. An immunocompetent 54-year-old woman was exposed to plant mulch during gardening and subsequently developed pulmonary failure that progressed to sepsis with multiorgan failure. Owing to her severe clinical condition, she was treated for acute respiratory distress syndrome (ARDS) with veno-venous ECMO. Empiric antifungal therapy comprising voriconazole was also initiated owing to her history and a previous case report of aspergillosis after plant mulch exposure, though there was no microbiological proof at the time. A. fumigatus was later cultured and detected on antibody testing. The patient recovered, and ECMO was discontinued 1 week later. After 7 days of antifungal treatment, Aspergillus antibodies were undetectable. In cases of sepsis that occur after gardening, clinicians should consider Aspergillus inhalation as an aetiology, and early antimycotic therapy is recommended.

Detection of human papillomavirus in nonmelanoma skin cancer lesions and healthy perilesional skin in kidney transplant recipients and immunocompetent patients.

PubMed

Bernat-García, J; Morales Suárez-Varela, M; Vilata-Corell, J J; Marquina-Vila, A

2014-04-01

The influence of human papillomavirus (HPV) on the development of nonmelanoma skin cancer (NMSC) is a topic of debate. HPV types from the beta genus (HPV-β) have been most frequently associated with the development of skin cancer. To analyze the prevalence and range of HPV types in NMSC lesions and healthy perilesional skin in immunodepressed and immunocompetent patients and to evaluate the influence of various clinical factors on the prevalence of HPV in skin cancer. Nested polymerase chain reaction and sequencing were used to detect HPV in 120 NMSC samples obtained by biopsy from 30 kidney transplant recipients and 30 immunocompetent patients. In all cases, a sample was taken from the tumor site and the surrounding healthy skin. Potential confounders were assessed and the data analyzed by multivariate logistic regression. HPV DNA was detected in 44 (73.3%) of the 60 samples from immunodepressed patients and in 32 (53.3%) of the 60 samples from immunocompetent patients (adjusted odds ratio, 3.4; 95% CI, 1.2-9.6). In both groups of patients, HPV was more common in healthy perilesional skin than in lesional skin. HPV-β was the most common type isolated. We found a wide range of HPV types (mostly HPV-β) in the skin of kidney transplant recipients and immunocompetent patients with skin cancer. Copyright © 2013 Elsevier España, S.L. and AEDV. All rights reserved.

Rothia mucilaginosa pneumonia in an immunocompetent patient.

PubMed

Baeza Martínez, Carlos; Zamora Molina, Lucia; García Sevila, Raquel; Gil Carbonell, Joan; Ramos Rincon, José Manuel; Martín Serrano, Concepción

2014-11-01

Rothia mucilaginosa is a gram-postive coccus that occurs as part of the normal flora of the oropharynx and upper respiratory tract. Lower respiratory tract infections caused by this organism are rare and usually occur in immunocompromised patients. This is the case of an immunocompetent 47-year-old woman with right upper lobe pneumonia in which R.mucilaginosa was isolated in sputum and bronchial aspirate. Infections caused by this agent in the last four years in our hospital were reviewed. The most common predisposing factor was COPD with bronchiectasis. R.mucilaginosa was identified as the causative agent for pneumonia in only two cases, of which one was our case and the other was a patient with lung cancer. Copyright © 2013 SEPAR. Published by Elsevier Espana. All rights reserved.

The effect of the anabolic steroid, nandrolone, in conditioned place preference and D1 dopamine receptor expression in adolescent and adult mice.

PubMed

Martínez-Rivera, Freddyson J; Natal-Albelo, Eduardo J; Martínez, Namyr A; Orozco-Vega, Roberto A; Muñiz-Seda, Oscar A; Barreto-Estrada, Jennifer L

2015-04-01

Adolescents and adults engage in anabolic-androgenic steroid (AAS) misuse seeking their anabolic effects, even though later on, many could develop neuropsychological dependence. Previously, we have shown that nandrolone induces conditioned place preference (CPP) in adult male mice. However, whether nandrolone induces CPP during adolescence remains unknown. In this study, the CPP test was used to determine the rewarding properties of nandrolone (7.5 mg/kg) in adolescent mice. In addition, since D1 dopamine receptors (D1DR) are critical for reward-related processes, the effect of nandrolone on the expression of D1DR in the nucleus accumbens (NAc) was investigated by Western blot analysis. Similar to our previous results, nandrolone induced CPP in adults. However, in adolescents, nandrolone failed to produce place preference. At the molecular level, nandrolone decreased D1DR expression in the NAc only in adult mice. Our data suggest that nandrolone may not be rewarding in adolescents at least during short-term use. The lack of nandrolone rewarding effects in adolescents may be due, in part to differences in D1DR expression during development. Copyright © 2015 Elsevier B.V. All rights reserved.

The effect of the anabolic steroid, nandrolone, in conditioned place preference and D1 dopamine receptor expression in adolescent and adult mice

PubMed Central

Martínez-Rivera, Freddyson J.; Natal-Albelo, Eduardo J.; Martínez, Namyr A.; Orozco-Vega, Roberto A.; Muñiz-Seda, Oscar A.; Barreto-Estrada, Jennifer L.

2015-01-01

Adolescents and adults engage in anabolic-androgenic steroid (AAS) misuse seeking their anabolic effects, even though later on, many could develop neuropsychological dependence. Previously, we have shown that nandrolone induces conditioned place preference (CPP) in adult male mice. However, whether nandrolone induces CPP during adolescence remains unknown. In this study, the CPP test was used to determine the rewarding properties of nandrolone (7.5 mg/kg) in adolescent mice. In addition, since D1 dopamine receptors (D1DR) are critical for reward-related processes, the effect of nandrolone on the expression of D1DR in the nucleus accumbens (NAc) was investigated by Western blot analysis. Similar to our previous results, nandrolone induced CPP in adults. However, in adolescents, nandrolone failed to produce place preference. At the molecular level, nandrolone decreased D1DR expression in the NAc only in adult mice. Our data suggest that nandrolone may not be rewarding in adolescents at least during short-term use. The lack of nandrolone rewarding effects in adolescents may be due, in part to differences in D1DR expression during development. PMID:25612844

The attenuated nine mile phase II clone 4/RSA439 strain of Coxiella burnetii is highly virulent for severe combined immunodeficient (SCID) mice.

PubMed

Islam, Aminul; Lockhart, Michelle; Stenos, John; Graves, Stephen

2013-10-01

The Nine Mile phase II clone 4 (NMIIC4) strain of Coxiella burnetii is an attenuated phase II strain that has lost the genes for virulence determinant type 1 lipopolysaccharide. These bacteria were very virulent for severe combined immunodeficient (SCID) mice. The lethal dose 50 (LD50) was ~10 bacteria. Infected SCID mice died between Day 28 and Day 53 post-infection. At termination of the experiment (Day 60) only 5 of 24 mice had survived. The degree of splenomegaly was directly related to the bacterial load in the SCID mice spleens. The NMIIC4 was avirulent in immunocompetent wild mice and bacterial DNA copies in splenic tissue were extremely low. The SCID mice that were inoculated with high doses of heat inactivated NMIIC4 C. burnetii were all alive at Day 60 and without splenomegaly. It appears that the phase I lipopolysaccharide present in virulent Nine Mile phase I but not in attenuated NMIIC4 is not the only virulence factor for C. burnetii.

Adult vitamin D deficiency exacerbates impairments caused by social stress in BALB/c and C57BL/6 mice.

PubMed

Groves, Natalie J; Zhou, Mei; Jhaveri, Dhanisha J; McGrath, John J; Burne, Thomas H J

2017-12-01

Vitamin D deficiency is prevalent in adults throughout the world. Epidemiological studies have shown significant associations between vitamin D deficiency and an increased risk of various neuropsychiatric and neurodegenerative disorders, such as schizophrenia, depression, Alzheimer's disease and cognitive impairment. However, studies based on observational epidemiology cannot address questions of causality; they cannot determine if vitamin D deficiency is a causal factor leading to the adverse health outcome. The main aim of this study was to determine if AVD deficiency would exacerbate the effects of a secondary exposure, in this case social stress, in BALB/c mice and in the more resilient C57BL/6 mice. Ten-week old male BALB/c and C57BL/6 mice were fed a control or vitamin D deficient diet for 10 weeks, and the mice were further separated into one of two groups for social treatment, either Separated (SEP) or Social Defeat (DEF). SEP mice were placed two per cage with a perforated Plexiglas divider, whereas the DEF mice underwent 10days of social defeat prior to behavioural testing. We found that AVD-deficient mice were more vulnerable to the effects of social stress using a social avoidance test, and this was dependent on strain. These results support the hypothesis that vitamin D deficiency may exacerbate behavioural outcomes in mice vulnerable to stress, a finding that can help guide future studies. Importantly, these discoveries support the epidemiological link between vitamin D deficiency and neuropsychiatric and neurodegenerative disorders; and has provided clues that can guide future studies related to unravelling the mechanisms of action linking adult vitamin D deficiency and adverse brain related outcomes. Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.

Primary central nervous system lymphoma with lymphomatosis cerebri in an immunocompetent child: MRI and 18F-FDG PET-CT findings.

PubMed

Jain, Tarun K; Sharma, Punit; Suman, Sudhir K C; Faizi, Nauroze A; Bal, Chandrasekhar; Kumar, Rakesh

2013-01-01

Primary central nervous system lymphoma (PCNSL) is extremely rare in immunocompetent children. We present the magnetic resonance imaging (MRI) and (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography-computed tomography (PET-CT) findings of such a case in a 14-year old immunocompetent boy. In this patient, PCNSL was associated with lymphomatosis cerebri. Familiarity with the findings of this rare condition will improve the diagnostic confidence of the nuclear radiologist and avoid misdiagnosis. Copyright © 2013 Elsevier España, S.L. and SEMNIM. All rights reserved.

Perinatal Lead Exposure Alters Gut Microbiota Composition and Results in Sex-specific Bodyweight Increases in Adult Mice.

PubMed

Wu, Jianfeng; Wen, Xiaoquan William; Faulk, Christopher; Boehnke, Kevin; Zhang, Huapeng; Dolinoy, Dana C; Xi, Chuanwu

2016-06-01

Heavy metal pollution is a principle source of environmental contamination. Epidemiological and animal data suggest that early life lead (Pb) exposure results in critical effects on epigenetic gene regulation and child and adult weight trajectories. Using a mouse model of human-relevant exposure, we investigated the effects of perinatal Pb exposure on gut microbiota in adult mice, and the link between gut microbiota and bodyweight changes. Following Pb exposure during gestation and lactation via maternal drinking water, bodyweight in A(vy) strain wild-type non-agouti (a/a) offspring was tracked through adulthood. Gut microbiota of adult mice were characterized by deep DNA sequencing of bacterial 16S ribosomal RNA genes. Data analyses were stratified by sex and adjusted for litter effects. A Bayesian variable selection algorithm was used to analyze associations between bacterial operational taxonomic units and offspring adult bodyweight. Perinatal Pb exposure was associated with increased adult bodyweight in male (P < .05) but not in female offspring (P = .24). Cultivable aerobes decreased and anaerobes increased in Pb-exposed offspring (P < .005 and P < .05, respectively). Proportions of the 2 predominant phyla (Bacteroidetes and Firmicutes) shifted inversely with Pb exposure, and whole bacterial compositions were significantly different (analysis of molecular variance, P < .05) by Pb exposure without sex bias. In males, changes in gut microbiota were highly associated with adult bodyweight (P = .028; effect size = 2.59). Thus, perinatal Pb exposure results in altered adult gut microbiota regardless of sex, and these changes are highly correlated with increased bodyweight in males. Adult gut microbiota can be shaped by early exposures and may contribute to disease risks in a sex-specific manner. © The Author 2016. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e

Perinatal Lead Exposure Alters Gut Microbiota Composition and Results in Sex-specific Bodyweight Increases in Adult Mice

PubMed Central

Wu, Jianfeng; Wen, Xiaoquan William; Faulk, Christopher; Boehnke, Kevin; Zhang, Huapeng; Dolinoy, Dana C.; Xi, Chuanwu

2016-01-01

Heavy metal pollution is a principle source of environmental contamination. Epidemiological and animal data suggest that early life lead (Pb) exposure results in critical effects on epigenetic gene regulation and child and adult weight trajectories. Using a mouse model of human-relevant exposure, we investigated the effects of perinatal Pb exposure on gut microbiota in adult mice, and the link between gut microbiota and bodyweight changes. Following Pb exposure during gestation and lactation via maternal drinking water, bodyweight in Avy strain wild-type non-agouti (a/a) offspring was tracked through adulthood. Gut microbiota of adult mice were characterized by deep DNA sequencing of bacterial 16S ribosomal RNA genes. Data analyses were stratified by sex and adjusted for litter effects. A Bayesian variable selection algorithm was used to analyze associations between bacterial operational taxonomic units and offspring adult bodyweight. Perinatal Pb exposure was associated with increased adult bodyweight in male (P < .05) but not in female offspring (P = .24). Cultivable aerobes decreased and anaerobes increased in Pb-exposed offspring (P < .005 and P < .05, respectively). Proportions of the 2 predominant phyla (Bacteroidetes and Firmicutes) shifted inversely with Pb exposure, and whole bacterial compositions were significantly different (analysis of molecular variance, P < .05) by Pb exposure without sex bias. In males, changes in gut microbiota were highly associated with adult bodyweight (P = .028; effect size = 2.59). Thus, perinatal Pb exposure results in altered adult gut microbiota regardless of sex, and these changes are highly correlated with increased bodyweight in males. Adult gut microbiota can be shaped by early exposures and may contribute to disease risks in a sex-specific manner. PMID:26962054

Tinea capitis in adults in southern Spain. A 17-year epidemiological study.

PubMed

Lova-Navarro, Miguel; Gómez-Moyano, Elisabeth; Martínez Pilar, Leandro; Fernandez-Ballesteros, María Dolores; Godoy-Díaz, Daniel Jesus; Vera-Casaño, Angel; Crespo-Erchiga, Vicente

2016-01-01

Tinea capitis is an infection of the hair due to keratinophilic fungi, known as dermatophytes. Although the disease is common in children, several studies have also shown that it is far from unusual in adults, especially in post-menopausal women and immunocompromised persons. To determine the incidence of tinea capitis in adults in our area, as well as the predisposing factors (gender, immunity), and causative species. A retrospective study was conducted over a period of 17 years, from 1995 to 2011, collecting data on cases of tinea capitis diagnosed in our dermatology department. Information collected for all patients included age, gender, location of the lesions, results of direct examination and culture, immune status, cause of immunosuppression, and the prescribed treatment. Thirty-three cases (11.4%) out of 289 cases of tinea capitis occurred in adults. Most of these adults (72%) were immunocompetent, and the rest were immunocompromised for different reasons. Three of the patients were men and 30 women, with 70% of the latter being post-menopausal. Trichophyton species were isolated in 76% of these adult patients, with Trichophyton violaceum being the most common. Treatment with oral terbinafine was successful in all these cases. Microsporum species were responsible for the other cases, all treated successfully with oral griseofulvin. This series of tinea capitis in adults is one of the largest to date. It shows that tinea capitis is not uncommon among the immunocompetent adult population. In our geographical area, except for prepubescent patients, most cases affecting the adult population were caused by species of the genus Trichophyton. In these cases the treatment of choice was oral terbinafine, which considerably shortened the treatment time, and was associated with fewer side effects than the classical griseofulvin. Copyright © 2015 Asociación Española de Micología. Published by Elsevier Espana. All rights reserved.

[Osteomyelitis due to Yokenella regensburgei following craniotomy in an immunocompetent patient].

PubMed

Penagos, Sara Catalina; Gómez, Sebastián; Villa, Pablo; Estrada, Santiago; Agudelo, Carlos Andrés

2015-01-01

The gram-negative bacillus Yokenella regensburgei (of the Enterobacteriaceae family) can be found in groundwater and foodstuffs, as well as the digestive tracts of insects and reptiles. Although it has been isolated from humans since its original description, it has rarely been reported as a cause of infection, and then, only in immunosuppressed patients. We report the first case of post-surgical secondary osteomyelitis due to Y. regensburgei in an immunocompetent woman who had undergone a craniotomy.

Peripubertal Vitamin D3 Deficiency Delays Puberty and Disrupts the Estrous Cycle in Adult Female Mice1

PubMed Central

Dicken, Cary L.; Israel, Davelene D.; Davis, Joe B.; Sun, Yan; Shu, Jun; Hardin, John; Neal-Perry, Genevieve

2012-01-01

ABSTRACT The mechanism(s) by which vitamin D3 regulates female reproduction is minimally understood. We tested the hypothesis that peripubertal vitamin D3 deficiency disrupts hypothalamic-pituitary-ovarian physiology. To test this hypothesis, we used wild-type mice and Cyp27b1 (the rate-limiting enzyme in the synthesis of 1,25-dihydroxyvitamin D3) null mice to study the effect of vitamin D3 deficiency on puberty and reproductive physiology. At the time of weaning, mice were randomized to a vitamin D3-replete or -deficient diet supplemented with calcium. We assessed the age of vaginal opening and first estrus (puberty markers), gonadotropin levels, ovarian histology, ovarian responsiveness to exogenous gonadotropins, and estrous cyclicity. Peripubertal vitamin D3 deficiency significantly delayed vaginal opening without affecting the number of GnRH-immunopositive neurons or estradiol-negative feedback on gonadotropin levels during diestrus. Young adult females maintained on a vitamin D3-deficient diet after puberty had arrested follicular development and prolonged estrous cycles characterized by extended periods of diestrus. Ovaries of vitamin D3-deficient Cyp27b1 null mice responded to exogenous gonadotropins and deposited significantly more oocytes into the oviducts than mice maintained on a vitamin D3-replete diet. Estrous cycles were restored when vitamin D3-deficient Cyp27b1 null young adult females were transferred to a vitamin D3-replete diet. This study is the first to demonstrate that peripubertal vitamin D3 sufficiency is important for an appropriately timed pubertal transition and maintenance of normal female reproductive physiology. These data suggest vitamin D3 is a key regulator of neuroendocrine and ovarian physiology. PMID:22572998

Postnatal light alters hypothalamic-pituitary-adrenal axis function and induces a depressive-like phenotype in adult mice.

PubMed

Coleman, Georgia; Gigg, John; Canal, Maria Mercè

2016-11-01

The postnatal light environment that a mouse experiences during the critical first three postnatal weeks has long-term effects on both its circadian rhythm output and clock gene expression. Furthermore, data from our lab suggest that postnatal light may also impact the hypothalamic-pituitary-adrenal (HPA) axis, which is a key regulator of stress. To test the effect of postnatal light exposure on adult stress responses and circadian rhythmicity, we raised mice under either 24-h light-dark cycles (LD), constant light (LL) or constant dark (DD) during the first three postnatal weeks. After weaning we then exposed all animals to LD cycles (basal conditions), followed by LL (stressed conditions) environments. We examined brain neuropeptide and glucocorticoid receptor (GR) expression, plasma corticosterone concentration rhythm and body temperature rhythm, together with depression- and anxiety-related behaviour. Results showed that LL- and DD-raised mice exhibited decreased GR expression in the hippocampus, increased plasma corticosterone concentration at the onset of the dark phase and a depressive phenotype when exposed to LD cycles later in life. Furthermore, LL-raised mice showed increased corticotrophin-releasing hormone mRNA expression in the paraventricular nucleus of the hypothalamus. When exposed to LL as adults, LL-raised mice showed a significant circadian rhythm of plasma corticosterone concentration, together with a shorter period and stronger circadian rhythm of body temperature compared to DD-raised mice. Taken together, these data suggest that altered postnatal light environments have long-term effects on the HPA axis and the circadian system, which can lead to altered stress responses and a depressive phenotype in adulthood. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Genetic correction of dystrophin deficiency and skeletal muscle remodeling in adult MDX mouse via transplantation of retroviral producer cells.

PubMed Central

Fassati, A; Wells, D J; Sgro Serpente, P A; Walsh, F S; Brown, S C; Strong, P N; Dickson, G

1997-01-01

Duchenne muscular dystrophy (DMD) is an X-linked, lethal disease caused by mutations of the dystrophin gene. No effective therapy is available, but dystrophin gene transfer to skeletal muscle has been proposed as a treatment for DMD. We have developed a strategy for efficient in vivo gene transfer of dystrophin cDNA into regenerating skeletal muscle. Retroviral producer cells, which release a vector carrying the therapeutically active dystrophin minigene, were mitotically inactivated and transplanted in adult nude/mdx mice. Transplantation of 3 x 10(6) producer cells in a single site of the tibialis anterior muscle resulted in the transduction of between 5.5 and 18% total muscle fibers. The same procedure proved also feasible in immunocompetent mdx mice under short-term pharmacological immunosuppression. Minidystrophin expression was stable for up to 6 mo and led to alpha-sarcoglycan reexpression. Muscle stem cells could be transduced in vivo using this procedure. Transduced dystrophic skeletal muscle showed evidence of active remodeling reminiscent of the genetic normalization process which takes place in female DMD carriers. Overall, these results demonstrate that retroviral-mediated dystrophin gene transfer via transplantation of producer cells is a valid approach towards the long-term goal of gene therapy of DMD. PMID:9239410

CUTANEOUS ZYGOMYCOSIS DUE TO SAKSENAEA VASIFORMIS IN AN IMMUNOCOMPETENT HOST

PubMed Central

Baradkar, V P; Kumar, S

2009-01-01

Saksenaea vasiformis is an emerging zygomycete species, most often associated with cutaneous, subcutaneous and rhino- orbito-cerebral infections. Herein, we report a case of cutaneous zygomycosis of face caused by Saksenaea vasiformis in a 54-year-old immunocompetent female. The diagnosis was carried out by microscopy using KOH mount, Gram staining, Gomori's methenamine silver staining, hemotoxylin and eosin staining and culture on Sabouraud's Dextrose agar without actidione. Slide cultures were put up on Czapek Dox agar, which showed typical flask-shaped sporangium with rhizoids. The patient was treated successfully with intravenous amphotericin B. PMID:20101346

Increased anxiety and fear memory in adult mice lacking type 2 deiodinase.

PubMed

Bárez-López, Soledad; Montero-Pedrazuela, Ana; Bosch-García, Daniel; Venero, César; Guadaño-Ferraz, Ana

2017-10-01

A euthyroid state in the brain is crucial for its adequate development and function. Impairments in thyroid hormones (THs; T3 or 3,5,3'-triiodothyronine and T4 or thyroxine) levels and availability in brain can lead to neurological alterations and to psychiatric disorders, particularly mood disorders. The thyroid gland synthetizes mainly T4, which is secreted to circulating blood, however, most actions of THs are mediated by T3, the transcriptionally active form. In the brain, intracellular concentrations of T3 are modulated by the activity of type 2 (D2) and type 3 (D3) deiodinases. In the present work, we evaluated learning and memory capabilities and anxiety-like behavior at adult stages in mice lacking D2 (D2KO) and we analyzed the impact of D2-deficiency on TH content and on the expression of T3-dependent genes in the amygdala and the hippocampus. We found that D2KO mice do not present impairments in spatial learning and memory, but they display emotional alterations with increased anxiety-like behavior as well as enhanced auditory-cued fear memory and spontaneous recovery of fear memory following extinction. D2KO mice also presented reduced T3 content in the hippocampus and decreased expression of the T3-dependent gene Dio3 in the amygdala suggesting a hypothyroid status in this structure. We propose that the emotional dysfunctions found in D2KO mice can arise from the reduced T3 content in their brain, which consequently leads to alterations in gene expression with functional consequences. We found a downregulation in the gene encoding for the calcium-binding protein calretinin (Calb2) in the amygdala of D2KO mice that could affect the GABAergic transmission. The current findings in D2KO mice can provide insight into emotional disorders present in humans with DIO2 polymorphisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

PENTACHLOROPHENOL POTENTIATES BENZO[A]PYRENE DNA ADDUCT FORMATION IN ADULT BUT NOT INFANT B6C3F1 MALE MICE

EPA Science Inventory

Abstract

The objective of this study is to determine whether pentachlorophenol (PCP) alters benzo[a]pyrene (B[a]P) induced DNA adduct formation in infant and adult B6C3Fl mice. Mice were exposed to 55 ug B[a]P/g body weight (BW) alone and in combination with several dose...

Using ICR and SCID mice as animal models for smallpox to assess antiviral drug efficacy.

PubMed

Titova, Ksenya A; Sergeev, Alexander A; Zamedyanskaya, Alena S; Galahova, Darya O; Kabanov, Alexey S; Morozova, Anastasia A; Bulychev, Leonid E; Sergeev, Artemiy A; Glotova, Tanyana I; Shishkina, Larisa N; Taranov, Oleg S; Omigov, Vladimir V; Zavjalov, Evgenii L; Agafonov, Alexander P; Sergeev, Alexander N

2015-09-01

The possibility of using immunocompetent ICR mice and immunodeficient SCID mice as model animals for smallpox to assess antiviral drug efficacy was investigated. Clinical signs of the disease did not appear following intranasal (i.n.) challenge of mice with strain Ind-3a of variola virus (VARV), even when using the highest possible dose of the virus (5.2 log10 p.f.u.). The 50 % infective doses (ID50) of VARV, estimated by the virus presence or absence in the lungs 3 and 4 days post-infection, were 2.7 ± 0.4 log10 p.f.u. for ICR mice and 3.5 ± 0.7 log10 p.f.u. for SCID mice. After i.n. challenge of ICR and SCID mice with VARV 30 and 50 ID50, respectively, steady reproduction of the virus occurred only in the respiratory tract (lungs and nose). Pathological inflammatory destructive changes were revealed in the respiratory tract and the primary target cells for VARV (macrophages and epithelial cells) in mice, similar to those in humans and cynomolgus macaques. The use of mice to assess antiviral efficacies of NIOCH-14 and ST-246 demonstrated the compliance of results with those described in scientific literature, which opens up the prospect of their use as an animal model for smallpox to develop anti-smallpox drugs intended for humans.

Cryptococcoma mimicking a brain tumor in an immunocompetent patient: case report of an extremely rare presentation.

PubMed

Paiva, Aline Lariessy Campos; Aguiar, Guilherme Brasileiro de; Lovato, Renan Maximilian; Zanetti, Arthus Vilar Deolindo; Panagopoulos, Alexandros Theodoros; Veiga, José Carlos Esteves

2017-11-06

Central nervous system (CNS) infectious diseases have high prevalence in developing countries and their proper diagnosis and treatment are very important for public health planning. Cryptococcus neoformans is a fungus that may cause several CNS manifestations, especially in immunocompromised patients. Cryptococcal meningitis is the most common type of involvement. Mass-effect lesions are uncommon: they are described as cryptococcomas and their prevalence is even lower among immunocompetent patients. The aim here was to report an extremely rare case of cryptococcoma causing a mass effect and mimicking a brain tumor in an immunocompetent patient. The literature on CNS cryptococcal infections was reviewed with emphasis on cryptococcomas. Clinical, surgical and radiological data on a female patient with this rare presentation of cryptococcoma mimicking a brain tumor are described. A 54-year-old female patient presented to the emergency department with a rapid-onset progressive history of confusion and completely dependency for basic activities. Neuroimaging showed a left occipital lesion and neurosurgical treatment was proposed. From histopathological evaluation, a diagnosis of cryptococcoma was established. She received clinical support with antifungals, but despite optimal clinical treatment, her condition evolved to death. Cryptococcal infections have several forms of presentation and, in immunocompetent patients, their manifestation may be even more different. Cryptococcoma is an extremely rare presentation in which proper surgical and clinical treatment should be instituted as quickly as possible, but even so, there is a high mortality rate.

Immunogenicity and efficacy following sequential parenterally-administered doses of Salmonella Enteritidis COPS:FliC glycoconjugates in infant and adult mice.

PubMed

Baliban, Scott M; Curtis, Brittany; Toema, Deanna; Tennant, Sharon M; Levine, Myron M; Pasetti, Marcela F; Simon, Raphael

2018-05-23

In sub-Saharan Africa, invasive nontyphoidal Salmonella (iNTS) infections with serovars S. Enteritidis, S. Typhimurium and I 4,[5],12:i:- are widespread in children < 5 years old. Development of an efficacious vaccine would provide an important public health tool to prevent iNTS disease in this population. Glycoconjugates of S. Enteritidis core and O-polysaccharide (COPS) coupled to the homologous serovar phase 1 flagellin protein (FliC) were previously shown to be immunogenic and protected adult mice against death following challenge with a virulent Malian S. Enteritidis blood isolate. This study extends these observations to immunization of mice in early life and also assesses protection with partial and full regimens. Anti-COPS and anti-FliC serum IgG titers were assessed in infant and adult mice after immunization with 1, 2 or 3 doses of S. Enteritidis COPS:FliC alone or co-formulated with aluminum hydroxide or monophosphoryl lipid A (MPL) adjuvants. S. Enteritidis COPS:FliC was immunogenic in both age groups, although the immune responses were quantitatively lower in infants. Kinetics of antibody production were similar for the native and adjuvanted formulations after three doses; conjugates formulated with MPL elicited significantly increased anti-COPS IgG titers in adult but not infant mice. Nevertheless, robust protection against S. Enteritidis challenge was seen for all three formulations when three doses were given either during infancy or as adults. We further found that significant protection could be achieved with two COPS:FliC doses, despite elicitation of modest serum anti-COPS IgG antibody titers. These findings guide potential immunization strategies that may be translated to develop a human pediatric iNTS vaccine for sub-Saharan Africa.

Identification of opportunistic enteric parasites among immunocompetent patients with diarrhoea from Northern India and genetic characterisation of Cryptosporidium and Microsporidia.

PubMed

Ghoshal, U; Dey, A; Ranjan, P; Khanduja, S; Agarwal, V; Ghoshal, U C

2016-01-01

Enteric parasitic infestation is a major public health problem in developing countries. Parasites such as Cryptosporidium spp., Cyclospora spp., Cystoisospora spp. and Microsporidia may cause severe diarrhoea among immunocompromised patients. There is scanty data on their frequency among immunocompetent patients. Accordingly, we studied the frequency of enteric opportunistic parasites among immunocompetent patients with diarrhoea from northern India; we also performed genetic characterisation of Cryptosporidia and Microsporidia among them. Stool samples from 80 immunocompetent patients with diarrhoea, and 110 healthy controls were examined. Parasites were detected by direct microscopy, modified acid-fast (Kinyoun's) and modified trichrome stain. Polymerase chain reaction--restriction fragment length polymorphism was used for genetic characterisation of selected species such as Cryptosporidia and Microsporidia. Enteric parasites were detected in 16/80 (20%) patients (mean age 28.8±20 years, 45, 56% males) and in 2/110 (1.8%) healthy controls (P=0.00007). Parasites detected were Cryptosporidium spp. (8/16, 50.0%), Cystoisospora spp. (4/16, 25%), Microsporidia (1/16, 6.25%), Cyclospora spp. (1/16, 6.25%) and Giardia spp. (1/16, 6.25%). One patient had mixed infection with Cystoisospora spp. and Giardia spp. The species of Cryptosporidia and Microsporidia detected were Cryptosporidium hominis and Enterocytozoon bieneusi, respectively. Parasites were more often detected in younger patients (≤20 years of age) than in older. Most of the parasite infected patients presented with chronic diarrhoea. Opportunistic enteric parasitic infestation was more common among immunocompetent patients with diarrhoea than healthy subjects. Special staining as well as molecular methods are essential for appropriate diagnosis of these parasites.

Enduring influences of peripubertal/adolescent stressors on behavioral response to estradiol and progesterone in adult female mice.

PubMed

Laroche, Julie; Gasbarro, Lauren; Herman, James P; Blaustein, Jeffrey D

2009-08-01

Exposure to stressors during particular stages of development leads to acute and long-term physiological and behavioral changes. We have reported that shipping mice during the peripubertal/adolescent period results in decreased induction of feminine sexual behavior by estradiol and progesterone in adult female mice. To study further the factors involved in this decreased behavioral response, female mice were exposed to a variety of experimental stressors when 6 wk old. Effects of peripubertal/adolescent exposure to these stressors on acute plasma corticosterone levels and changes in body weight and adult behavioral response to estradiol and progesterone were assessed. Although restraint for three daily 3-h periods, 36-h food deprivation, or a multiple stressor regimen acutely increased plasma corticosterone levels and reduced body weight, only exposure to particular doses of the bacterial endotoxin lipopolysaccharide (LPS; 1-1.5 mg/kg body weight, doses that induced moderate levels of sickness behavior in these studies) resulted in reduced behavioral response to estradiol and progesterone in adulthood. Like the effects of shipping, the effects of LPS on adult feminine sexual behavior appear most robust when injected at 6 wk old and are limited to exposure during a vulnerable period at approximately 4-6 wk of age. Therefore, an immune stressor during the peripubertal/adolescent period, but not restraint, food restriction, or a combined stressor, has an enduring influence on behavioral response to estradiol and progesterone. This demonstrates that the decreased response to estradiol and progesterone is not a general response to all stressors during this developmental stage.

Craniocerebral aspergillosis in immunocompetent hosts: surgical perspective.

PubMed

Shamim, Muhammad Shahzad; Siddiqui, Arshad A; Enam, Syed Ather; Shah, Ahmed Ali; Jooma, Rashid; Anwar, Saleha

2007-01-01

Craniocerebral aspergillosis is a rare but dangerous variety of central nervous system infections. Surgery is being widely recognized as the cornerstone of management. Due to the rarity of the disease, difficulty and delay in diagnosis and poor outcome, there is very little in the literature regarding the various surgical strategies that may be adopted in these patients. Early aggressive surgery followed by chemotherapy offers the best chances. Surgical planning would depend upon the type and location of the disease process as well as the condition of the patient. Perioperative care holds immense importance and knowledge of possible complications is essential. Aspergillosis of the central nervous system is difficult to diagnose and equally difficult to treat. Surgery remains the cornerstone of management followed by systemic antifungal medications. Results are better in immunocompetent patients as compared to those who are immunocompromised.

Acute tau knockdown in the hippocampus of adult mice causes learning and memory deficits.

PubMed

Velazquez, Ramon; Ferreira, Eric; Tran, An; Turner, Emily C; Belfiore, Ramona; Branca, Caterina; Oddo, Salvatore

2018-05-10

Misfolded and hyperphosphorylated tau accumulates in several neurodegenerative disorders including Alzheimer's disease, frontotemporal dementia with Parkinsonism, corticobasal degeneration, progressive supranuclear palsy, Down syndrome, and Pick's disease. Tau is a microtubule-binding protein, and its role in microtubule stabilization is well defined. In contrast, while growing evidence suggests that tau is also involved in synaptic physiology, a complete assessment of tau function in the adult brain has been hampered by robust developmental compensation of other microtubule-binding proteins in tau knockout mice. To circumvent these developmental compensations and assess the role of tau in the adult brain, we generated an adeno-associated virus (AAV) expressing a doxycycline-inducible short-hairpin (Sh) RNA targeted to tau, herein referred to as AAV-ShRNATau. We performed bilateral stereotaxic injections in 7-month-old C57Bl6/SJL wild-type mice with either the AAV-ShRNATau or a control AAV. We found that acute knockdown of tau in the adult hippocampus significantly impaired motor coordination and spatial memory. Blocking the expression of the AAV-ShRNATau, thereby allowing tau levels to return to control levels, restored motor coordination and spatial memory. Mechanistically, the reduced tau levels were associated with lower BDNF levels, reduced levels of synaptic proteins associated with learning, and decreased spine density. We provide compelling evidence that tau is necessary for motor and cognitive function in the adult brain, thereby firmly supporting that tau loss-of-function may contribute to the clinical manifestations of many tauopathies. These findings have profound clinical implications given that anti-tau therapies are in clinical trials for Alzheimer's disease. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Development of a novel mouse glioma model using lentiviral vectors

PubMed Central

Marumoto, Tomotoshi; Tashiro, Ayumu; Friedmann-Morvinski, Dinorah; Scadeng, Miriam; Soda, Yasushi; Gage, Fred H; Verma, Inder M

2009-01-01

We report the development of a new method to induce glioblastoma multiforme in adult immunocompetent mice by injecting Cre-loxP–controlled lentiviral vectors expressing oncogenes. Cell type- or region-specific expression of activated forms of the oncoproteins Harvey-Ras and AKT in fewer than 60 glial fibrillary acidic protein–positive cells in the hippocampus, subventricular zone or cortex of mice heterozygous for the gene encoding the tumor suppressor Tp53 were tested. Mice developed glioblastoma multiforme when transduced either in the subventricular zone or the hippocampus. However, tumors were rarely detected when the mice were transduced in the cortex. Transplantation of brain tumor cells into naive recipient mouse brain resulted in the formation of glioblastoma multiforme–like tumors, which contained CD133+ cells, formed tumorspheres and could differentiate into neurons and astrocytes. We suggest that the use of Cre-loxP–controlled lentiviral vectors is a novel way to generate a mouse glioblastoma multiforme model in a region- and cell type-specific manner in adult mice. PMID:19122659

Effect of extract of Hibiscus on the ultrastructure of the testis in adult mice.

PubMed

Mahmoud, Yomna Ibrahim

2012-07-01

Hibiscus sabdariffa extract is a popular beverage in many tropical and sub-tropical countries. Although, Hibiscus tea is known for its medicinal effects for thousands of years, scientific evidence of its systemic safety is very limited. The current study aimed to assess the potential adverse effects of H. sabdariffa extract on sperm morphology and testicular ultrastructure of albino mice. Thirty adult male albino mice were divided into three equal groups and were given: (a) distilled water, (b) cold Hibiscus aqueous extract, and (c) boiled Hibiscus aqueous extract. Hibiscus extract was administered orally daily for 4 weeks in a dose of 200 mg/kg body weight/mouse. Twenty-four hours after the last treatment, mice were decapitated and the testes and epididymides were excised and processed for transmission electron microscopy to assess ultrastructural and sperm abnormalities. The results clearly demonstrate that aqueous extracts from dried calyx of H. sabdariffa, either cold or boiled, alter normal sperm morphology and testicular ultrastructure and adversely influence the male reproductive fertility in albino mice. The current data suggest that Hibiscus extract should be consumed with caution, and reasonable estimates of the human risk associated with its consumption should be provided. Copyright © 2011 Elsevier GmbH. All rights reserved.

X-rays and photocarcinogenesis in hairless mice.

PubMed

Lerche, Catharina M; Philipsen, Peter A; Wulf, Hans Christian

2013-08-01

It is well known that excessive X-ray radiation can cause non-melanoma skin cancers. With the increased incidence of sun-related skin cancer there is a need to investigate the combination of sunlight and X-rays. Immunocompetent C3.Cg/TifBomTac mice (n = 298) were divided into 12 groups. Mice were irradiated with 12, 29 or 50 kV X-rays. The mice received a total dose of 45 Gy. They were irradiated with 3 SED simulated solar radiation (SSR) either before or after irradiation with X-rays. The groups irradiated with X-rays alone, 0, 3, 9 and 10 mice (0, 12, 29 and 50 kV, respectively) developed squamous cell carcinoma. In the groups irradiated with SSR after X-rays the development of tumours was significantly faster in the 50 kV group than in the corresponding control group (175 vs. 194 days, p < 0.001). In the groups irradiated with SSR prior to the X-ray radiation the development of tumours was significantly faster in the 29 and the 50 kV groups than in the corresponding control group (175 vs. 202 days, p < 0.001 and 158 vs. 202 days, p < 0.001, respectively). In conclusion, X-ray radiation alone is a weak carcinogen in hairless mice. There is an added carcinogenic effect if X-ray radiation is given on prior sun-exposed skin or if the skin is sun-exposed after X-rays. We still believe that X-ray radiation is a safe and effective therapy for various dermatological diseases but caution should be observed if a patient has severely sun-damaged skin or has a high-risk sun behaviour.

The pathogenesis of severe fever with thrombocytopenia syndrome virus infection in alpha/beta interferon knockout mice: insights into the pathologic mechanisms of a new viral hemorrhagic fever.

PubMed

Liu, Yan; Wu, Bin; Paessler, Slobodan; Walker, David H; Tesh, Robert B; Yu, Xue-jie

2014-02-01

Severe fever with thrombocytopenia syndrome virus (SFTSV) is a newly discovered Phlebovirus causing an emerging hemorrhagic fever in East Asia, with reported case fatality rates up to 30%. Despite the high case fatality rate and large number of persons at risk of infection, the pathobiology of the disease is unknown, and no effective animal model has been available for investigating its pathogenesis. We have studied mice and hamsters as potential small-animal models of SFTSV infection following subcutaneous, intraperitoneal, or intracerebral inoculation. Animal tissues were processed for viral load determination, histopathology, immunohistochemistry, and confocal microscopic studies. We found that immunocompetent adult mice and hamsters did not become ill after SFTSV infection. However, alpha/beta interferon receptor knockout (IFNAR(-/-)) mice were highly susceptible to SFTSV infection, and all mice died within 3 to 4 days after subcutaneous inoculation of 10(6) focus-forming units of SFTSV. Histologic examination of tissues of IFNAR(-/-) mice infected with SFTSV showed no detectable lesions. In contrast, by immunohistochemistry virus antigen was found in liver, intestine, kidney, spleen, lymphoid tissue, and brain, but not in the lungs. Mesenteric lymph nodes and spleen were the most heavily infected tissues. Quantitative reverse transcription-PCR (RT-PCR) confirmed the presence of virus in these tissues. Confocal microscopy showed that SFTSV colocalized with reticular cells but did not colocalize with dendritic cells, monocytes/macrophages, neutrophils, or endothelium. Our results indicate that SFTSV multiplied in all organs except for lungs and that mesenteric lymph nodes and spleen were the most heavily infected tissues. The major target cells of SFTSV appear to be reticular cells in lymphoid tissues of intestine and spleen.

Prenatal Exposure to DEHP Induces Neuronal Degeneration and Neurobehavioral Abnormalities in Adult Male Mice.

PubMed

Barakat, Radwa; Lin, Po-Ching; Park, Chan Jin; Best-Popescu, Catherine; Bakery, Hatem H; Abosalum, Mohamed E; Abdelaleem, Nabila M; Flaws, Jodi A; Ko, CheMyong

2018-04-23

Phthalates are a family of synthetic chemicals that are used in producing a variety of consumer products. Di-(2-ethylhexyl) phthalate (DEHP) is an widely used phthalate and poses a public health concern. Prenatal exposure to DEHP has been shown to induce premature reproductive senescence in animal studies. In this study, we tested the hypothesis that prenatal exposure to DEHP impairs neurobehavior and recognition memory in her male offspring and we investigated one possible mechanism-oxidative damage in the hippocampus. Pregnant CD-1 female mice were orally administered 200μg, 500mg, or 750mg/kg/day DEHP or vehicle from gestational day 11 until birth. The neurobehavioral impact of the prenatal DEHP exposure was assessed at the ages of 16 to 22 months. Elevated plus maze and open field tests were used to measure anxiety levels. Y-maze and novel object recognition tests were employed to measure memory function. The oxidative damage in the hippocampus was measured by the levels of oxidative DNA damage and by SLIM microscopic counting of hippocampal neurons. Adult male mice that were prenatally exposed to DEHP exhibited anxious behaviors and impaired spatial and short-term recognition memory. The number of hippocampal pyramidal neurons was significantly decreased in the DEHP mice. Furthermore, DEHP mice expressed remarkably high levels of cyclooxygenase-2, 8-hydroxyguanine, and thymidine glycol in their hippocampal neurons. DEHP mice also had lower circulating testosterone concentrations and displayed a weaker immunoreactivity than the control mice to androgen receptor expression in the brain. This study found that prenatal exposure to DEHP caused elevated anxiety behavior and impaired recognition memory. These behavioral changes may originate from neurodegeneration caused by oxidative damage and inflammation in the hippocampus. Decreased circulating testosterone concentrations and decreased expression of androgen receptor in the brain also may be factors contributing

Suppressive effects of chlorphenesin on lymphocyte function in mice and humans.

PubMed

Stites, D P; Brecher, G; Schmidt, L; Berger, F M

1979-12-01

The immunosuppressive action of chlorphenesin was investigated in a wide variety of in vitro assays for cellular immunity in humans and mice. Chlorphenesin, at doses of 20-50 micrograms/ml, inhibited mitogenic responses of both mouse and human B and T cells. These doses did not kill cells exposed to the drug for 72 hr. Mixed lymphocyte reactions in inbred strains of mice and in unrelated humans were also inhibited at concentrations of about 50 micrograms/ml. However, the generation of cytotoxic T cells in cell-mediated lympholysis assays was not inhibited to the same degree as proliferation in mixed lymphocyte reaction and the cytotoxic potential of presensitized mouse T cells for allogeneic targets was totally unaffected. These studies suggest that chlorphenesin may have a broad spectrum of suppressive effects both on T and B cells and that the predominant inhibition of proliferative responses in these cells may reduce the expansion of clones of immunocompetent cells in vivo.

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice.

PubMed

Huang, Chih-Yu; Yao, Hui-Wen; Wang, Li-Chiu; Shen, Fang-Hsiu; Hsu, Sheng-Min; Chen, Shun-Hua

2017-02-15

Herpes simplex virus 1 (HSV-1) establishes latency in neural tissues of immunocompetent mice but persists in both peripheral and neural tissues of lymphocyte-deficient mice. Thymidine kinase (TK) is believed to be essential for HSV-1 to persist in neural tissues of immunocompromised mice, because infectious virus of a mutant with defects in both TK and UL24 is detected only in peripheral tissues, but not in neural tissues, of severe combined immunodeficiency mice (T. Valyi-Nagy, R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner, and N. W. Fraser, Virology 199:484-490, 1994, https://doi.org/10.1006/viro.1994.1150). Here we find infiltration of CD4 and CD8 T cells in peripheral and neural tissues of mice infected with a TK-negative mutant. We therefore investigated the significance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutants with defects in only TK or in both TK and UL24 and two strains of nude mice. Surprisingly, all three mutants establish persistent infection in up to 100% of brain stems and 93% of trigeminal ganglia of adult nude mice at 28 days postinfection, as measured by the recovery of infectious virus. Thus, in mouse neural tissues, host T cells block persistent HSV-1 infection, and viral TK is dispensable for the virus to establish persistent infection. Furthermore, we found 30- to 200-fold more virus in neural tissues than in the eye and detected glycoprotein C, a true late viral antigen, in brainstem neurons of nude mice persistently infected with the TK-negative mutant, suggesting that adult mouse neurons can support the replication of TK-negative HSV-1. Acyclovir is used to treat herpes simplex virus 1 (HSV-1)-infected immunocompromised patients, but treatment is hindered by the emergence of drug-resistant viruses, mostly those with mutations in viral thymidine kinase (TK), which activates acyclovir. TK mutants are detected in brains of immunocompromised

Thymidine Kinase-Negative Herpes Simplex Virus 1 Can Efficiently Establish Persistent Infection in Neural Tissues of Nude Mice

PubMed Central

Huang, Chih-Yu; Yao, Hui-Wen; Wang, Li-Chiu; Shen, Fang-Hsiu

2016-01-01

ABSTRACT Herpes simplex virus 1 (HSV-1) establishes latency in neural tissues of immunocompetent mice but persists in both peripheral and neural tissues of lymphocyte-deficient mice. Thymidine kinase (TK) is believed to be essential for HSV-1 to persist in neural tissues of immunocompromised mice, because infectious virus of a mutant with defects in both TK and UL24 is detected only in peripheral tissues, but not in neural tissues, of severe combined immunodeficiency mice (T. Valyi-Nagy, R. M. Gesser, B. Raengsakulrach, S. L. Deshmane, B. P. Randazzo, A. J. Dillner, and N. W. Fraser, Virology 199:484–490, 1994, https://doi.org/10.1006/viro.1994.1150). Here we find infiltration of CD4 and CD8 T cells in peripheral and neural tissues of mice infected with a TK-negative mutant. We therefore investigated the significance of viral TK and host T cells for HSV-1 to persist in neural tissues using three genetically engineered mutants with defects in only TK or in both TK and UL24 and two strains of nude mice. Surprisingly, all three mutants establish persistent infection in up to 100% of brain stems and 93% of trigeminal ganglia of adult nude mice at 28 days postinfection, as measured by the recovery of infectious virus. Thus, in mouse neural tissues, host T cells block persistent HSV-1 infection, and viral TK is dispensable for the virus to establish persistent infection. Furthermore, we found 30- to 200-fold more virus in neural tissues than in the eye and detected glycoprotein C, a true late viral antigen, in brainstem neurons of nude mice persistently infected with the TK-negative mutant, suggesting that adult mouse neurons can support the replication of TK-negative HSV-1. IMPORTANCE Acyclovir is used to treat herpes simplex virus 1 (HSV-1)-infected immunocompromised patients, but treatment is hindered by the emergence of drug-resistant viruses, mostly those with mutations in viral thymidine kinase (TK), which activates acyclovir. TK mutants are detected in brains of

Serratia marcescens endogenous endophthalmitis in an immunocompetent host

PubMed Central

Memon, Muhammad; Raman, Vasant

2016-01-01

A systemically well 66-year-old white Caucasian man presented to the urgent care department with a short history of progressive pain and blurring of vision in his left eye. He denied a history of trauma, intraocular surgery or use of illicit drugs. He was diagnosed with endogenous endophthalmitis. Vitreous biopsy grew Serratia marcescens, a Gram negative bacteria. In spite of extensive investigation, there was no obvious source of infection. He had an indwelling urine catheter for prostate hypertrophy, but urine culture was negative. There was no evidence of immunocompromise. He was treated with systemic as well as intravitreal antibiotics. In spite of appropriate treatment, the patient lost vision. S. marcescens endophthalmitis, seen even in immunocompetent people, carries a poor visual prognosis. PMID:26791115

Serratia marcescens endogenous endophthalmitis in an immunocompetent host.

PubMed

Memon, Muhammad; Raman, Vasant

2016-01-20

A systemically well 66-year-old white Caucasian man presented to the urgent care department with a short history of progressive pain and blurring of vision in his left eye. He denied a history of trauma, intraocular surgery or use of illicit drugs. He was diagnosed with endogenous endophthalmitis. Vitreous biopsy grew Serratia marcescens, a Gram negative bacteria. In spite of extensive investigation, there was no obvious source of infection. He had an indwelling urine catheter for prostate hypertrophy, but urine culture was negative. There was no evidence of immunocompromise. He was treated with systemic as well as intravitreal antibiotics. In spite of appropriate treatment, the patient lost vision. S. marcescens endophthalmitis, seen even in immunocompetent people, carries a poor visual prognosis. 2016 BMJ Publishing Group Ltd.

Pkd1 transgenic mice: adult model of polycystic kidney disease with extrarenal and renal phenotypes

PubMed Central

Kurbegovic, Almira; Côté, Olivier; Couillard, Martin; Ward, Christopher J.; Harris, Peter C.; Trudel, Marie

2010-01-01

While high levels of Pkd1 expression are detected in tissues of patients with autosomal dominant polycystic kidney disease (ADPKD), it is unclear whether enhanced expression could be a pathogenetic mechanism for this systemic disorder. Three transgenic mouse lines were generated from a Pkd1-BAC modified by introducing a silent tag via homologous recombination to target a sustained wild-type genomic Pkd1 expression within the native tissue and temporal regulation. These mice specifically overexpressed the Pkd1 transgene in extrarenal and renal tissues from ∼2- to 15-fold over Pkd1 endogenous levels in a copy-dependent manner. All transgenic mice reproducibly developed tubular and glomerular cysts leading to renal insufficiency. Interestingly, Pkd1TAG mice also exhibited renal fibrosis and calcium deposits in papilla reminiscent of nephrolithiasis as frequently observed in ADPKD. Similar to human ADPKD, these mice consistently displayed hepatic fibrosis and ∼15% intrahepatic cysts of the bile ducts affecting females preferentially. Moreover, a significant proportion of mice developed cardiac anomalies with severe left-ventricular hypertrophy, marked aortic arch distention and/or valvular stenosis and calcification that had profound functional impact. Of significance, Pkd1TAG mice displayed occasional cerebral lesions with evidence of ruptured and unruptured cerebral aneurysms. This Pkd1TAG mouse model demonstrates that overexpression of wild-type Pkd1 can trigger the typical adult renal and extrarenal phenotypes resembling human ADPKD. PMID:20053665

Monoacylglycerol lipase inhibitor JZL184 reduces neuroinflammatory response in APdE9 mice and in adult mouse glial cells.

PubMed

Pihlaja, Rea; Takkinen, Jatta; Eskola, Olli; Vasara, Jenni; López-Picón, Francisco R; Haaparanta-Solin, Merja; Rinne, Juha O

2015-04-28

Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice. Transgenic APdE9 mice (5 months old) were treated with JZL184 (40 mg/kg) or vehicle every day for 1 month. In vivo binding of the neuroinflammation-related, microglia-specific translocator protein (TSPO) targeting radioligand [(18) F]GE-180 decreased slightly but statistically non-significantly in multiple brain areas compared to vehicle-treated mice. JZL184 treatment induced a significant decrease in expression levels of inflammation-induced, Iba1-immunoreactive microglia in the hippocampus (P < 0.01) and temporal and parietal (P < 0.05) cortices. JZL184 also induced a marked decrease in total Aβ burden in the temporal (P < 0.001) and parietal (P < 0.01) cortices and, to some extent, in the hippocampus. Adult microglial and astrocyte cultures pre-treated with JZL184 and then exposed to the neuroinflammation-inducing agents lipopolysaccharide (LPS), interferon-gamma (IFN-γ), and Aβ42 had significantly reduced proinflammatory responses compared to cells without JZL184 treatment. JZL184 decreased the proinflammatory reactions of microglia and reduced the total Aβ burden and its precursors in the APdE9 mouse model. It also reduced the proinflammatory responses of microglia and astrocytes isolated from adult mice.

The Role of Heterotypic DENV-specific CD8+T Lymphocytes in an Immunocompetent Mouse Model of Secondary Dengue Virus Infection.

PubMed

Talarico, Laura B; Batalle, Juan P; Byrne, Alana B; Brahamian, Jorge M; Ferretti, Adrián; García, Ayelén G; Mauri, Aldana; Simonetto, Carla; Hijano, Diego R; Lawrence, Andrea; Acosta, Patricio L; Caballero, Mauricio T; Paredes Rojas, Yésica; Ibañez, Lorena I; Melendi, Guillermina A; Rey, Félix A; Damonte, Elsa B; Harris, Eva; Polack, Fernando P

2017-06-01

Dengue is the most prevalent arthropod-borne viral disease worldwide and is caused by the four dengue virus serotypes (DENV-1-4). Sequential heterologous DENV infections can be associated with severe disease manifestations. Here, we present an immunocompetent mouse model of secondary DENV infection using non mouse-adapted DENV strains to investigate the pathogenesis of severe dengue disease. C57BL/6 mice infected sequentially with DENV-1 (strain Puerto Rico/94) and DENV-2 (strain Tonga/74) developed low platelet counts, internal hemorrhages, and increase of liver enzymes. Cross-reactive CD8 + T lymphocytes were found to be necessary and sufficient for signs of severe disease by adoptively transferring of DENV-1-immune CD8 + T lymphocytes before DENV-2 challenge. Disease signs were associated with production of tumor necrosis factor (TNF)-α and elevated cytotoxicity displayed by heterotypic anti-DENV-1 CD8 + T lymphocytes. These findings highlight the critical role of heterotypic anti-DENV CD8 + T lymphocytes in manifestations of severe dengue disease. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Recurrent seizures during acute acquired toxoplasmosis in an immunocompetent traveller returning from Africa.

PubMed

Beltrame, Anna; Venturini, Sergio; Crichiutti, Giovanni; Meroni, Valeria; Buonfrate, Dora; Bassetti, Matteo

2016-04-01

We report an unusual case of acute acquired toxoplasmosis (AAT) presenting as lymphadenopathy and recurrent seizures in an immunocompetent 15-year-old boy. The patient reported an 18-day vacation to Africa (Ethiopia), 39 days prior to the first seizure. Electroencephalogram (EEG) showed sporadic single-spike or sharp-wave paroxysms and the magnetic resonance imaging (RMI) of the brain was negative. The serology for T. gondii was compatible with an acute infection defined as positive for both toxoplasma-specific IgG and IgM and a low avidity (6 %), confirmed by a reference laboratory. The patient reported other two episodes of seizures, occurring 7 days apart. He was treated with pyrimethamine plus sulfadiazine and leucovorin for 4 weeks, with an improvement of lymphadenitis and normalization of EEG. After 5 months, new seizures were reported and a diagnosis of epilepsy was done. Toxoplasma polymerase chain reaction (PCR) of cerebrospinal fluid (CSF) and blood were negative. A treatment with valproic acid was started, obtaining control of the neurological disease. Awareness of this neurologic manifestation by clinicians is required, also in immunocompetent patients. The relationship between toxoplasmosis and recurrent seizure needs to be investigated by new studies.

Tegumental alterations of adult Schistosoma japonicum harbored in mice treated with a single oral dose of mefloquine.

PubMed

Xiao, Shu-hua; Xue, Jian; Shen, Bing-gui

2010-02-01

To observe the effect of mefloquine on the tegument of adult Schistosoma japonicum harbored in mice. Twelve mice were each infected with 60-80 S. japonicum cercariae. At 35 days post-infection, 10 mice were treated orally with mefloquine at a single dose of 400 mg/kg. Two mice were sacrificed at 8 h, 24 h, 3 days, 7 days, and 14 days post-treatment respectively, and schistosomes were collected by the perfusion technique, fixed and examined under a scanning electron microscope. Schistosomes obtained from the remaining 2 untreated mice served as control. 8 h post-treatment, male and female schistosomes showed focal swelling of the worm body accompanied by extensive swelling, tough junction and fusion of tegumental ridges. Meanwhile, some of the sensory structures showed enlargement and part of them collapsed. 24 h after mefloquine administration, head portion of some male and female worms revealed high swelling accompanied by severe damage to oral sucker. 3 days post-treatment, focal swelling of worm body along the whole worm was universal. In some male and female worms, the damaged tegument fused together to form a large mass protruding from the tegumental surface. In addition, focal or extensive peeling of tegumental ridges was seen or collapse of enlarged sensory structure resulted in formation of hole-like appearance. 7 days post administration, focal swelling of worm body and damage to tegument induced by mefloquine were similar to those aforementioned, but focal peeling, collapse of enlarged sensory structures, and deformation of oral sucker in male and female worms were universal. 14 days post-treatment, individual male worm survived the treatment revealed normal appearance of tegumental ridges in head portion, although light focal swelling of worm body was still observed. Mefloquine causes focal swelling of worm body, extensive and severe damage to the tegument in adult S. japonicum.

Dynamic of distribution of human bone marrow-derived mesenchymal stem cells after transplantation into adult unconditioned mice.

PubMed

Allers, Carolina; Sierralta, Walter D; Neubauer, Sonia; Rivera, Francisco; Minguell, José J; Conget, Paulette A

2004-08-27

The use of mesenchymal stem cells (MSC) for cell therapy relies on their capacity to engraft and survive long-term in the appropriate target tissue(s). Animal models have demonstrated that the syngeneic or xenogeneic transplantation of MSC results in donor engraftment into the bone marrow and other tissues of conditioned recipients. However, there are no reliable data showing the fate of human MSC infused into conditioned or unconditioned adult recipients. In the present study, the authors investigated, by using imaging, polymerase chain reaction (PCR), and in situ hybridization, the biodistribution of human bone marrow-derived MSC after intravenous infusion into unconditioned adult nude mice. As assessed by imaging (gamma camera), PCR, and in situ hybridization analysis, the authors' results demonstrate the presence of human MSC in bone marrow, spleen, and mesenchymal tissues of recipient mice. These results suggest that human MSC transplantation into unconditioned recipients represents an option for providing cellular therapy and avoids the complications associated with drugs or radiation conditioning.

Immunization of Aged Mice with a Pneumococcal Conjugate Vaccine Combined with an Unmethylated CpG-Containing Oligodeoxynucleotide Restores Defective Immunoglobulin G Antipolysaccharide Responses and Specific CD4+-T-Cell Priming to Young Adult Levels

DTIC Science & Technology

2006-04-01

aged and young adult mice made comparable levels of proinflammatory cytokines in response to CpG-ODN, although cells from aged mice secreted higher...sepsis, is significantly elevated in the elderly relative to young adults (37, 60). Defective innate immunity including diminished neutrophil and...young adult recipients (15). Exposure to inflammatory cy- tokines in vivo could restore the defective CD4-T-cell function in aged mice (20). Pn

Enriched environment increases neurogenesis and improves social memory persistence in socially isolated adult mice.

PubMed

Monteiro, Brisa M M; Moreira, Fabrício A; Massensini, André R; Moraes, Márcio F D; Pereira, Grace S

2014-02-01

Social memory consists of the information necessary to identify and recognize cospecifics and is essential to many forms of social interaction. Social memory persistence is strongly modulated by the animal's experiences. We have shown in previous studies that social isolation (SI) in adulthood impairs social memory persistence and that an enriched environment (EE) prevents this impairment. However, the mechanisms involved in the effects of SI and EE on social memory persistence remain unknown. We hypothesized that the mechanism by which SI and EE affect social memory persistence is through their modulation of neurogenesis. To investigate this hypothesis, adult mice were submitted to 7 days of one of the following conditions: group-housing in a standard (GH) or enriched environment (GH+EE); social isolation in standard (SI) or enriched environment (SI+EE). We observed an increase in the number of newborn neurons in the dentate gyrus of the hippocampus (DG) and glomerular layer of the olfactory bulb (OB) in both GH+EE and SI+EE mice. However, this increase of newborn neurons in the granule cell layer of the OB was restricted to the GH+EE group. Furthermore, both SI and SI+EE groups showed less neurogenesis in the mitral layer of the OB. Interestingly, the performance of the SI mice in the buried food-finding task was inferior to that of the GH mice. To further analyze whether increased neurogenesis is in fact the mechanism by which the EE improves social memory persistence in SI mice, we administered the mitotic inhibitor AraC or saline directly into the lateral ventricles of the SI+EE mice. We found that the AraC treatment decreased cell proliferation in both the DG and OB, and impaired social memory persistence in the SI+EE mice. Taken together, our results strongly suggest that neurogenesis is what supports social memory persistence in socially isolated mice. © 2013 Wiley Periodicals, Inc.

EGFRvIII mCAR-modified T-cell therapy cures mice with established intracerebral glioma and generates host immunity against tumor-antigen loss.

PubMed

Sampson, John H; Choi, Bryan D; Sanchez-Perez, Luis; Suryadevara, Carter M; Snyder, David J; Flores, Catherine T; Schmittling, Robert J; Nair, Smita K; Reap, Elizabeth A; Norberg, Pamela K; Herndon, James E; Kuan, Chien-Tsun; Morgan, Richard A; Rosenberg, Steven A; Johnson, Laura A

2014-02-15

Chimeric antigen receptor (CAR) transduced T cells represent a promising immune therapy that has been shown to successfully treat cancers in mice and humans. However, CARs targeting antigens expressed in both tumors and normal tissues have led to significant toxicity. Preclinical studies have been limited by the use of xenograft models that do not adequately recapitulate the immune system of a clinically relevant host. A constitutively activated mutant of the naturally occurring epidermal growth factor receptor (EGFRvIII) is antigenically identical in both human and mouse glioma, but is also completely absent from any normal tissues. We developed a third-generation, EGFRvIII-specific murine CAR (mCAR), and performed tests to determine its efficacy in a fully immunocompetent mouse model of malignant glioma. At elevated doses, infusion with EGFRvIII mCAR T cells led to cures in all mice with brain tumors. In addition, antitumor efficacy was found to be dependent on lymphodepletive host conditioning. Selective blockade with EGFRvIII soluble peptide significantly abrogated the activity of EGFRvIII mCAR T cells in vitro and in vivo, and may offer a novel strategy to enhance the safety profile for CAR-based therapy. Finally, mCAR-treated, cured mice were resistant to rechallenge with EGFRvIII(NEG) tumors, suggesting generation of host immunity against additional tumor antigens. All together, these data support that third-generation, EGFRvIII-specific mCARs are effective against gliomas in the brain and highlight the importance of syngeneic, immunocompetent models in the preclinical evaluation of tumor immunotherapies. ©2013 AACR

Induced Wnt5a expression perturbs embryonic outgrowth and intestinal elongation, but is well-tolerated in adult mice.

PubMed

Bakker, Elvira R M; Raghoebir, Lalini; Franken, Patrick F; Helvensteijn, Werner; van Gurp, Léon; Meijlink, Frits; van der Valk, Martin A; Rottier, Robbert J; Kuipers, Ernst J; van Veelen, Wendy; Smits, Ron

2012-09-01

Wnt5a is essential during embryonic development, as indicated by mouse Wnt5a knockout embryos displaying outgrowth defects of multiple structures including the gut. The dynamics of Wnt5a involvement in these processes is unclear, and perinatal lethality of Wnt5a knockout embryos has hampered investigation of Wnt5a during postnatal stages in vivo. Although in vitro studies have suggested a relevant role for Wnt5a postnatally, solid evidence for a significant impact of Wnt5a within the complexity of an adult organism is lacking. We generated a tightly-regulated inducible Wnt5a transgenic mouse model and investigated the effects of Wnt5a induction during different time-frames of embryonic development and in adult mice, focusing on the gastrointestinal tract. When induced in embryos from 10.5 dpc onwards, Wnt5a expression led to severe outgrowth defects affecting the gastrointestinal tracts, limbs, facial structures and tails, closely resembling the defects observed in Wnt5a knockout mice. However, Wnt5a induction from 13.5 dpc onwards did not cause this phenotype, indicating that the most critical period for Wnt5a in embryonic development is prior to 13.5 dpc. In adult mice, induced Wnt5a expression did not reveal abnormalities, providing the first in vivo evidence that Wnt5a has no major impact on mouse intestinal homeostasis postnatally. Protein expression of Wnt5a receptor Ror2 was strongly reduced in adult intestine compared to embryonic stages. Moreover, we uncovered a regulatory process where induction of Wnt5a causes downregulation of its receptor Ror2. Taken together, our results indicate a role for Wnt5a during a restricted time-frame of embryonic development, but suggest no impact during homeostatic postnatal stages. Copyright © 2012 Elsevier Inc. All rights reserved.

Zika virus infection confers protection against West Nile virus challenge in mice

PubMed Central

Vázquez-Calvo, Ángela; Blázquez, Ana-Belén; Escribano-Romero, Estela; Merino-Ramos, Teresa; Saiz, Juan-Carlos; Martín-Acebes, Miguel A; Jiménez de Oya, Nereida

2017-01-01

Flaviviruses are RNA viruses that constitute a worrisome threat to global human and animal health. Zika virus (ZIKV), which was initially reported to cause a mild disease, recently spread in the Americas, infecting millions of people. During this recent epidemic, ZIKV infection has been linked to serious neurological diseases and birth defects, specifically Guillain-Barrè syndrome (GBS) and microcephaly. Because information about ZIKV immunity remains scarce, we assessed the humoral response of immunocompetent mice to infection with three viral strains of diverse geographical origin (Africa, Asia and America). No infected animals showed any sign of disease or died after infection. However, specific neutralizing antibodies were elicited in all infected mice. Considering the rapid expansion of ZIKV throughout the American continent and its co-circulation with other medically relevant flaviviruses, such as West Nile virus (WNV), the induction of protective immunity between ZIKV and WNV was analyzed. Remarkably, protection after challenge with WNV was observed in mice previously infected with ZIKV, as survival rates were significantly higher than in control mice. Moreover, previous ZIKV infection enhanced the humoral immune response against WNV. These findings may be relevant in geographical areas where both ZIKV and WNV co-circulate, as well as for the future development of broad-spectrum flavivirus vaccines. PMID:28928416

Zika virus infection confers protection against West Nile virus challenge in mice.

PubMed

Vázquez-Calvo, Ángela; Blázquez, Ana-Belén; Escribano-Romero, Estela; Merino-Ramos, Teresa; Saiz, Juan-Carlos; Martín-Acebes, Miguel A; Jiménez de Oya, Nereida

2017-09-20

Flaviviruses are RNA viruses that constitute a worrisome threat to global human and animal health. Zika virus (ZIKV), which was initially reported to cause a mild disease, recently spread in the Americas, infecting millions of people. During this recent epidemic, ZIKV infection has been linked to serious neurological diseases and birth defects, specifically Guillain-Barrè syndrome (GBS) and microcephaly. Because information about ZIKV immunity remains scarce, we assessed the humoral response of immunocompetent mice to infection with three viral strains of diverse geographical origin (Africa, Asia and America). No infected animals showed any sign of disease or died after infection. However, specific neutralizing antibodies were elicited in all infected mice. Considering the rapid expansion of ZIKV throughout the American continent and its co-circulation with other medically relevant flaviviruses, such as West Nile virus (WNV), the induction of protective immunity between ZIKV and WNV was analyzed. Remarkably, protection after challenge with WNV was observed in mice previously infected with ZIKV, as survival rates were significantly higher than in control mice. Moreover, previous ZIKV infection enhanced the humoral immune response against WNV. These findings may be relevant in geographical areas where both ZIKV and WNV co-circulate, as well as for the future development of broad-spectrum flavivirus vaccines.

Developmental Exposure of Mice to TCDD Elicits a Similar Uterine Phenotype in Adult Animals as Observed in Women with Endometriosis

PubMed Central

Nayyar, Tultul; Bruner-Tran, Kaylon L.; Piestrzeniewicz-Ulanska, Dagmara; Osteen, Kevin G.

2007-01-01

Whether environmental toxicants impact an individual woman’s risk for developing endometriosis remains uncertain. Although the growth of endometrial glands and stroma at extra-uterine sites is associated with retrograde menstruation, our studies suggest that reduced responsiveness to progesterone may increase the invasive capacity of endometrial tissue in women with endometriosis. Interestingly, our recent studies using isolated human endometrial cells in short-term culture suggest that experimental exposure to the environmental contaminant 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD) can alter the expression of progesterone receptor isotypes. Compared to adult exposure, toxicant exposure during development can exert a significantly greater biological impact, potentially affecting the incidence of endometriosis in adults. To address this possibility, we exposed mice to TCDD at critical developmental time points and subsequently examined uterine progesterone receptor expression and steroid responsive transforming growth factor-β2 expression in adult animals. We find that the uterine phenotype of toxicant-exposed mice is markedly similarly to the endometrial phenotype of women with endometriosis. PMID:17056225

Adiposity, compared with masculinity, serves as a more valid cue to immunocompetence in human mate choice.

PubMed

Rantala, Markus J; Coetzee, Vinet; Moore, Fhionna R; Skrinda, Ilona; Kecko, Sanita; Krama, Tatjana; Kivleniece, Inese; Krams, Indrikis

2013-01-22

According to the 'good genes' hypothesis, females choose males based on traits that indicate the male's genetic quality in terms of disease resistance. The 'immunocompetence handicap hypothesis' proposed that secondary sexual traits serve as indicators of male genetic quality, because they indicate that males can contend with the immunosuppressive effects of testosterone. Masculinity is commonly assumed to serve as such a secondary sexual trait. Yet, women do not consistently prefer masculine looking men, nor is masculinity consistently related to health across studies. Here, we show that adiposity, but not masculinity, significantly mediates the relationship between a direct measure of immune response (hepatitis B antibody response) and attractiveness for both body and facial measurements. In addition, we show that circulating testosterone is more closely associated with adiposity than masculinity. These findings indicate that adiposity, compared with masculinity, serves as a more important cue to immunocompetence in female mate choice.

Acute systemic histoplasmosis associated with chorioretinitis in an immunocompetent adolescent

PubMed Central

Fowler, Brian; Shen, Christopher; Mastellone, Joseph; Chaum, Edward

2011-01-01

Summary Histoplasmosis is an endemic, systemic mycosis caused by the dimorphic fungus Histoplasma capsulatum. A minority of patients develop asymptomatic chorioretinitis known as presumed ocular histoplasmosis syndrome (POHS), which is typically associated with chorioretinal scarring and peripapillary atrophy and occasionally with choroidal neovascularization secondary to maculopathy. We report a case of acute severe bilateral chorioretinitis associated with disseminated H. capsulatum in an immunocompetent adolescent boy living in an endemic area. The chorioretinitis did not respond to systemic antifungal therapy, but both his systemic illness and ocular lesions resolved with the addition of systemic steroids. PMID:23362391

Anti-influenza A virus characteristics of a fucoidan from sporophyll of Undaria pinnatifida in mice with normal and compromised immunity.

PubMed

Hayashi, Kyoko; Lee, Jung-Bum; Nakano, Takahisa; Hayashi, Toshimitsu

2013-04-01

Undaria pinnatifida, an edible brown alga, contains fucoidan (FuC), a sulfated polysaccharide, that inhibited the in vitro replication of influenza A virus, and stimulated both innate and adaptive immune defense functions in virus-infected mice. In the present study, the effects of oral administration of FuC were evaluated on influenza virus infection in immunocompetent and immunocompromised mice, where the efficacy of FuC was demonstrated in reducing viral replication, decreasing weight loss and mortality, and prolonging survival. Oral FuC resulted in increased neutralizing antibody production in the mucosa and blood. In contrast, while suppressing virus yields in mice more markedly than FuC, oseltamivir significantly reduced the neutralizing antibody titers in both the mucosa and blood. In immunocompromised mice, drug-resistant viruses frequently recovered after oseltamivir treatment; no resistant viruses were isolated from FuC-treated mice. FuC could be a candidate for the development of new therapeutic options including its combination with neuraminidase inhibitors such as oseltamivir. Copyright © 2013 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Hair Follicle Generation by Injections of Adult Human Follicular Epithelial and Dermal Papilla Cells into Nude Mice

PubMed Central

Nilforoushzadeh, Mohammadali; Rahimi Jameh, Elham; Jaffary, Fariba; Abolhasani, Ehsan; Keshtmand, Gelavizh; Zarkob, Hajar; Mohammadi, Parvaneh; Aghdami, Nasser

2017-01-01

Objective Dermal papilla and hair epithelial stem cells regulate hair formation and the growth cycle. Damage to or loss of these cells can cause hair loss. Although several studies claim to reconstitute hairs using rodent cells in an animal model, additional research is needed to develop a stable human hair follicle reconstitution protocol. In this study, we have evaluated hair induction by injecting adult cultured human dermal papilla cells and a mixture of hair epithelial and dermal papilla cells in a mouse model. Materials and Methods In this experimental study, discarded human scalp skins were used to obtain dermal papilla and hair epithelial cells. After separation, cells were cultured and assessed for their characteristics. We randomly allocated 15 C57BL/6 nude mice into three groups that received injections in their dorsal skin. The first group received cultured dermal papilla cells, the second group received a mixture of cultured epithelial and dermal papilla cells, and the third group (control) received a placebo [phosphate-buffered saline (PBS-)]. Results Histopathologic examination of the injection sites showed evidence of hair growth in samples that received cells compared with the control group. However, the group that received epithelial and dermal papilla cells had visible evidence of hair growth. PKH tracing confirmed the presence of transplanted cells in the new hair. Conclusion Our data showed that injection of a combination of adult human cultured dermal papilla and epithelial cells could induce hair growth in nude mice. This study emphasized that the combination of human adult cultured dermal papilla and epithelial cells could induce new hair in nude mice. PMID:28670518

Adult exposure to tributyltin affects hypothalamic neuropeptide Y, Y1 receptor distribution, and circulating leptin in mice.

PubMed

Bo, E; Farinetti, A; Marraudino, M; Sterchele, D; Eva, C; Gotti, S; Panzica, G

2016-07-01

Tributyltin (TBT), a pesticide used in antifouling paints, is toxic for aquatic invertebrates. In vertebrates, TBT may act in obesogen- inducing adipogenetic gene transcription for adipocyte differentiation. In a previous study, we demonstrated that acute administration of TBT induces c-fos expression in the arcuate nucleus. Therefore, in this study, we tested the hypothesis that adult exposure to TBT may alter a part of the nervous pathways controlling animal food intake. In particular, we investigated the expression of neuropeptide Y (NPY) immunoreactivity. This neuropeptide forms neural circuits dedicated to food assumption and its action is mediated by Y1 receptors that are widely expressed in the hypothalamic nuclei responsible for the regulation of food intake and energy homeostasis. To this purpose, TBT was orally administered at a dose of 0.025 mg/kg/day/body weight to adult animals [male and female C57BL/6 (Y1-LacZ transgenic mice] for 4 weeks. No differences were found in body weight and fat deposition, but we observed a significant increase in feed efficiency in TBT-treated male mice and a significant decrease in circulating leptin in both sexes. Computerized quantitative analysis of NPY immunoreactivity and Y1-related β-galactosidase activity demonstrated a statistically significant reduction in NPY and Y1 transgene expression in the hypothalamic circuit controlling food intake of treated male mice in comparison with controls. In conclusion, the present results indicate that adult exposure to TBT is profoundly interfering with the nervous circuits involved in the stimulation of food intake. © 2016 American Society of Andrology and European Academy of Andrology.

Tumors and Proliferative Lesions in Adult Offspring After Maternal Exposure to Methylarsonous Acid During Gestation in CDl Mice.

EPA Science Inventory

Inorganic arsenic exposure is carcinogenic in humans and rodents. When pregnant mice are exposed to inorganic arsenic in the drinking water their offspring, when adults, develop tumors and proliferative lesions at several sites, such as lung, liver, adrenal, uterus, ovary and ovi...

Contacts with children and young people and adult risk of suffering herpes zoster.

PubMed

Salleras, M; Domínguez, A; Soldevila, N; Prat, A; Garrido, P; Torner, N; Borrás, E; Salleras, L

2011-10-13

We carried out a matched case-control study to analyze the possible association between exposure to the children and the risk of suffering herpes-zoster in adulthood. Cases of herpes zoster in immunocompetent healthy patients aged ≥ 25 years seen in the dermatology department of the Sagrado Corazón Hospital in 2007-2008 were matched with four controls. Data were analyzed using conditional logistic regression. 153 cases and 604 matched controls were included. Contacts with children were significantly associated with a reduction in the risk of suffering herpes zoster in adulthood (adjusted OR 0.56 [0.37-0.85]). Herpes-zoster vaccination in immunocompetent people aged ≥ 50 years could counteract the possible negative effects of mass varicella vaccination in childhood on the epidemiology of herpes zoster in adults. Copyright © 2011 Elsevier Ltd. All rights reserved.

5' Rapid Amplification of cDNA Ends and Illumina MiSeq Reveals B Cell Receptor Features in Healthy Adults, Adults With Chronic HIV-1 Infection, Cord Blood, and Humanized Mice.

PubMed

Waltari, Eric; Jia, Manxue; Jiang, Caroline S; Lu, Hong; Huang, Jing; Fernandez, Cristina; Finzi, Andrés; Kaufmann, Daniel E; Markowitz, Martin; Tsuji, Moriya; Wu, Xueling

2018-01-01

Using 5' rapid amplification of cDNA ends, Illumina MiSeq, and basic flow cytometry, we systematically analyzed the expressed B cell receptor (BCR) repertoire in 14 healthy adult PBMCs, 5 HIV-1+ adult PBMCs, 5 cord blood samples, and 3 HIS-CD4/B mice, examining the full-length variable region of μ, γ, α, κ, and λ chains for V-gene usage, somatic hypermutation (SHM), and CDR3 length. Adding to the known repertoire of healthy adults, Illumina MiSeq consistently detected small fractions of reads with high mutation frequencies including hypermutated μ reads, and reads with long CDR3s. Additionally, the less studied IgA repertoire displayed similar characteristics to that of IgG. Compared to healthy adults, the five HIV-1 chronically infected adults displayed elevated mutation frequencies for all μ, γ, α, κ, and λ chains examined and slightly longer CDR3 lengths for γ, α, and λ. To evaluate the reconstituted human BCR sequences in a humanized mouse model, we analyzed cord blood and HIS-CD4/B mice, which all lacked the typical SHM seen in the adult reference. Furthermore, MiSeq revealed identical unmutated IgM sequences derived from separate cell aliquots, thus for the first time demonstrating rare clonal members of unmutated IgM B cells by sequencing.

Prefrontal Cortex Dysfunction in Fragile X Mice Depends on the Continued Absence of Fragile X Mental Retardation Protein in the Adult Brain.

PubMed

Siegel, Jennifer J; Chitwood, Raymond A; Ding, James M; Payne, Clayton; Taylor, William; Gray, Richard; Zemelman, Boris V; Johnston, Daniel

2017-08-02

Fragile X Syndrome (FX) is generally considered a developmental disorder, arising from a mutation that disrupts the transcription of Fragile X Mental Retardation Protein (FMRP). However, FMRP regulates the transcription of other proteins and participates in an unknown number of protein-protein interactions throughout life. In addition to known developmental issues, it is thus likely that some dysfunction is also due to the ongoing absence of FMRP. Dissociating dysfunction due to developmental dysregulation from dysfunction due to the continued absence of FMRP is necessary to understand the different roles of FMRP and to treat patients effectively throughout life. We show here that FX model mice display substantial deficits in a PFC-dependent task. We then use conditional knock-out mice to eliminate FMRP only in the PFC alone of adult mice. We observe an increase in the proportion of nonlearners and a delay in the onset of learning in both FX and conditional knock-out mice. The results suggest that these deficits (1) are due to the absence of FMRP in the PFC alone and (2) are not the result of developmental dysregulation. Furthermore, PFC-associated deficits are rescued by initiating production of FMRP in adult conditional restoration mice, suggesting that PFC dysfunction may persist as long as FMRP is absent and therefore can be rescued after development. The data suggest that it is possible to dissociate the roles of FMRP in neural function from developmental dysregulation, and that PFC function can be restored in the adult FX brain. SIGNIFICANCE STATEMENT The absence of Fragile X Mental Retardation Protein (FMRP) from birth results in developmental disabilities and lifelong impairments. We show here that in mouse models PFC dysfunction in Fragile X Syndrome (FX) can be attributed to the continued absence of FMRP from the PFC, independent of FMRP status during development. Furthermore, initiation of FMRP production in the PFC of adult FX animals rescues PFC

Leptin Signaling in AgRP Neurons Modulates Puberty Onset and Adult Fertility in Mice.

PubMed

Egan, Olivia K; Inglis, Megan A; Anderson, Greg M

2017-04-05

The hormone leptin indirectly communicates metabolic information to brain neurons that control reproduction, using GABAergic circuitry. Agouti-related peptide (AgRP) neurons in the arcuate nucleus are GABAergic, express leptin receptors (LepR), and are known to influence reproduction. This study tested whether leptin actions on AgRP neurons are required and sufficient for puberty onset and subsequent fertility. First, Agrp- Cre and Lepr- flox mice were used to target deletion of LepR to AgRP neurons. AgRP-LepR knock-out female mice exhibited mild obesity and adiposity as described previously, as well as a significant delay in the pubertal onset of estrous cycles compared with control animals. No significant differences in male puberty onset or adult fecundity in either sex were observed. Next, mice with a floxed polyadenylation signal causing premature transcriptional termination of the Lepr gene were crossed with AgRP-Cre mice to generate mice with AgRP neuron-specific rescue of LepR. Lepr-null control males and females were morbidly obese and exhibited delayed puberty onset, no evidence of estrous cycles, and minimal fecundity. Remarkably, AgRP-LepR rescue partially or fully restored all of these reproductive attributes to levels similar to those of LepR-intact controls despite minimal rescue of metabolic function. These results indicate that leptin signaling in AgRP neurons is sufficient for puberty onset and normal adult fecundity in both sexes when leptin signaling is absent in all other cells and that in females, the absence of AgRP neuron leptin signaling delays puberty. These actions appear to be independent of leptin's metabolic effects. SIGNIFICANCE STATEMENT Sexual maturation and fertility are dispensable at the individual level but critical for species survival. Conditions such as nutritional imbalance may therefore suppress puberty onset and fertility in an individual. In societies characterized by widespread obesity, the sensitivity of reproduction to

The Attenuated Nine Mile Phase II Clone 4/RSA439 Strain of Coxiella burnetii Is Highly Virulent for Severe Combined Immunodeficient (SCID) Mice

PubMed Central

Islam, Aminul; Lockhart, Michelle; Stenos, John; Graves, Stephen

2013-01-01

The Nine Mile phase II clone 4 (NMIIC4) strain of Coxiella burnetii is an attenuated phase II strain that has lost the genes for virulence determinant type 1 lipopolysaccharide. These bacteria were very virulent for severe combined immunodeficient (SCID) mice. The lethal dose 50 (LD50) was ∼10 bacteria. Infected SCID mice died between Day 28 and Day 53 post-infection. At termination of the experiment (Day 60) only 5 of 24 mice had survived. The degree of splenomegaly was directly related to the bacterial load in the SCID mice spleens. The NMIIC4 was avirulent in immunocompetent wild mice and bacterial DNA copies in splenic tissue were extremely low. The SCID mice that were inoculated with high doses of heat inactivated NMIIC4 C. burnetii were all alive at Day 60 and without splenomegaly. It appears that the phase I lipopolysaccharide present in virulent Nine Mile phase I but not in attenuated NMIIC4 is not the only virulence factor for C. burnetii. PMID:23958905

γδ T Cells Are a Component of Early Immunity against Preerythrocytic Malaria Parasites

PubMed Central

McKenna, Kyle C.; Tsuji, Moriya; Sarzotti, Marcella; Sacci, John B.; Witney, Adam A.; Azad, Abdu F.

2000-01-01

We tested the hypothesis that γδ T cells are a component of an early immune response directed against preerythrocytic malaria parasites that are required for the induction of an effector αβ T-cell immune response generated by irradiated-sporozoite (irr-spz) immunization. γδ T-cell-deficient (TCRδ−/−) mice on a C57BL/6 background were challenged with Plasmodium yoelii (17XNL strain) sporozoites, and then liver parasite burden was measured at 42 h postchallenge. Liver parasite burden was measured by quantification of parasite-specific 18S rRNA in total liver RNA by quantitative-competitive reverse transcription-PCR and by an automated 5′ exonuclease PCR. Sporozoite-challenged TCRδ−/− mice showed a significant (P < 0.01) increase in liver parasite burden compared to similarly challenged immunocompetent mice. In support of this result, TCRδ−/− mice were also found to be more susceptible than immunocompetent mice to a sporozoite challenge when blood-stage parasitemia was used as a readout. A greater percentage of TCRδ−/− mice than of immunocompetent mice progressed to a blood-stage infection when challenged with five or fewer sporozoites (odds ratio = 2.35, P = 0.06). TCRδ−/− mice receiving a single irr-spz immunization showed percent inhibition of liver parasites comparable to that of immunized immunocompetent mice following a sporozoite challenge. These data support the hypothesis that γδ T cells are a component of early immunity directed against malaria preerythrocytic parasites and suggest that γδ T cells are not required for the induction of an effector αβ T-cell immune response generated by irr-spz immunization. PMID:10722623

Maternal exposure to Western diet affects adult body composition and voluntary wheel running in a genotype-specific manner in mice.

PubMed

Hiramatsu, Layla; Kay, Jarren C; Thompson, Zoe; Singleton, Jennifer M; Claghorn, Gerald C; Albuquerque, Ralph L; Ho, Brittany; Ho, Brett; Sanchez, Gabriela; Garland, Theodore

2017-10-01

Some human diseases, including obesity, Type II diabetes, and numerous cancers, are thought to be influenced by environments experienced in early life, including in utero. Maternal diet during the perinatal period may be especially important for adult offspring energy balance, potentially affecting both body composition and physical activity. This effect may be mediated by the genetic background of individuals, including, for example, potential "protective" mechanisms for individuals with inherently high levels of physical activity or high basal metabolic rates. To examine some of the genetic and environmental factors that influence adult activity levels, we used an ongoing selection experiment with 4 replicate lines of mice bred for high voluntary wheel running (HR) and 4 replicate, non-selected control lines (C). Dams (half HR and half C) were fed a "Western" diet (WD, high in fat and sucrose) or a standard diet (SD) from 2weeks prior to mating until their pups could feed on solid food (14days of age). We analyzed dam and litter characteristics from birth to weaning, and offspring mass and physical activity into adulthood. One male offspring from each litter received additional metabolic and behavioral tests. Maternal WD caused pups to eat solid food significantly earlier for C litters, but not for HR litters (interaction of maternal environment and genotype). With dam mass as a covariate, mean pup mass was increased by maternal WD but litter size was unaffected. HR dams had larger litters and tended to have smaller pups than C dams. Home-cage activity of juvenile focal males was increased by maternal WD. Juvenile lean mass, fat mass, and fat percent were also increased by maternal WD, but food consumption (with body mass as a covariate) was unaffected (measured only for focal males). Behavior in an elevated plus maze, often used to indicate anxiety, was unaffected by maternal WD. Maximal aerobic capacity (VO 2 max) was also unaffected by maternal WD, but HR had

Sulforaphane induces Nrf2 target genes and attenuates inflammatory gene expression in microglia from brain of young adult and aged mice.

PubMed

Townsend, Brigitte E; Johnson, Rodney W

2016-01-01

Increased neuroinflammation and oxidative stress resulting from heightened microglial activation are associated with age-related cognitive impairment. The objectives of this study were to examine the effects of the bioactive sulforaphane (SFN) on the nuclear factor E2-related factor 2 (Nrf2) pathway in BV2 microglia and primary microglia, and to evaluate proinflammatory cytokine expression in lipopolysaccharide (LPS)-stimulated primary microglia from adult and aged mice. BV2 microglia and primary microglia isolated from young adult and aged mice were treated with SFN and LPS. Changes in Nrf2 activity, expression of Nrf2 target genes, and levels of proinflammatory markers were assessed by quantitative PCR and immunoassay. SFN increased Nrf2 DNA-binding activity and upregulated Nrf2 target genes in BV2 microglia, while reducing LPS-induced interleukin (IL-)1β, IL-6, and inducible nitric oxide synthase (iNOS). In primary microglia from adult and aged mice, SFN increased expression of Nrf2 target genes and attenuated IL-1β, IL-6, and iNOS induced by LPS. These data indicate that SFN is a potential beneficial supplement that may be useful for reducing microglial mediated neuroinflammation and oxidative stress associated with aging. Copyright © 2015 Elsevier Inc. All rights reserved.

Taste bud cells of adult mice are responsive to Wnt/β-catenin signaling: implications for the renewal of mature taste cells

PubMed Central

Gaillard, Dany; Barlow, Linda A.

2012-01-01

Wnt/β-catenin signaling initiates taste papilla development in mouse embryos, however, its involvement in taste cell turnover in adult mice has not been explored. Here we used the BATGAL reporter mouse model, which carries an engineered allele in which the LacZ gene is expressed in the presence of activated β-catenin, to determine the responsiveness of adult taste bud cells to canonical Wnt signaling. Double immunostaining with markers of differentiated taste cells revealed that a subset of type I, II and III taste cells express β-galactosidase. Using in situ hybridization, we showed that β-catenin activates the transcription of the LacZ gene mainly in intragemmal basal cells that are immature taste cells, identified by their expression of Sonic Hedgehog (Shh). Finally, we showed that β-catenin activity is significantly reduced in taste buds of 25 week-old mice compared to 10 week-old animals. Our data suggest that Wnt/β-catenin signaling may influence taste cell turnover by regulating cell differentiation. Reduced canonical Wnt signaling in older mice could explain in part the loss of taste sensitivity with aging, implicating a possible deficiency in the rate of taste cell renewal. More investigations are now necessary to understand if and how Wnt signaling regulates adult taste cell turnover. PMID:21328519

Adiposity, compared with masculinity, serves as a more valid cue to immunocompetence in human mate choice

PubMed Central

Rantala, Markus J.; Coetzee, Vinet; Moore, Fhionna R.; Skrinda, Ilona; Kecko, Sanita; Krama, Tatjana; Kivleniece, Inese; Krams, Indrikis

2013-01-01

According to the ‘good genes’ hypothesis, females choose males based on traits that indicate the male's genetic quality in terms of disease resistance. The ‘immunocompetence handicap hypothesis’ proposed that secondary sexual traits serve as indicators of male genetic quality, because they indicate that males can contend with the immunosuppressive effects of testosterone. Masculinity is commonly assumed to serve as such a secondary sexual trait. Yet, women do not consistently prefer masculine looking men, nor is masculinity consistently related to health across studies. Here, we show that adiposity, but not masculinity, significantly mediates the relationship between a direct measure of immune response (hepatitis B antibody response) and attractiveness for both body and facial measurements. In addition, we show that circulating testosterone is more closely associated with adiposity than masculinity. These findings indicate that adiposity, compared with masculinity, serves as a more important cue to immunocompetence in female mate choice. PMID:23193134

CD8 T cells protect adult naive mice from JEV-induced morbidity via lytic function

PubMed Central

Chawla, Amanpreet Singh; Agrawal, Tanvi; Biswas, Moanaro; Vrati, Sudhanshu; Rath, Satyajit; George, Anna; Medigeshi, Guruprasad R.

2017-01-01

Following Japanese encephalitis virus (JEV) infection neutralizing antibodies are shown to provide protection in a significant proportion of cases, but not all, suggesting additional components of immune system might also contribute to elicit protective immune response. Here we have characterized the role of T cells in offering protection in adult mice infected with JEV. Mice lacking α/β–T cells (TCRβ–null) are highly susceptible and die over 10–18 day period as compared to the wild-type (WT) mice which are resistant. This is associated with high viral load, higher mRNA levels of proinflammatory cytokines and breach in the blood-brain-barrier (BBB). Infected WT mice do not show a breach in BBB; however, in contrast to TCRβ-null, they show the presence of T cells in the brain. Using adoptive transfer of cells with specific genetic deficiencies we see that neither the presence of CD4 T cells nor cytokines such as IL-4, IL-10 or interferon-gamma have any significant role in offering protection from primary infection. In contrast, we show that CD8 T cell deficiency is more critical as absence of CD8 T cells alone increases mortality in mice infected with JEV. Further, transfer of T cells from beige mice with defects in granular lytic function into TCRβ-null mice shows poor protection implicating granule-mediated target cell lysis as an essential component for survival. In addition, for the first time we report that γ/δ-T cells also make significant contribution to confer protection from JEV infection. Our data show that effector CD8 T cells play a protective role during primary infection possibly by preventing the breach in BBB and neuronal damage. PMID:28151989

CD8 T cells protect adult naive mice from JEV-induced morbidity via lytic function.

PubMed

Jain, Nidhi; Oswal, Neelam; Chawla, Amanpreet Singh; Agrawal, Tanvi; Biswas, Moanaro; Vrati, Sudhanshu; Rath, Satyajit; George, Anna; Bal, Vineeta; Medigeshi, Guruprasad R

2017-02-01

Following Japanese encephalitis virus (JEV) infection neutralizing antibodies are shown to provide protection in a significant proportion of cases, but not all, suggesting additional components of immune system might also contribute to elicit protective immune response. Here we have characterized the role of T cells in offering protection in adult mice infected with JEV. Mice lacking α/β-T cells (TCRβ-null) are highly susceptible and die over 10-18 day period as compared to the wild-type (WT) mice which are resistant. This is associated with high viral load, higher mRNA levels of proinflammatory cytokines and breach in the blood-brain-barrier (BBB). Infected WT mice do not show a breach in BBB; however, in contrast to TCRβ-null, they show the presence of T cells in the brain. Using adoptive transfer of cells with specific genetic deficiencies we see that neither the presence of CD4 T cells nor cytokines such as IL-4, IL-10 or interferon-gamma have any significant role in offering protection from primary infection. In contrast, we show that CD8 T cell deficiency is more critical as absence of CD8 T cells alone increases mortality in mice infected with JEV. Further, transfer of T cells from beige mice with defects in granular lytic function into TCRβ-null mice shows poor protection implicating granule-mediated target cell lysis as an essential component for survival. In addition, for the first time we report that γ/δ-T cells also make significant contribution to confer protection from JEV infection. Our data show that effector CD8 T cells play a protective role during primary infection possibly by preventing the breach in BBB and neuronal damage.

Immunopathological Changes in the Brain of Immunosuppressed Mice Experimentally Infected with Toxocara canis

PubMed Central

Eid, Mohamed M.; El-Kowrany, Samy I.; Othman, Ahmad A.; Gendy, Dina I. El; Saied, Eman M.

2015-01-01

Toxocariasis is a soil-transmitted helminthozoonosis due to infection of humans by larvae of Toxocara canis. The disease could produce cognitive and behavioral disturbances especially in children. Meanwhile, in our modern era, the incidence of immunosuppression has been progressively increasing due to increased incidence of malignancy as well as increased use of immunosuppressive agents. The present study aimed at comparing some of the pathological and immunological alterations in the brain of normal and immunosuppressed mice experimentally infected with T. canis. Therefore, 180 Swiss albino mice were divided into 4 groups including normal (control) group, immunocompetent T. canis-infected group, immunosuppressed group (control), and immunosuppressed infected group. Infected mice were subjected to larval counts in the brain, and the brains from all mice were assessed for histopathological changes, astrogliosis, and IL-5 mRNA expression levels in brain tissues. The results showed that under immunosuppression, there were significant increase in brain larval counts, significant enhancement of reactive gliosis, and significant reduction in IL-5 mRNA expression. All these changes were maximal in the chronic stage of infection. In conclusion, the immunopathological alterations in the brains of infected animals were progressive over time, and were exaggerated under the effect of immunosuppression as did the intensity of cerebral infection. PMID:25748709

Risk factors for drug-resistant pathogens in immunocompetent patients with pneumonia: Evaluation of PES pathogens.

PubMed

Ishida, Tadashi; Ito, Akihiro; Washio, Yasuyoshi; Yamazaki, Akio; Noyama, Maki; Tokioka, Fumiaki; Arita, Machiko

2017-01-01

The new acronym, PES pathogens (Pseudomonas aeruginosa, Enterobacteriaceae extended-spectrum beta-lactamase-positive, and methicillin-resistant Staphylococcus aureus), was recently proposed to identify drug-resistant pathogens associated with community-acquired pneumonia. To evaluate the risk factors for antimicrobial-resistant pathogens in immunocompetent patients with pneumonia and to validate the role of PES pathogens. A retrospective analysis of a prospective observational study of immunocompetent patients with pneumonia between March 2009 and June 2015 was conducted. We clarified the risk factors for PES pathogens. Of the total 1559 patients, an etiological diagnosis was made in 705 (45.2%) patients. PES pathogens were identified in 51 (7.2%) patients, with 53 PES pathogens (P. aeruginosa, 34; ESBL-positive Enterobacteriaceae, 6; and MRSA, 13). Patients with PES pathogens had tendencies toward initial treatment failure, readmission within 30 days, and a prolonged hospital stay. Using multivariate analysis, female sex (adjusted odds ratio [AOR] 1.998, 95% confidence interval [CI] 1.047-3.810), admission within 90 days (AOR 2.827, 95% CI 1.250-6.397), poor performance status (AOR 2.380, 95% CI 1.047-5.413), and enteral feeding (AOR 5.808, 95% CI 1.813-18.613) were independent risk factors for infection with PES pathogens. The area under the receiver operating characteristics curve for the risk factors was 0.66 (95% CI 0.577-0.744). We believe the definition of PES pathogens is an appropriate description of drug-resistant pathogens associated with pneumonia in immunocompetent patients. The frequency of PES pathogens is quite low. However, recognition is critical because they can cause refractory pneumonia and different antimicrobial treatment is required. Copyright © 2016 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Report of Two Fatal Cases of Mycobacterium mucogenicum Central Nervous System Infection in Immunocompetent Patients

PubMed Central

Adékambi, Toïdi; Foucault, Cedric; La Scola, Bernard; Drancourt, Michel

2006-01-01

Neurological infections due to rapidly growing mycobacteria (RGM) have rarely been reported. We recently investigated two unrelated immunocompetent patients, one with community-acquired lymphocytic meningitis and the other with cerebral thrombophlebitis. Mycobacterium mucogenicum was isolated in pure culture and detected by PCR sequencing of cerebrospinal fluid samples. Both patients eventually died. The two isolates exhibited an overlapping antimicrobial susceptibility pattern. They were susceptible in vitro to tetracyclines, macrolides, quinolones, amikacin, imipenem, cefoxitin, and trimethoprim-sulfamethoxazole and resistant to ceftriaxone. They shared 100% 16S rRNA gene sequence similarity with M. mucogenicum ATCC 49650T over 1,482 bp. Their partial rpoB sequences shared 97.8% and 98.1% similarity with M. mucogenicum ATCC 49650T, suggesting that the two isolates were representative of two sequevars of M. mucogenicum species. This case report should make clinicians aware that M. mucogenicum, an RGM frequently isolated from tap water or from respiratory specimens and mostly without clinical significance, can even be encountered in the central nervous system of immunocompetent patients. PMID:16517863

Antibody responses to natural influenza A/H1N1/09 disease or following immunization with adjuvanted vaccines, in immunocompetent and immunocompromised children.

PubMed

Meier, Sara; Bel, Michael; L'huillier, Arnaud; Crisinel, Pierre-Alex; Combescure, Christophe; Kaiser, Laurent; Grillet, Stéphane; Pósfay-Barbe, Klara; Siegrist, Claire-Anne

2011-04-27

To compare antibody responses elicited by influenza A/H1N1/09 disease and immunization with adjuvanted vaccines, in immunocompetent or immunocompromised children. Prospective parallel cohort field study enrolling children with confirmed influenza A/H1N1/09 disease or immunized with 1 (immunocompetent) or 2 (immunocompromised) doses of influenza A/H1N1/09 squalene-based AS03- or MF59-adjuvanted vaccines. Antibody geometric mean titers (GMT) were measured by hemagglutination inhibition (HAI) and microneutralization (MN) assays 4-6 weeks after vaccination/disease. Vaccine adverse events were self-recorded in a 7-day diary. Antibody titers were as high in 48 immunocompetent children after a single immunization (HAI and MN seroprotection rates: 98%; HAI-GMT: 395, MN-GMT: 370) as in 51 convalescent children (seroprotection rates: 98% (HAI) and 92% (MN); GMT: 350 (HAI) and 212 (MN). Twenty-seven immunocompromised children reached slightly lower seroprotection rates (HAI: 89%, MN: 85%) but similar antibody titers (HAI-GMT: 306, MN-GMT: 225) after 2 immunizations. Adverse events increased with age (P=0.01) and were more frequent with Pandemrix® than Focetria® (P=0.03). Similarly high seroresponses may be expected in immunocompetent children after a single dose of adjuvanted vaccines as responses of convalescent children. Two vaccine doses were sufficient for most immunocompromised children. NCT0102293 and NCT01022905. Copyright © 2011 Elsevier Ltd. All rights reserved.

Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

PubMed

Jara, Adam; Liu, Xingbo; Sim, Don; Benner, Chance M; Duran-Ortiz, Silvana; Qian, Yanrong; List, Edward O; Berryman, Darlene E; Kim, Jason K; Kopchick, John J

2016-05-01

GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice. Therefore, to clarify the direct effects GH has on cardiac tissue, we developed a tamoxifen-inducible, cardiac-specific GHR disrupted (iC-GHRKO) mouse line. Cardiac GH receptor was disrupted in 4-month-old iC-GHRKO mice to avoid developmental effects due to perinatal GHR gene disruption. Surprisingly, iC-GHRKO mice showed no difference vs controls in baseline or postdobutamine stress test echocardiography measurements, nor did iC-GHRKO mice show differences in longitudinal systolic blood pressure measurements. Interestingly, iC-GHRKO mice had decreased fat mass and improved insulin sensitivity at 6.5 months of age. By 12.5 months of age, however, iC-GHRKO mice no longer had significant decreases in fat mass and had developed glucose intolerance and insulin resistance. Furthermore, investigation via immunoblot analysis demonstrated that iC-GHRKO mice had appreciably decreased insulin stimulated Akt phosphorylation, specifically in heart and liver, but not in epididymal white adipose tissue. These changes were accompanied by a decrease in circulating IGF-1 levels in 12.5-month-old iC-GHRKO mice. These data indicate that whereas the disruption of cardiomyocyte GH-induced signaling in adult mice does not affect cardiac function, it does play a role in systemic glucose homeostasis, in part through modulation of circulating IGF-1.

Undernutrition during pregnancy in mice leads to dysfunctional cardiac muscle respiration in adult offspring.

PubMed

Beauchamp, Brittany; Thrush, A Brianne; Quizi, Jessica; Antoun, Ghadi; McIntosh, Nathan; Al-Dirbashi, Osama Y; Patti, Mary-Elizabeth; Harper, Mary-Ellen

2015-04-10

Intrauterine growth restriction (IUGR) is associated with an increased risk of developing obesity, insulin resistance and cardiovascular disease. However, its effect on energetics in heart remains unknown. In the present study, we examined respiration in cardiac muscle and liver from adult mice that were undernourished in utero. We report that in utero undernutrition is associated with impaired cardiac muscle energetics, including decreased fatty acid oxidative capacity, decreased maximum oxidative phosphorylation rate and decreased proton leak respiration. No differences in oxidative characteristics were detected in liver. We also measured plasma acylcarnitine levels and found that short-chain acylcarnitines are increased with in utero undernutrition. Results reveal the negative impact of suboptimal maternal nutrition on adult offspring cardiac energy metabolism, which may have life-long implications for cardiovascular function and disease risk. © 2015 Authors.

Cutaneous mucormycosis caused by Rhizopus microsporus in an immunocompetent patient: A case report and review of literature.

PubMed

Wang, Yilun; Zhu, Min; Bao, Yunqi; Li, Li; Zhu, Liping; Li, Feng; Xu, Jinhua; Liang, Jun

2018-06-01

Cutaneous mucormycosis is an uncommon disease and occurs rarely in immunocompetent patients. We reported the case of a 37-year-old man presenting with a skin lesion on the left side of the chest wall with no history of trauma or primary diseases. He was firstly misdiagnosed as tuberculosis and the proper treatment was thus delayed. Histopathological examination and fungal culture of the lesion confirmed cutaneous mucormycosis. The isolate was identified as Rhizopus microspores by ITS sequencing. The patient was treated with oral posaconazole 400 mg bid for 150 days. The patient recovered satisfactorily. No recurrence was found during the follow-up and no side effect of liver function was found. This case helps doctors to consider the possibility of serious fungal infection in immunocompetent patients. It also suggested that posaconazole could be an alternative choice for the treatment of mucormycosis considering the severe side effect of Amphotericin B.

Glucose transporters GLUT4 and GLUT8 are upregulated after facial nerve axotomy in adult mice.

PubMed

Gómez, Olga; Ballester-Lurbe, Begoña; Mesonero, José E; Terrado, José

2011-10-01

Peripheral nerve axotomy in adult mice elicits a complex response that includes increased glucose uptake in regenerating nerve cells. This work analyses the expression of the neuronal glucose transporters GLUT3, GLUT4 and GLUT8 in the facial nucleus of adult mice during the first days after facial nerve axotomy. Our results show that whereas GLUT3 levels do not vary, GLUT4 and GLUT8 immunoreactivity increases in the cell body of the injured motoneurons after the lesion. A sharp increase in GLUT4 immunoreactivity was detected 3 days after the nerve injury and levels remained high on Day 8, but to a lesser extent. GLUT8 also increased the levels but later than GLUT4, as they only rose on Day 8 post-lesion. These results indicate that glucose transport is activated in regenerating motoneurons and that GLUT4 plays a main role in this function. These results also suggest that metabolic defects involving impairment of glucose transporters may be principal components of the neurotoxic mechanisms leading to motoneuron death. © 2011 The Authors. Journal of Anatomy © 2011 Anatomical Society of Great Britain and Ireland.

Antibody response to Giardia muris trophozoites in mouse intestine.

PubMed

Heyworth, M F

1986-05-01

The protozoan parasite Giardia muris colonizes the mouse small intestinal lumen. This parasite is cleared immunologically from the intestine of normal mice. In contrast, T-lymphocyte-deficient (nude) mice have an impaired immunological response to G. muris and become chronically infected. In the present study, trophozoites were harvested from the intestinal lumen of immunocompetent BALB/c mice and nude mice and examined for surface-bound mouse immunoglobulins by immunofluorescence microscopy. Immunoglobulin A (IgA) and IgG, but not IgM, were detected on trophozoites obtained from BALB/c mice, from day 10 of the infection onwards. Trophozoites from nude mice showed very little evidence of surface-bound mouse immunoglobulin at any time during the 5-week period immediately following infection of these animals with G. muris cysts. Intestinal G. muris infection was cleared by the BALB/c mice but not by the nude animals. The data suggest that parasite-specific IgA and IgG bind to G. muris trophozoites in the intestinal lumen of immunocompetent BALB/c mice. Intestinal antibodies that bind to trophozoite surfaces are likely to play an important part in the clearance of G. muris infection by immunocompetent mice. The inability of nude mice to clear this infection at a normal rate is likely to be due to impairment of Giardia-specific intestinal antibody production.

Root Cause Analysis: An Examination of Odontogenic Origins of Acute Maxillary Sinusitis in Both Immunocompetent & Immunocompromised Patients.

PubMed

McCarty, Jennifer L; David, Ryan M; Lensing, Shelly Y; Samant, Rohan S; Kumar, Manoj; Van Hemert, Rudy L; Angtuaco, Edgardo J C; Fitzgerald, Ryan T

Dental and periodontal diseases represent important but often overlooked causes of acute sinusitis. Our goal was to examine the prevalence of potential odontogenic sources of acute maxillary sinusitis according to immune status and their associations with sinusitis. A retrospective review of maxillofacial computed tomography studies from 2013 to 2014 was performed. Each maxillary sinus and its ipsilateral dentition were evaluated for findings of acute sinusitis and dental/periodontal disease. Eighty-four patients (24 immunocompetent, 60 immunocompromised) had 171 maxillary sinuses that met inclusion criteria for acute maxillary sinusitis. Inspection of dentition revealed oroantral fistula in 1%, periapical lucencies in 16%, and projecting tooth root(s) in 71% of cases. Immunocompromised patients were more likely to have bilateral sinusitis than immunocompetent patients (67% vs 33%, P = 0.005). A paired case-control analysis in a subset of patients with unilateral maxillary sinusitis (n = 39) showed a higher prevalence of periapical lucency in association with sinuses that had an air fluid level-29% of sinuses with a fluid level had periapical lucency compared with 12% without sinus fluid (P = 0.033). Potential odontogenic sources of acute maxillary sinusitis are highly prevalent in both immunocompetent and immunocompromised patients, although the 2 patient populations demonstrate no difference in the prevalence of these potential odontogenic sources. Periapical lucencies were found to be associated with an ipsilateral sinus fluid level. Increased awareness of the importance of dental and periodontal diseases as key components of maxillofacial computed tomography interpretation would facilitate a more appropriate and timely treatment.

In vivo activation of Wnt signaling pathway enhances cognitive function of adult mice and reverses cognitive deficits in an Alzheimer's disease model.

PubMed

Vargas, Jessica Y; Fuenzalida, Marco; Inestrosa, Nibaldo C

2014-02-05

The role of the Wnt signaling pathway during synaptic development has been well established. In the adult brain, different components of Wnt signaling are expressed, but little is known about its role in mature synapses. Emerging in vitro studies have implicated Wnt signaling in synaptic plasticity. Furthermore, activation of Wnt signaling has shown to protect against amyloid-β-induced synaptic impairment. The present study provides the first evidence that in vivo activation of Wnt signaling improves episodic memory, increases excitatory synaptic transmission, and enhances long-term potentiation in adult wild-type mice. Moreover, the activation of Wnt signaling also rescues memory loss and improves synaptic dysfunction in APP/PS1-transgenic mice that model the amyloid pathology of Alzheimer's diseases. These findings indicate that Wnt signaling modulates cognitive function in the adult brain and could be a novel promising target for Alzheimer's disease therapy.

Enhancement of vision by monocular deprivation in adult mice.

PubMed

Prusky, Glen T; Alam, Nazia M; Douglas, Robert M

2006-11-08

Plasticity of vision mediated through binocular interactions has been reported in mammals only during a "critical" period in juvenile life, wherein monocular deprivation (MD) causes an enduring loss of visual acuity (amblyopia) selectively through the deprived eye. Here, we report a different form of interocular plasticity of vision in adult mice in which MD leads to an enhancement of the optokinetic response (OKR) selectively through the nondeprived eye. Over 5 d of MD, the spatial frequency sensitivity of the OKR increased gradually, reaching a plateau of approximately 36% above pre-deprivation baseline. Eye opening initiated a gradual decline, but sensitivity was maintained above pre-deprivation baseline for 5-6 d. Enhanced function was restricted to the monocular visual field, notwithstanding the dependence of the plasticity on binocular interactions. Activity in visual cortex ipsilateral to the deprived eye was necessary for the characteristic induction of the enhancement, and activity in visual cortex contralateral to the deprived eye was necessary for its maintenance after MD. The plasticity also displayed distinct learning-like properties: Active testing experience was required to attain maximal enhancement and for enhancement to persist after MD, and the duration of enhanced sensitivity after MD was extended by increasing the length of MD, and by repeating MD. These data show that the adult mouse visual system maintains a form of experience-dependent plasticity in which the visual cortex can modulate the normal function of subcortical visual pathways.

Taste bud cells of adult mice are responsive to Wnt/β-catenin signaling: implications for the renewal of mature taste cells.

PubMed

Gaillard, Dany; Barlow, Linda A

2011-04-01

Wnt/β-catenin signaling initiates taste papilla development in mouse embryos, however, its involvement in taste cell turnover in adult mice has not been explored. Here we used the BATGAL reporter mouse model, which carries an engineered allele in which the LacZ gene is expressed in the presence of activated β-catenin, to determine the responsiveness of adult taste bud cells to canonical Wnt signaling. Double immunostaining with markers of differentiated taste cells revealed that a subset of Type I, II, and III taste cells express β-galactosidase. Using in situ hybridization, we showed that β-catenin activates the transcription of the LacZ gene mainly in intragemmal basal cells that are immature taste cells, identified by their expression of Sonic Hedgehog (Shh). Finally, we showed that β-catenin activity is significantly reduced in taste buds of 25-week-old mice compared with 10-week-old animals. Our data suggest that Wnt/β-catenin signaling may influence taste cell turnover by regulating cell differentiation. Reduced canonical Wnt signaling in older mice could explain in part the loss of taste sensitivity with aging, implicating a possible deficiency in the rate of taste cell renewal. More investigations are now necessary to understand if and how Wnt signaling regulates adult taste cell turnover. Copyright © 2011 Wiley-Liss, Inc.

Taste Bud Labeling in Whole Tongue Epithelial Sheet in Adult Mice.

PubMed

Venkatesan, Nandakumar; Boggs, Kristin; Liu, Hong-Xiang

2016-04-01

Molecular labeling in whole-mount tissues provides an efficient way to obtain general information about the formation, maintenance, degeneration, and regeneration of many organs and tissues. However, labeling of lingual taste buds in whole tongue tissues in adult mice has been problematic because of the strong permeability barrier of the tongue epithelium. In this study, we present a simple method for labeling taste buds in the intact tongue epithelial sheet of an adult mouse. Following intralingual protease injection and incubation, immediate fixation of the tongue on mandible in 4% paraformaldehyde enabled the in situ shape of the tongue epithelium to be well maintained after peeling. The peeled epithelium was accessible to taste bud labeling with a pan-taste cell marker, keratin 8, and a type II taste cell marker, α-gustducin, in all three types of taste papillae, that is, fungiform, foliate, and circumvallate. Overnight incubation of tongue epithelial sheets with primary and secondary antibodies was sufficient for intense labeling of taste buds with both fluorescent and DAB visualizations. Labeled individual taste buds were easy to identify and quantify. This protocol provides an efficient way for phenotypic analyses of taste buds, especially regarding distribution pattern and number.

Characterization of a Unique Cell Population Marked by Transgene Expression in the Adult Cochlea of Nestin-CreERT2/tdTomato-Reporter Mice

PubMed Central

Chow, Cynthia L.; Guo, Weixiang; Trivedi, Parul; Zhao, Xinyu; Gubbels, Samuel P.

2015-01-01

Hair cells in the adult mammalian cochlea cannot spontaneously regenerate after damage resulting in the permanency of hearing loss. Stem cells have been found to be present in the cochlea of young rodents; however, there has been little evidence for their existence into adulthood. We used nestin-CreERT2/tdTomato-reporter mice to trace the lineage of putative nestin-expressing cells and their progeny in the cochleae of adult mice. Nestin, an intermediate filament found in neural progenitor cells during early development and adulthood, is regarded as a multi-potent and neural stem cell marker. Other investigators have reported its presence in postnatal and young adult rodents; however, there are discrepancies amongst these reports. Using lineage tracing, we documented a robust population of tdTomato-expressing cells and evaluated these cells at a series of adult time points. Upon activation of the nestin promoter, tdTomato was observed just below and medial to the inner hair cell layer. All cells co-localized with the stem cell and cochlear-supporting-cell marker Sox2 as well as the supporting cell and Schwann cell marker Sox10; however, they did not co-localize with the Schwann cell marker Krox20, spiral ganglion marker NF200, or GFAP-expressing supporting cell marker. The cellular identity of this unique population of tdTomato-expressing cells in the adult cochlea of nestin-CreERT2/tdTomato mice remains unclear however these cells may represent a type of supporting cell on the neural aspect of the inner hair cell layer. PMID:25611038

Effect of standardized extract of Bacopa monnieri (CDRI-08) on testicular functions in adult male mice.

PubMed

Patel, Shishir Kumar; Singh, Shilpi; Singh, Hemant Kumar; Singh, Shio Kumar

2017-02-02

Bacopa monnieri (BM) has been used in India since the time of Rig-Veda for augmentation of learning, memory, brain health etc. The memory augmenting effect of BM is well documented. CDRI-08 is a standardized extract of Bacopa monnieri, but its effect on the male reproductive health has not been investigated. Therefore, the aim of the present study was to examine the effect of CDRI-08 administration on the male reproductive organs with special emphasis on testis in adult mice. CDRI-08, containing at least 55% bacosides (the major constituent of BM), was investigated for its effect on testicular functions in adult Parkes (P) mice. A suspension of CDRI-08 was orally administered in doses of 40 and 80mgkg -1 body weight day -1 for 28 days and various male reproductive end points were evaluated. Compared to control, CDRI-08 treatment caused a significant increase (p<0.05) in spermatogenic cell density (germinal epithelial height: control, 55.03±4.22 vs 40mg, 67.15±2.65 and 80mg, 69.93±3.76; and tubular diameter: control, 206.55±2.62 vs 80mg, 253.23±12.19), PCNA index (control, 59.85±2.09 vs 40mg, 82.17±1.56 and 80mg, 84.05±3.51) and in steroidogenic indices in the testis, and in sperm viability (control, 0.67±0.010 vs 80mg, 0.80±0.04) in cauda epididymidis of the treated mice. On the other hand, however, the same treatment caused a significant decrease (p<0.05) in abnormal sperm morphology (control, 21.72±1.06 vs 40mg, 10.63±1.50 and 80mg, 15.86±0.87) in cauda epididymidis, and in lipid peroxidation level in testis of the treated mice compared to controls. The results suggest that treatment with CDRI-08 extract improves sperm quality, and spermatogenic cell density and steroidogenic indices in the testis of P mice. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Vaccination with recombinant adenoviruses expressing Ebola virus glycoprotein elicits protection in the interferon alpha/beta receptor knock-out mouse.

PubMed

O'Brien, Lyn M; Stokes, Margaret G; Lonsdale, Stephen G; Maslowski, David R; Smither, Sophie J; Lever, Mark S; Laws, Thomas R; Perkins, Stuart D

2014-03-01

The resistance of adult immunocompetent mice to infection with ebolaviruses has led to the development of alternative small animal models that utilise immunodeficient mice, for example the interferon α/β receptor knock-out mouse (IFNR(-/-)). IFNR(-/-) mice have been shown to be susceptible to infection with ebolaviruses by multiple routes but it is not known if this murine model is suitable for testing therapeutics that rely on the generation of an immune response for efficacy. We have tested recombinant adenovirus vectors for their ability to protect IFNR(-/-) mice from challenge with Ebola virus and have analysed the humoral response generated after immunisation. The recombinant vaccines elicited good levels of protection in the knock-out mouse and the antibody response in IFNR(-/-) mice was similar to that observed in vaccinated wild-type mice. These results indicate that the IFNR(-/-) mouse is a relevant small animal model for studying ebolavirus-specific therapeutics. Copyright © 2014. Published by Elsevier Inc.

Enriched expression of the ciliopathy gene Ick in cell proliferating regions of adult mice.

PubMed

Tsutsumi, Ryotaro; Chaya, Taro; Furukawa, Takahisa

2018-04-07

Cilia are essential for sensory and motile functions across species. In humans, ciliary dysfunction causes "ciliopathies", which show severe developmental abnormalities in various tissues. Several missense mutations in intestinal cell kinase (ICK) gene lead to endocrine-cerebro-osteodysplasia syndrome or short rib-polydactyly syndrome, lethal recessive developmental ciliopathies. We and others previously reported that Ick-deficient mice exhibit neonatal lethality with developmental defects. Mechanistically, Ick regulates intraflagellar transport and cilia length at ciliary tips. Although Ick plays important roles during mammalian development, roles of Ick at the adult stage are poorly understood. In the current study, we investigated the Ick gene expression in adult mouse tissues. RT-PCR analysis showed that Ick is ubiquitously expressed, with enrichment in the retina, brain, lung, intestine, and reproductive system. In the adult brain, we found that Ick expression is enriched in the walls of the lateral ventricle, in the rostral migratory stream of the olfactory bulb, and in the subgranular zone of the hippocampal dentate gyrus by in situ hybridization analysis. We also observed that Ick staining pattern is similar to pachytene spermatocyte to spermatid markers in the mature testis and to an intestinal stem cell marker in the adult small intestine. These results suggest that Ick is expressed in proliferating regions in the adult mouse brain, testis, and intestine. Copyright © 2018 Elsevier B.V. All rights reserved.

The effects of neonatal isoflurane exposure in mice on brain cell viability, adult behavior, learning, and memory.

PubMed

Loepke, Andreas W; Istaphanous, George K; McAuliffe, John J; Miles, Lili; Hughes, Elizabeth A; McCann, John C; Harlow, Kathryn E; Kurth, C Dean; Williams, Michael T; Vorhees, Charles V; Danzer, Steve C

2009-01-01

Volatile anesthetics, such as isoflurane, are widely used in infants and neonates. Neurodegeneration and neurocognitive impairment after exposure to isoflurane, midazolam, and nitrous oxide in neonatal rats have raised concerns regarding the safety of pediatric anesthesia. In neonatal mice, prolonged isoflurane exposure triggers hypoglycemia, which could be responsible for the neurocognitive impairment. We examined the effects of neonatal isoflurane exposure and blood glucose on brain cell viability, spontaneous locomotor activity, as well as spatial learning and memory in mice. Seven-day-old mice were randomly assigned to 6 h of 1.5% isoflurane with or without injections of dextrose or normal saline, or to 6 h of room air without injections (no anesthesia). Arterial blood gases and glucose were measured. After 2 h, 18 h, or 11 wk postexposure, cellular viability was assessed in brain sections stained with Fluoro-Jade B, caspase 3, or NeuN. Nine weeks postexposure, spontaneous locomotor activity was assessed, and spatial learning and memory were evaluated in the Morris water maze using hidden and reduced platform trials. Apoptotic cellular degeneration increased in several brain regions early after isoflurane exposure, compared with no anesthesia. Despite neonatal cell loss, however, adult neuronal density was unaltered in two brain regions significantly affected by the neonatal degeneration. In adulthood, spontaneous locomotor activity and spatial learning and memory performance were similar in all groups, regardless of neonatal isoflurane exposure. Neonatal isoflurane exposure led to an 18% mortality, and transiently increased Paco(2), lactate, and base deficit, and decreased blood glucose levels. However, hypoglycemia did not seem responsible for the neurodegeneration, as dextrose supplementation failed to prevent neuronal loss. Prolonged isoflurane exposure in neonatal mice led to increased immediate brain cell degeneration, however, no significant reductions

[Haemophilus influenzae type b meningitis in a vaccinated, immunocompetent infant with reactive arthritis].

PubMed

Nystrup, Kristin Brønnum; Wilms, Line Kønig

2015-01-26

Due to the excellent immunogenicity of the Haemophilus influenzae type b (Hib) conjugate vaccines, vaccine failures are rarely seen in patients following the recommended national immunization programmes. We present an infant with Hib meningitis despite relevant prophylaxis, without known risk factors such as medical co-morbidity, immunosuppression, immunoglobulin deficiency or prematurity. Later, a reactive arthritis developed. In conclusion, Hib-meningitis can occur in vaccinated, immunocompetent patients, and antibiotics covering Hib should be chosen in patients presenting with meningitis.

CuZnSOD gene deletion targeted to skeletal muscle leads to loss of contractile force but does not cause muscle atrophy in adult mice

PubMed Central

Zhang, Yiqiang; Davis, Carol; Sakellariou, George K.; Shi, Yun; Kayani, Anna C.; Pulliam, Daniel; Bhattacharya, Arunabh; Richardson, Arlan; Jackson, Malcolm J.; McArdle, Anne; Brooks, Susan V.; Van Remmen, Holly

2013-01-01

We have previously shown that deletion of CuZnSOD in mice (Sod1−/− mice) leads to accelerated loss of muscle mass and contractile force during aging. To dissect the relative roles of skeletal muscle and motor neurons in this process, we used a Cre-Lox targeted approach to establish a skeletal muscle-specific Sod1-knockout (mKO) mouse to determine whether muscle-specific CuZnSOD deletion is sufficient to cause muscle atrophy. Surprisingly, mKO mice maintain muscle masses at or above those of wild-type control mice up to 18 mo of age. In contrast, maximum isometric specific force measured in gastrocnemius muscle is significantly reduced in the mKO mice. We found no detectable increases in global measures of oxidative stress or ROS production, no reduction in mitochondrial ATP production, and no induction of adaptive stress responses in muscle from mKO mice. However, Akt-mTOR signaling is elevated and the number of muscle fibers with centrally located nuclei is increased in skeletal muscle from mKO mice, which suggests elevated regenerative pathways. Our data demonstrate that lack of CuZnSOD restricted to skeletal muscle does not lead to muscle atrophy but does cause muscle weakness in adult mice and suggest loss of CuZnSOD may potentiate muscle regenerative pathways.—Zhang, Y., Davis, C., Sakellariou, G.K., Shi, Y., Kayani, A.C., Pulliam, D., Bhattacharya, A., Richardson, A., Jackson, M.J., McArdle, A., Brooks, S.V., Van Remmen, H. CuZnSOD gene deletion targeted to skeletal muscle leads to loss of contractile force but does not cause muscle atrophy in adult mice. PMID:23729587

Invasive pulmonary aspergillosis and Influenza co-infection in immunocompetent hosts: case reports and review of the literature☆

PubMed Central

Shah, Melisa M.; Hsiao, Eric I.; Kirsch, Carl M.; Gohil, Amit; Narasimhan, Supriya; Stevens, David A.

2018-01-01

Invasive pulmonary aspergillosis (IPA) is classically considered an illness of severely immunocompromised patients with limited host defenses. However, IPA has been reported in immunocompetent but critically ill patients. This report describes two fatal cases of pathologically confirmed IPA in patients with Influenza in the intensive care unit. One patient had Influenza B infection, whereas the other had Influenza A H1N1. Both patients died despite broad-spectrum antimicrobials, mechanical ventilation, and vasopressor support. Microscopic and histologic postmortem examination confirmed IPA. Review of the English language and foreign literature indicates that galactomannan antigen testing and classic radiologic findings for IPA may not be reliable in immunocompetent patients. Respiratory cultures which grow Aspergillus species in critically ill patients, particularly those with underlying Influenza infection, should not necessarily be disregarded as contaminants or colonizers. Further research is needed to better understand the immunological relationship between Influenza and IPA for improved prevention and treatment of Influenza and Aspergillus co-infections. PMID:29454654

[Imprinting as a mechanism of information memorizing in the adult BALB/c mice].

PubMed

Nikol'skaia, K A; Berezhnoĭ, D S

2011-09-01

Study of spatial learning in adult BALB/c mice revealed that a short exposition to the environment (from 3 to 8 minutes) could be enough for spatial information to be fixed in the long-term memory, and affected subsequent learning process in the new environment. Control group, learning in the same maze, followed the "shortest path" principle during formation of the optimal food-obtaining habit. Experimental animals, learning in a slightly changed environment, were unable to apply this rule due to persistent coupling of the new spatial information with the old memory traces which led to constant errors. The obtained effect was observed during the whole learning period and depended neither on frequency nor on interval of repetition during the initial information acquisition. The obtained data testify that memorizing in adult state share the properties with the imprinting process inherent in the early ontogeny. The memory fixation on all development stages seems to be based on a universal mechanism.

Spatial Discrimination Reversal and Incremental Repeated Acquisition in Adolescent and Adult BALB/c Mice

PubMed Central

Shen, Andrew Nathanael; Pope, Derek A.; Hutsell, Blake A.; Newland, M. Christopher

2015-01-01

Adolescence is characterized by neural and behavior development that includes increases in novel experiences and impulsive choice. Experimental rodent models can characterize behavior phenotypes that typify adolescence. The present experiment was designed to characterize differences between adolescent (post-natal day (PND) 34 - 60) and adult (PND 70 - 96) BALB/c mice using a response-initiated spatial discrimination reversal (SDR) and incremental repeated acquisition of response chains (IRA) procedures. During SDR, adolescents omitted more trials and were slower to initiate trials than adults, but the age groups did not differ on accuracy and perseveration measures. During IRA, adolescents displayed poorer overall performance (measured by progress quotient), lower accuracy at individual chain links, and completed fewer long response chains (>3 links) than adults. In both procedures (SDR and IRA), the poorer performance of adolescents appeared to be related to the use of a response device that was spatially removed from reinforcer delivery. These results indicate that SDR and IRA performance can be established during the brief rodent adolescent period but that these two age groups’ performances differ. We hypothesize that adolescent behavior is more sensitive than adult behavior to the spatiotemporal distance between response device and location of reinforcer delivery. PMID:26051193

Immunocompetent, Immunized Male With Mumps, Complicated by Orchitis and Meningitis.

PubMed

Tomich, Allison; Grubish, Lindsay; Young, Scott; Franklin, Jillian

2015-10-01

Mumps is a rare pathology often not encountered in the emergency department setting. It is an especially unusual finding in a fully immunized individual. We present a case of a 26-year-old Army active duty male who was evaluated in the emergency department for mumps over the course of two visits. The military population is presumed fully immunized and immunocompetent, travels widely and often lives in close quarters. This case highlights the importance for providers to consider such a disease that carries a risk of significant morbidity, and rarely, mortality. A literature review was performed evaluating mumps in the vaccinated population. Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.

Age-related T2 changes in hindlimb muscles of mdx mice.

PubMed

Vohra, Ravneet S; Mathur, Sunita; Bryant, Nathan D; Forbes, Sean C; Vandenborne, Krista; Walter, Glenn A

2016-01-01

Magnetic resonance imaging (MRI) was used to monitor changes in the transverse relaxation time constant (T2) in lower hindlimb muscles of mdx mice at different ages. Young (5 weeks), adult (44 weeks), and old mdx (96 weeks), and age-matched control mice were studied. Young mdx mice were imaged longitudinally, whereas adult and old mdx mice were imaged at a single time-point. Mean muscle T2 and percent of pixels with elevated T2 were significantly different between mdx and control mice at all ages. In young mdx mice, mean muscle T2 peaked at 7-8 weeks and declined at 9-11 weeks. In old mdx mice, mean muscle T2 was decreased compared with young and adult mice, which could be attributed to fibrosis. MRI captured longitudinal changes in skeletal muscle integrity of mdx mice. This information will be valuable for pre-clinical testing of potential therapeutic interventions for muscular dystrophy. © 2015 Wiley Periodicals, Inc.

Effect of dietary selenium and cancer cell xenograft on peripheral T and B lymphocytes in adult nude mice.

PubMed

Cheng, Wen-Hsing; Holmstrom, Alexandra; Li, Xiangdong; Wu, Ryan T Y; Zeng, Huawei; Xiao, Zhengguo

2012-05-01

Selenium (Se) is known to regulate tumorigenesis and immunity at the nutritional and supranutritional levels. Because the immune system provides critical defenses against cancer and the athymic, immune-deficient NU/J nude mice are known to gradually develop CD8(+) and CD4(+) T cells, we investigated whether B and T cell maturation could be modulated by dietary Se and by tumorigenesis in nude mice. Fifteen homozygous nude mice were fed a Se-deficient, Torula yeast basal diet alone (Se-) or supplemented with 0.15 (Se+) or 1.0 (Se++) mg Se/kg (as Na(2)SeO(4)) for 6 months, followed by a 7-week time course of PC-3 prostate cancer cell xenograft (2 × 10(6) cells/site, 2 sites/mouse). Here, we show that peripheral B cell levels decreased in nude mice fed the Se -  or Se++ diet and the CD4(+) T cell levels increased in mice fed the Se++ diet. During the PC-3 cell tumorigenesis, dietary Se status did not affect peripheral CD4(+) or CD8(+) T cells in nude mice whereas mice fed with the Se++ diet appeared to exhibit greater peripheral CD25(+)CD4(+) T cells on day 9. Dietary Se status did not affect spleen weight in nude mice 7 weeks after the xenograft. Spleen weight was associated with frequency of peripheral CD4(+), but not CD8(+) T cells. Taken together, dietary Se at the nutritional and supranutritional levels regulates peripheral B and T cells in adult nude mice before and after xenograft with PC-3 prostate cancer cells.

Evidence of immunocompetence reduction induced by cadmium exposure in honey bees (Apis mellifera).

PubMed

Polykretis, P; Delfino, G; Petrocelli, I; Cervo, R; Tanteri, G; Montori, G; Perito, B; Branca, J J V; Morucci, G; Gulisano, M

2016-11-01

In the last decades a dramatic loss of Apis mellifera hives has been reported in both Europe and USA. Research in this field is oriented towards identifying a synergy of contributing factors, i.e. pathogens, pesticides, habitat loss and pollution to the weakening of the hive. Cadmium (Cd) is a hazardous anthropogenic pollutant whose effects are proving to be increasingly lethal. Among the multiple damages related to Cd contamination, some studies report that it causes immunosuppression in various animal species. The aim of this paper is to determine whether contamination by Cd, may have a similar effect on the honey bees' immunocompetence. Our results, obtained by immune challenge experiments and confirmed by structural and ultrastructural observations show that such metal causes a reduction in immunocompetence in 3 days Cd exposed bees. As further evidence of honey bee response to Cd treatment, Energy Dispersive X-ray Spectroscopy (X-EDS) has revealed the presence of zinc (Zn) in peculiar electron-dense granules in fat body cells. Zn is a characteristic component of metallothioneins (MTs), which are usually synthesized as anti-oxidant and scavenger tools against Cd contamination. Our findings suggest that honey bee colonies may have a weakened immune system in Cd polluted areas, resulting in a decreased ability in dealing with pathogens. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sex-specific phenotypes of hyperthyroidism and hypothyroidism in aged mice.

PubMed

Rakov, Helena; Engels, Kathrin; Hönes, Georg Sebastian; Brix, Klaudia; Köhrle, Josef; Moeller, Lars Christian; Zwanziger, Denise; Führer, Dagmar

2017-12-22

Sex and age play a role in the prevalence of thyroid dysfunction (TD), but their interrelationship for manifestation of hyper- and hypothyroidism is still not well understood. Using a murine model, we asked whether sex impacts the phenotypes of hyper- and hypothyroidism at two life stages. Hyper- and hypothyroidism were induced by i.p. T4 or MMI/ClO 4 -/LoI treatment over 7 weeks in 12- and 20-months-old female and male C57BL/6N mice. Control animals underwent PBS treatment (n = 7-11 animals/sex/treatment). Animals were investigated for impact of sex on body weight, food and water intake, body temperature, heart rate, behaviour (locomotor activity, motor coordination and strength) and serum thyroid hormone (TH) status. Distinct sex impact was found in eu- and hyperthyroid mice, while phenotypic traits of hypothyroidism were similar in male and female mice. No sex difference was found in TH status of euthyroid mice; however, T4 treatment resulted in twofold higher TT4, FT4 and FT3 serum concentrations in adult and old females compared to male animals. Hyperthyroid females consistently showed higher locomotor activity and better coordination but more impairment of muscle function by TH excess at adult age. Importantly and in contrast to male mice, adult and old hyperthyroid female mice showed increased body weight. Higher body temperature in female mice was confirmed in all age groups. No sex impact was found on heart rate irrespective of TH status in adult and old mice. By comparison of male and female mice with TD at two life stages, we found that sex modulates TH action in an organ- and function-specific manner. Sex differences were more pronounced under hyperthyroid conditions. Importantly, sex-specific differences in features of TD in adult and old mice were not conclusively explained by serum TH status in mice.

An Early Postnatal Oxytocin Treatment Prevents Social and Learning Deficits in Adult Mice Deficient for Magel2, a Gene Involved in Prader-Willi Syndrome and Autism.

PubMed

Meziane, Hamid; Schaller, Fabienne; Bauer, Sylvian; Villard, Claude; Matarazzo, Valery; Riet, Fabrice; Guillon, Gilles; Lafitte, Daniel; Desarmenien, Michel G; Tauber, Maithé; Muscatelli, Françoise

2015-07-15

Mutations of MAGEL2 have been reported in patients presenting with autism, and loss of MAGEL2 is also associated with Prader-Willi syndrome, a neurodevelopmental genetic disorder. This study aimed to determine the behavioral phenotype of Magel2-deficient adult mice, to characterize the central oxytocin (OT) system of these mutant mice, and to test the curative effect of a peripheral OT treatment just after birth. We assessed the social and cognitive behavior of Magel2-deficient mice, analyzed the OT system of mutant mice treated or not by a postnatal administration of OT, and determined the effect of this treatment on the brain. Magel2 inactivation induces a deficit in social recognition and social interaction and a reduced learning ability in adult male mice. In these mice, we reveal anatomical and functional modifications of the OT system and show that these defects change from birth to adulthood. Daily administration of OT in the first postnatal week was sufficient to prevent deficits in social behavior and learning abilities in adult mutant male mice. We show that this OT treatment partly restores a normal OT system. Thus, we report that an alteration of the OT system around birth has long-term consequences on behavior and on cognition. Importantly, an acute OT treatment of Magel2-deficient pups has a curative effect. Our study reveals that OT plays a crucial role in setting social behaviors during a period just after birth. An early OT treatment in this critical period could be a novel therapeutic approach for the treatment of neurodevelopmental disorders such as Prader-Willi syndrome and autism. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Generation of cloned mice from adult neurons by direct nuclear transfer.

PubMed

Mizutani, Eiji; Oikawa, Mami; Kassai, Hidetoshi; Inoue, Kimiko; Shiura, Hirosuke; Hirasawa, Ryutaro; Kamimura, Satoshi; Matoba, Shogo; Ogonuki, Narumi; Nagatomo, Hiroaki; Abe, Kuniya; Wakayama, Teruhiko; Aiba, Atsu; Ogura, Atsuo

2015-03-01

Whereas cloning mammals by direct somatic cell nuclear transfer has been successful using a wide range of donor cell types, neurons from adult brain remain "unclonable" for unknown reasons. Here, using a combination of two epigenetic approaches, we examined whether neurons from adult mice could be cloned. First, we used a specific antibody to discover cell types with reduced amounts of a repressive histone mark-dimethylated histone H3 lysine 9 (H3K9me2)-and identified CA1 pyramidal cells in the hippocampus and Purkinje cells in the cerebellum as candidates. Second, reconstructed embryos were treated with trichostatin A (TSA), a potent histone deacetylase inhibitor. Using CA1 cells, cloned offspring were obtained at high rates, reaching 10.2% and 4.6% (of embryos transferred) for male and female donors, respectively. Cerebellar Purkinje cell nuclei were too large to maintain their genetic integrity during nuclear transfer, leading to developmental arrest of embryos. However, gene expression analysis using cloned blastocysts corroborated a high rate of genomic reprogrammability of CA1 pyramidal and Purkinje cells. Neurons from the hippocampal dentate gyrus and cerebral cortex, which had higher amounts of H3K9me2, could also be used for producing cloned offspring, but the efficiencies were low. A more thorough analysis revealed that TSA treatment was essential for cloning adult neuronal cells. This study demonstrates, to our knowledge for the first time, that adult neurons can be cloned by nuclear transfer. Furthermore, our data imply that reduced amounts of H3K9me2 and increased histone acetylation appear to act synergistically to improve the development of cloned embryos. © 2015 by the Society for the Study of Reproduction, Inc.

The neonicotinoids thiacloprid, imidacloprid, and clothianidin affect the immunocompetence of honey bees (Apis mellifera L.).

PubMed

Brandt, Annely; Gorenflo, Anna; Siede, Reinhold; Meixner, Marina; Büchler, Ralph

2016-03-01

A strong immune defense is vital for honey bee health and colony survival. This defense can be weakened by environmental factors that may render honey bees more vulnerable to parasites and pathogens. Honey bees are frequently exposed to neonicotinoid pesticides, which are being discussed as one of the stress factors that may lead to colony failure. We investigated the sublethal effects of the neonicotinoids thiacloprid, imidacloprid, and clothianidin on individual immunity, by studying three major aspects of immunocompetence in worker bees: total hemocyte number, encapsulation response, and antimicrobial activity of the hemolymph. In laboratory experiments, we found a strong impact of all three neonicotinoids. Thiacloprid (24h oral exposure, 200 μg/l or 2000 μg/l) and imidacloprid (1 μg/l or 10 μg/l) reduced hemocyte density, encapsulation response, and antimicrobial activity even at field realistic concentrations. Clothianidin had an effect on these immune parameters only at higher than field realistic concentrations (50-200 μg/l). These results suggest that neonicotinoids affect the individual immunocompetence of honey bees, possibly leading to an impaired disease resistance capacity. Copyright © 2016 Elsevier Ltd. All rights reserved.

Active immunizations with peptide-DC vaccines and passive transfer with antibodies protect neutropenic mice against disseminated candidiasis.

PubMed

Xin, Hong

2016-01-04

We previously report that peptide-pulsed dendritic cell (DC) vaccination, which targeting two peptides (Fba and Met6) expressed on the cell surface of Candida albicans, can induce high degree of protection against disseminated candidiasis in immunocompetent mice. Passive transfer of immune sera from the peptide immunized mice or peptide-related monoclonal antibodies demonstrated that protection was medicated by peptide-specific antibodies. In this study the efficacy of active and passive immunization against disseminated candidiasis was tested in mice with cyclophosphamide-induced neutropenia. Peptide-DC vaccines were given to mice prior to induction of neutropenia. We show active immunization with either Fba or Met6 peptide-DC vaccine significantly improved the survival and reduced the fungal burden of disseminated candidiasis in those immunocompromised mice. Importantly, we show that administration of two protective monoclonal antibodies also protect neutropenic mice against the disease, implying possibility of developing a successful passive immunotherapy strategy to treat the disease and protect against disseminated candidiasis. The results of this study are crucial as they address the fundamental questions as to whether the synthetic peptide vaccine induced immunity protects the host during a neutropenic episode. We anticipate that this peptide-vaccine study will serve as the foundation of future investigations into new peptide vaccines comprised of cell surface peptides from other medically important Candida species, as well as other fungi. Copyright © 2015 Elsevier Ltd. All rights reserved.

Active Immunizations with Peptide-DC Vaccines and Passive Transfer with Antibodies Protect Neutropenic Mice against Disseminated Candidiasis

PubMed Central

Xin, Hong

2015-01-01

We previously report that peptide-pulsed dendritic cell (DC) vaccination, which targeting two peptides (Fba and Met6) expressed on the cell surface of Candida albicans, can induce high degree of protection against disseminated candidiasis in immunocompetent mice. Passive transfer of immune sera from the peptide immunized mice or peptide-related monoclonal antibodies demonstrated that protection was medicated by peptide-specific antibodies. In this study the efficacy of active and passive immunization against disseminated candidiasis was tested in mice with cyclophosphamide-induced neutropenia. Peptide-DC vaccines were given to mice prior to induction of neutropenia. We show active immunization with either Fba or Met6 peptide-DC vaccine significantly improved the survival and reduced the fungal burden of disseminated candidiasis in those immunocompromised mice. Importantly, we show that administration of two protective monoclonal antibodies also protect neutropenic mice against the disease, implying possibility of developing a successful passive immunotherapy strategy to treat the disease and protect against disseminated candidiasis. The results of this study are crucial as they address the fundamental questions as to whether the synthetic peptide vaccine induced immunity protects the host during a neutropenic episode. We anticipate that this peptide-vaccine study will serve as the foundation of future investigations into new peptide vaccines comprised of cell surface peptides from other medically important Candida species, as well as other fungi. PMID:26620842

Discrimination and avoidance learning in adult mice following developmental exposure to diisopropylfluorophosphate.

PubMed

Levi, Yifat; Kofman, Ora; Schwebel, Margalit; Shaldubina, Alona

2008-02-01

Exposure to acetylcholinesterase inhibitors during development was shown in the past to induce sex-dependent changes in locomotion and specific cognitive and emotional tests in rodents. Adult mice that had been treated with 0.5 mg/kg diisopropylfluorphosphate (DFP), on post-natal days 14-20 were tested on active avoidance and a set-shifting task. DFP pre-treatment did not affect the active avoidance task, but impaired performance on the extra-dimensional shift task. DFP-treated females showed more general deficits in the acquisition of simple discrimination, intra-dimensional shift, extra-dimensional shift and reversal learning. These data suggest that pre-weanling exposure to cholinesterase inhibitors may have long-term consequences on attentional capabilities.

Comparison of the effects of bisphenol A alone and in a combination with X-irradiation on sperm count and quality in male adult and pubescent mice.

PubMed

Dobrzyńska, Małgorzata M; Jankowska-Steifer, Ewa A; Tyrkiel, Ewa J; Gajowik, Aneta; Radzikowska, Joanna; Pachocki, Krzysztof A

2014-11-01

Bisphenol A (BPA) is employed in the manufacturing of epoxy, polyester-styrene, and polycarbonate resins, which are used for the production of baby and water bottles and reusable containers, food and beverage packing, dental fillings and sealants. The study was designed to examine the effects of 8-week exposure (a full cycle of spermatogenesis) to BPA alone and in a combination with X-irradiation on the reproductive organs and germ cells of adult and pubescent male mice. Pzh:Sfis male mice were exposed to BPA (5, 10, and 20 mg/kg) or X-rays (0.05 Gy) or to a combination of both (0.05 Gy + 5 mg/kg bw BPA). The following parameters were examined: sperm count, sperm motility, sperm morphology, and DNA damage in male gametes. Both BPA and X-rays alone diminished sperm quality. BPA exposure significantly reduced sperm count in pubescent males compared to adult mice, with degenerative changes detected in seminiferous epithelium. This may suggest a higher susceptibility of germ cells of younger males to BPA action. Combined BPA with X-ray treatment enhanced the harmful effect induced by BPA alone in male germ cells of adult males, whereas low-dose irradiation showed sometimes protective or additive effects in pubescent mice. Copyright © 2013 Wiley Periodicals, Inc., a Wiley company.

Atypical manifestation of cat-scratch disease: isolated epigastric pain in an immunocompetent, 12-year-old child.

PubMed

Kayemba-Kay's, Simon; Kovács, Tamas; Rakotoharinandrasana, Iarolalao; Benosman, Sidi Mohamed

2015-07-01

We present a 12-year-old immunocompetent girl with hepato splenic cat-scratch disease (CSD). Her sole inaugural complaint was isolated epigastric pain. She fully recovered, with normalized abdominal CT scan following 2 weeks course of Azythromycin®. CSD should be included in differential diagnosis in children with epigastric pain, especially in those with domestic pets.

Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice

PubMed Central

Buchanan, J.B.; Sparkman, N.L.; Chen, J.; Johnson, R.W.

2008-01-01

Summary Peripheral immune stimulation as well as certain types of psychological stress increases brain levels of inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor α (TNFα). We have demonstrated that aged mice show greater increases in central inflammatory cytokines, as well as greater cognitive deficits, compared to adults in response to peripheral lipopolysaccharide (LPS) administration. Because aged mice are typically more sensitive to systemic stressors such as LPS, and certain psychological stressors induce physiological responses similar to those that follow LPS, we hypothesized that aged mice would be more sensitive to the physiological and cognitive effects of mild stress than adult mice. Here, adult (3–5 mo) and aged (22–23 mo) male BALB/c mice were trained in the Morris water maze for 5 days. Mice were then exposed to a mild restraint stress of 30 minutes before being tested in a working memory version of the water maze over a 3 day period. On day 4 mice were stressed and then killed for collection of blood and brain. In a separate group of animals, mice were killed immediately after one, two or three 30 min restraint sessions and blood for peripheral corticosterone and cytokine protein measurement, and brains were dissected for central cytokine mRNA measurement. Stress disrupted spatial working memory in both adult and aged mice but to a much greater extent in the aged mice. In addition, aged mice showed an increase in stress-induced expression of hippocampal IL-1β mRNA and MHC class II protein compared to non-stressed controls while expression in adult mice was unaffected by stress. These data show that aged mice are more sensitive to both the cognitive and inflammatory effects of mild stress than are adult mice and suggest a possible a role for IL-1β. PMID:18407425

Dynamics of circulating gamma delta T cell activity in an immunocompetent mouse model of high-grade glioma

USDA-ARS?s Scientific Manuscript database

Human gamma delta T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 m...

Perinatal Exposure of Mice to the Pesticide DDT Impairs Energy Expenditure and Metabolism in Adult Female Offspring

PubMed Central

La Merrill, Michele; Karey, Emma; Moshier, Erin; Lindtner, Claudia; La Frano, Michael R.; Newman, John W.; Buettner, Christoph

2014-01-01

Dichlorodiphenyltrichloroethane (DDT) has been used extensively to control malaria, typhus, body lice and bubonic plague worldwide, until countries began restricting its use in the 1970s. Its use in malaria control continues in some countries according to recommendation by the World Health Organization. Individuals exposed to elevated levels of DDT and its metabolite dichlorodiphenyldichloroethylene (DDE) have an increased prevalence of diabetes and insulin resistance. Here we hypothesize that perinatal exposure to DDT disrupts metabolic programming leading to impaired metabolism in adult offspring. To test this, we administered DDT to C57BL/6J mice from gestational day 11.5 to postnatal day 5 and studied their metabolic phenotype at several ages up to nine months. Perinatal DDT exposure reduced core body temperature, impaired cold tolerance, decreased energy expenditure, and produced a transient early-life increase in body fat in female offspring. When challenged with a high fat diet for 12 weeks in adulthood, female offspring perinatally exposed to DDT developed glucose intolerance, hyperinsulinemia, dyslipidemia, and altered bile acid metabolism. Perinatal DDT exposure combined with high fat feeding in adulthood further impaired thermogenesis as evidenced by reductions in core temperature and in the expression of numerous RNA that promote thermogenesis and substrate utilization in the brown adipose tissue of adult female mice. These observations suggest that perinatal DDT exposure impairs thermogenesis and the metabolism of carbohydrates and lipids which may increase susceptibility to the metabolic syndrome in adult female offspring. PMID:25076055

Zika virus-induced acute myelitis and motor deficits in adult interferon αβ/γ receptor knockout mice.

PubMed

Zukor, Katherine; Wang, Hong; Siddharthan, Venkatraman; Julander, Justin G; Morrey, John D

2018-06-01

Zika virus (ZIKV) has received widespread attention because of its effect on the developing fetus. It is becoming apparent, however, that severe neurological sequelae, such as Guillian-Barrë syndrome (GBS), myelitis, encephalitis, and seizures can occur after infection of adults. This study demonstrates that a contemporary strain of ZIKV can widely infect astrocytes and neurons in the brain and spinal cord of adult, interferon α/β receptor knockout mice (AG129 strain) and cause progressive hindlimb paralysis, as well as severe seizure-like activity during the acute phase of disease. The severity of hindlimb motor deficits correlated with increased numbers of ZIKV-infected lumbosacral spinal motor neurons and decreased numbers of spinal motor neurons. Electrophysiological compound muscle action potential (CMAP) amplitudes in response to stimulation of the lumbosacral spinal cord were reduced when obvious motor deficits were present. ZIKV immunoreactivity was high, intense, and obvious in tissue sections of the brain and spinal cord. Infection in the brain and spinal cord was also associated with astrogliosis as well as T cell and neutrophil infiltration. CMAP and histological analysis indicated that peripheral nerve and muscle functions were intact. Consequently, motor deficits in these circumstances appear to be primarily due to myelitis and possibly encephalitis as opposed to a peripheral neuropathy or a GBS-like syndrome. Thus, acute ZIKV infection of adult AG129 mice may be a useful model for ZIKV-induced myelitis, encephalitis, and seizure activity.

Gestational exposure to diethylstilbestrol alters cardiac structure/function, protein expression and DNA methylation in adult male mice progeny

DOE Office of Scientific and Technical Information (OSTI.GOV)

Haddad, Rami, E-mail: rami.haddad@mail.mcgill.ca; Division of Experimental Medicine, Department of Medicine, McGill University, 850 Sherbrooke Street, Montréal, Québec, Canada H3A 1A2; Kasneci, Amanda, E-mail: amanda.kasneci@mail.mcgill.ca

2013-01-01

Pregnant women, and thus their fetuses, are exposed to many endocrine disruptor compounds (EDCs). Fetal cardiomyocytes express sex hormone receptors making them potentially susceptible to re-programming by estrogenizing EDCs. Diethylstilbestrol (DES) is a proto-typical, non-steroidal estrogen. We hypothesized that changes in adult cardiac structure/function after gestational exposure to the test compound DES would be a proof in principle for the possibility of estrogenizing environmental EDCs to also alter the fetal heart. Vehicle (peanut oil) or DES (0.1, 1.0 and 10.0 μg/kg/da.) was orally delivered to pregnant C57bl/6n dams on gestation days 11.5–14.5. At 3 months, male progeny were left sedentarymore » or were swim trained for 4 weeks. Echocardiography of isoflurane anesthetized mice revealed similar cardiac structure/function in all sedentary mice, but evidence of systolic dysfunction and increased diastolic relaxation after swim training at higher DES doses. The calcium homeostasis proteins, SERCA2a, phospholamban, phospho-serine 16 phospholamban and calsequestrin 2, are important for cardiac contraction and relaxation. Immunoblot analyses of ventricle homogenates showed increased expression of SERCA2a and calsequestrin 2 in DES mice and greater molecular remodeling of these proteins and phospho-serine 16 phospholamban in swim trained DES mice. DES increased cardiac DNA methyltransferase 3a expression and DNA methylation in the CpG island within the calsequestrin 2 promoter in heart. Thus, gestational DES epigenetically altered ventricular DNA, altered cardiac function and expression, and reduced the ability of adult progeny to cardiac remodel when physically challenged. We conclude that gestational exposure to estrogenizing EDCs may impact cardiac structure/function in adult males. -- Highlights: ► Gestational DES changes cardiac SERCA2a and CASQ2 expression. ► Echocardiography identified systolic dysfunction and increased diastolic relaxation. �

Within-Colony Variation in the Immunocompetency of Managed and Feral Honey Bees (Apis mellifera L.) in Different Urban Landscapes.

PubMed

Appler, R Holden; Frank, Steven D; Tarpy, David R

2015-10-29

Urbanization has the potential to dramatically affect insect populations worldwide, although its effects on pollinator populations are just beginning to be understood. We compared the immunocompetency of honey bees sampled from feral (wild-living) and managed (beekeeper-owned) honey bee colonies. We sampled foragers from feral and managed colonies in rural, suburban, and urban landscapes in and around Raleigh, NC, USA. We then analyzed adult workers using two standard bioassays for insect immune function (encapsulation response and phenoloxidase activity). We found that there was far more variation within colonies for encapsulation response or phenoloxidase activity than among rural to urban landscapes, and we did not observe any significant difference in immune response between feral and managed bees. These findings suggest that social pollinators, like honey bees, may be sufficiently robust or variable in their immune responses to obscure any subtle effects of urbanization. Additional studies of immune physiology and disease ecology of social and solitary bees in urban, suburban, and natural ecosystems will provide insights into the relative effects of changing urban environments on several important factors that influence pollinator productivity and health.

Immediate Protein Dietary Effects on Movement and the Generalised Immunocompetence of Migrating Mormon Crickets Anabrus simplex (Orthoptera: Tettigoniidae)

USDA-ARS?s Scientific Manuscript database

1. Mormon crickets form large migratory bands that march over rangeland in the western United States seeking salt and protein. Immune defense is particularly relevant to survival in migratory bands, but little is known about the role of nutrition in insect immunocompetence. We hypothesized that imm...

Dual-color STED microscopy reveals a sandwich structure of Bassoon and Piccolo in active zones of adult and aged mice.

PubMed

Nishimune, Hiroshi; Badawi, Yomna; Mori, Shuuichi; Shigemoto, Kazuhiro

2016-06-20

Presynaptic active zones play a pivotal role as synaptic vesicle release sites for synaptic transmission, but the molecular architecture of active zones in mammalian neuromuscular junctions (NMJs) at sub-diffraction limited resolution remains unknown. Bassoon and Piccolo are active zone specific cytosolic proteins essential for active zone assembly in NMJs, ribbon synapses, and brain synapses. These proteins are thought to colocalize and share some functions at active zones. Here, we report an unexpected finding of non-overlapping localization of these two proteins in mouse NMJs revealed using dual-color stimulated emission depletion (STED) super resolution microscopy. Piccolo puncta sandwiched Bassoon puncta and aligned in a Piccolo-Bassoon-Piccolo structure in adult NMJs. P/Q-type voltage-gated calcium channel (VGCC) puncta colocalized with Bassoon puncta. The P/Q-type VGCC and Bassoon protein levels decreased significantly in NMJs from aged mouse. In contrast, the Piccolo levels in NMJs from aged mice were comparable to levels in adult mice. This study revealed the molecular architecture of active zones in mouse NMJs at sub-diffraction limited resolution, and described the selective degeneration mechanism of active zone proteins in NMJs from aged mice. Interestingly, the localization pattern of active zone proteins described herein is similar to active zone structures described using electron microscope tomography.

Early Life Stress Differentially Modulates Distinct Forms of Brain Plasticity in Young and Adult Mice

PubMed Central

Reichardt, Wilfried; Clark, Kristin; Geiger, Julia; Gross, Claus M.; Heyer, Andrea; Neagu, Valentin; Bhatia, Harsharan; Atas, Hasan C.; Fiebich, Bernd L.; Bischofberger, Josef; Haas, Carola A.; Normann, Claus

2012-01-01

Background Early life trauma is an important risk factor for many psychiatric and somatic disorders in adulthood. As a growing body of evidence suggests that brain plasticity is disturbed in affective disorders, we examined the short-term and remote effects of early life stress on different forms of brain plasticity. Methodology/Principal Findings Mice were subjected to early deprivation by individually separating pups from their dam in the first two weeks after birth. Distinct forms of brain plasticity were assessed in the hippocampus by longitudinal MR volumetry, immunohistochemistry of neurogenesis, and whole-cell patch-clamp measurements of synaptic plasticity. Depression-related behavior was assessed by the forced swimming test in adult animals. Neuropeptides and their receptors were determined by real-time PCR and immunoassay. Early maternal deprivation caused a loss of hippocampal volume, which returned to normal in adulthood. Adult neurogenesis was unaffected by early life stress. Long-term synaptic potentiation, however, was normal immediately after the end of the stress protocol but was impaired in adult animals. In the forced swimming test, adult animals that had been subjected to early life stress showed increased immobility time. Levels of substance P were increased both in young and adult animals after early deprivation. Conclusion Hippocampal volume was affected by early life stress but recovered in adulthood which corresponded to normal adult neurogenesis. Synaptic plasticity, however, exhibited a delayed impairment. The modulation of synaptic plasticity by early life stress might contribute to affective dysfunction in adulthood. PMID:23071534

Mice chronically infected with chimeric HIV resist peripheral and brain superinfection: a model of protective immunity to HIV.

PubMed

Kelschenbach, Jennifer L; Saini, Manisha; Hadas, Eran; Gu, Chao-Jiang; Chao, Wei; Bentsman, Galina; Hong, Jessie P; Hanke, Tomas; Sharer, Leroy R; Potash, Mary Jane; Volsky, David J

2012-06-01

Infection by some viruses induces immunity to reinfection, providing a means to identify protective epitopes. To investigate resistance to reinfection in an animal model of HIV disease and its control, we employed infection of mice with chimeric HIV, EcoHIV. When immunocompetent mice were infected by intraperitoneal (IP) injection of EcoHIV, they resisted subsequent secondary infection by IP injection, consistent with a systemic antiviral immune response. To investigate the potential role of these responses in restricting neurotropic HIV infection, we established a protocol for efficient EcoHIV expression in the brain following intracranial (IC) inoculation of virus. When mice were inoculated by IP injection and secondarily by IC injection, they also controlled EcoHIV replication in the brain. To investigate their role in EcoHIV antiviral responses, CD8+ T lymphocytes were isolated from spleens of EcoHIV infected and uninfected mice and adoptively transferred to isogenic recipients. Recipients of EcoHIV primed CD8+ cells resisted subsequent EcoHIV infection compared to recipients of cells from uninfected donors. CD8+ spleen cells from EcoHIV-infected mice also mounted modest but significant interferon-γ responses to two HIV Gag peptide pools. These findings suggest EcoHIV-infected mice may serve as a useful system to investigate the induction of anti-HIV protective immunity for eventual translation to human beings.

Sulforaphane attenuates postnatal proteasome inhibition and improves spatial learning in adult mice.

PubMed

Sunkaria, Aditya; Bhardwaj, Supriya; Yadav, Aarti; Halder, Avishek; Sandhir, Rajat

2018-01-01

Proteasomes are known to degrade proteins involved in various processes like metabolism, signal transduction, cell-cycle regulation, inflammation, and apoptosis. Evidence showed that protein degradation has a strong influence on developing neurons as well as synaptic plasticity. Here, we have shown that sulforaphane (SFN) could prevent the deleterious effects of postnatal proteasomal inhibition on spatial reference and working memory of adult mice. One day old Balb/c mice received intracerebroventricular injections of MG132 and SFN. Sham received an equal volume of aCSF. We observed that SFN pre-administration could attenuate MG132 mediated decrease in proteasome and calpain activities. In vitro findings revealed that SFN could induce proteasomal activity by enhancing the expression of catalytic subunit-β5. SFN pre-administration prevented the hippocampus based spatial memory impairments during adulthood, mediated by postnatal MG132 exposure. Histological examination showed deleterious effects of MG132 on pyramidal neurons and granule cell neurons in DG and CA3 sub-regions respectively. Furthermore, SFN pre-administration has shown to attenuate the effect of MG132 on proteasome subunit-β5 expression and also induce the Nrf2 nuclear translocation. In addition, SFN pre-administered mice have also shown to induce expression of pCaMKII, pCreb, and mature/pro-Bdnf, molecules which play a crucial role in spatial learning and memory consolidation. Our findings have shown that proteasomes play an important role in hippocampal synaptic plasticity during the early postnatal period and SFN pre-administration could enhance the proteasomal activity as well as improve spatial learning and memory consolidation. Copyright © 2017 Elsevier Inc. All rights reserved.

Herpes zoster meningitis with multidermatomal rash in an immunocompetent patient.

PubMed

Goyal, Hemant; Thakkar, Nirav; Bagheri, Farshad; Srivastava, Sneha

2013-11-01

A case of herpetic rash in an immunocompetent patient is described, which was present in multiple dermatomes at the same time. First, patient was thought to have immunodeficiency, but further workup turned out to be negative for it. Patient also had pleocytic lymphocytosis in cerebrospinal fluid, which was suggestive of viral meningitis. Later, the patient responded well to the acyclovir therapy and was discharged home without any sequel. This case illustrates the need for emergency physicians to be extra vigilant for involvement of other dermatomes in case a patient presents with herpetic rash in 1 dermatome because patients with multidermatomal/disseminated herpetic rash need to be started on airborne isolation in addition to contact precautions to prevent the transmission of disease in health care settings.

REPRODUCTIVE EFFECTS OF THE WATER DISINFECTANT BYPRODUCT BROMOCHLOROACETIC ACID (BCA) IN ADULT AND JUVENILE MALE C57BL/6 MICE

EPA Science Inventory

REPRODUCTIVE EFFECTS OF THE WATER DISINFECTANT BYPRODUCT BROMOCHLOROACETIC ACID (BCA) IN ADULT AND JUVENILE MALE C57BL/6 MICE.
JC Rockett, JC Luft, JB Garges and DJ Dix. Reproductive Toxicology Division, USEPA, RTP, NC, USA.
Sponsor: G Klinefelter
The development of wate...

A novel cause of community-acquired pneumonia in a young immunocompetent host.

PubMed

James, Nicholas; Gilman, Matthew; Duncan, Robert; Gray, Anthony

2016-09-01

Diffuse pulmonary infiltrates represent a common problem encountered by pulmonologists. The differential diagnosis is extensive and includes infectious, inflammatory, environmental and malignant conditions. Appropriate evaluation, aside from a thorough history and physical examination, includes serologic, radiographic and procedural elements. We describe a case of a healthy male with diffuse pulmonary infiltrates. Work up revealed a novel infectious etiology. Although this particular microorganism has been described to cause native valve endocarditis, recurrent breast abscesses, osteomyelitis and bacteremia, it has to date not been described as a cause for community acquired pneumonia in immunocompetent hosts. © 2014 John Wiley & Sons Ltd.

Cessation of voluntary wheel running increases anxiety-like behavior and impairs adult hippocampal neurogenesis in mice.

PubMed

Nishijima, Takeshi; Llorens-Martín, María; Tejeda, Gonzalo Sanchez; Inoue, Koshiro; Yamamura, Yuhei; Soya, Hideaki; Trejo, José Luis; Torres-Alemán, Ignacio

2013-05-15

While increasing evidence demonstrates that physical exercise promotes brain health, little is known on how the reduction of physical activity affects brain function. We investigated whether the cessation of wheel running alters anxiety-like and depression-like behaviors and its impact on adult hippocampal neurogenesis in mice. Male C57BL/6 mice (4 weeks old) were assigned to one of the following groups, and housed until 21 weeks old; (1) no exercise control (noEx), housed in a standard cage; (2) exercise (Ex), housed in a running wheel cage; and (3) exercise-no exercise (Ex-noEx), housed in a running wheel cage for 8 weeks and subsequently in a standard cage. Behavioral evaluations suggested that Ex-noEx mice were more anxious compared to noEx control mice, but no differences were found in depression-like behavior. The number of BrdU-labeled surviving cells in the dentate gyrus was significantly higher in Ex but not in Ex-noEx compared with noEx, indicating that the facilitative effects of exercise on cell survival are reversible. Surprisingly, the ratio of differentiation of BrdU-positive cells to doublecortin-positive immature neurons was significantly lower in Ex-noEx compared to the other groups, suggesting that the cessation of wheel running impairs an important component of hippocampal neurogenesis in mice. These results indicate that hippocampal adaptation to physical inactivity is not simply a return to the conditions present in sedentary mice. As the impaired neurogenesis is predicted to increase a vulnerability to stress-induced mood disorders, the reduction of physical activity may contribute to a greater risk of these disorders. Copyright © 2013 Elsevier B.V. All rights reserved.

Morphology of the external genitalia of the adult male and female mice as an endpoint of sex differentiation

PubMed Central

Weiss, Dana A.; Rodriguez, Esequiel; Cunha, Tristan; Menshenina, Julia; Barcellos, Dale; Chan, Lok Yun; Risbridger, Gail; Baskin, Laurence; Cunha, Gerald