Progressive Dissemination Research Articles

Modeling of cerebral tuberculosis in BALB/c mice using clinical strain from patients with CNS -TB infection

Background: This study describes development of a TBM animal model in mice using C3 strain isolated from CSF of TBM patients which can be used to study pathogenesis of C3 strain in mice. Methods & Materials: Female BALB/c mice aged 6–10 weeks were housed in a BSL- 3 facility. Two groups of mice (n = 12) were challenged intravenously through tail vein with 2 × 107 of C3 strain. Control group of mice (n = 10) was separately maintained and injected with sterile saline. Mice were killed at 30 and 50 days after development of infection, for estimating number of mycobacteria colonizing in brain,lungs and for histopathological changes. The mycobacterial burden was determined by plating and counting the number of CFUs. Serially diluted homogenates of individual lungs and brains were plated onto Middlebrook 7H11 medium. CFU's were counted after 3–4 weeks of infection. Histological sections were stained using hematoxylin and eosin. Results: Mice infected with C3 strain showed prominent edema of the brain in left hemisphere at 30 days, which increased at later stage compared to control mice. Histopathological examination of brain showed swelling of neurons along with lymphocytic infiltration which was progressively more at 50 days. The lung section at 30 days revealed >40 lession in lung parenchyma which improved at 50 days, with lession reduced to <20. Brain and lungs of control mice showed no major changes. Infection with C3 strain showed significant levels of mycobacterial load in brains with progress in infection. Analysis of CFU count revealed significantly high load in lungs (6.80 ± 0.1) at 30 days post infection, however the mycobacterial burden gradually decreased in lungs (5.8 ± 0.2) with progress in infection at 50 days. Analysis of CFU load in brain showed significantly high mycobacterial load at 50 days (4.0 ± 0.2) compared to infection at 30 days (5.0 ± 0.1). No mycobacterial load was observed in brains and lungs of control mice.C3 strain infection was associated with reduced survival-40% and high mortality rate -60%compared to control mice. Conclusion: Our present study demonstrated that intravenous inoculation by C3 strain from TBM patient's leads to progressive dissemination and development of TBM disease in mice.

Cutaneous histoplasmosis.

Cutaneous lesions as a manifestation of histoplasmosis, primarily a disease of the respiratory system, are rare and most commonly appear secondary to progressive dissemination. A patient with documented progressive, disseminated histoplasmosis, having been treated previously with amphotericin B, presented on a second occasion with cutaneous lesions as the chief complaint. Biopsy and cultures of these lesions were positive for Histoplasma capsulatum. A review of the English literature revealed only 7 reported cases of secondary skin histoplasmosis in the past 20 years. All patients, including the current one, either had diseases associated with depressed immunity or were receiving steroid therapy.

Storytelling beyond the Academy: Exploring Roles, Responsibilities and Regulations in the Open Access Dissemination of Research Outputs and Visual Data

In the last decade there has been a movement towards facilitating Open Access to academic outputs via the World Wide Web. This movement has been characterised as one that embodies corporate citizenship because such sharing has the potential to benefit all stakeholders; academics, policy makers, charitable sectors and the wider public. In the UK, the Economic and Social Research Council are implementing Open Access compliance guidelines for research that they fund; which is interpreted by individual institutions in their school regulations. In the case of doctoral theses, there is now a requirement for students to provide an electronic format of their final work to be included in their schools online digital repository. In a number of UK institutions, University Awards and Progress Committees will only consider awarding the doctoral degree once these requirements have been satisfied. Although this move to Open Access can be considered as an egalitarian endeavour; this paper argues that an important stakeholder may have been over looked in the march towards progressive dissemination. The temporal space between gaining informed consent from research participants; and the changing nature of the accessibility of outputs can both engender a breach of ethics in terms of the initial agreements negotiated with participants and raise issues around representation in the ongoing dissemination and reformulation of the original work; particularly where visual images are central to research outputs. The paper utilises autoethnography and poetry to reflect on my own encounter with the requirement for Open Access and the ways in which this brings up concerns around ethics, obligations and integrity.

Secreted mucins in pseudomyxoma peritonei: pathophysiological significance and potential therapeutic prospects.

Pseudomyxoma peritonei (PMP, ORPHA26790) is a clinical syndrome characterized by progressive dissemination of mucinous tumors and mucinous ascites in the abdomen and pelvis. PMP is a rare disease with an estimated incidence of 1–2 out of a million. Clinically, PMP usually presents with a variety of unspecific signs and symptoms, including abdominal pain and distention, ascites or even bowel obstruction. It is also diagnosed incidentally at surgical or non-surgical investigations of the abdominopelvic viscera. PMP is a neoplastic disease originating from a primary mucinous tumor of the appendix with a distinctive pattern of the peritoneal spread. Computed tomography and histopathology are the most reliable diagnostic modalities. The differential diagnosis of the disease includes secondary peritoneal carcinomatoses and some rare peritoneal conditions. Optimal elimination of mucin and the mucin-secreting tumor comprises the current standard of care for PMP offered in specialized centers as visceral resections and peritonectomy combined with intraperitoneal chemotherapy. This multidisciplinary approach has reportedly provided a median survival rate of 16.3 years, a median progression-free survival rate of 8.2 years and 10- and 15-year survival rates of 63% and 59%, respectively. Despite its indolent, bland nature as a neoplasm, PMP is a debilitating condition that severely impacts quality of life. It tends to be diagnosed at advanced stages and frequently recurs after treatment. Being ignored in research, however, PMP remains a challenging, enigmatic entity. Clinicopathological features of the PMP syndrome and its morbid complications closely correspond with the multifocal distribution of the secreted mucin collections and mucin-secreting implants. Novel strategies are thus required to facilitate macroscopic, as well as microscopic, elimination of mucin and its source as the key components of the disease. In this regard, MUC2, MUC5AC and MUC5B have been found as the secreted mucins of relevance in PMP. Development of mucin-targeted therapies could be a promising avenue for future research which is addressed in this article.

945 VERIFICATION OF SENTINEL LYMPHADENECTOMY IN PENILE CANCER IN CONSIDERATION OF THE EUROPEAN GUIDELINES

You have accessJournal of UrologyPenis/Testis/Urethra: Benign & Malignant Disease (III)1 Apr 2013945 VERIFICATION OF SENTINEL LYMPHADENECTOMY IN PENILE CANCER IN CONSIDERATION OF THE EUROPEAN GUIDELINES Alexander Winter, Jens Uphoff, Rolf-Peter Henke, and Friedhelm Wawroschek Alexander WinterAlexander Winter Oldenburg, Germany More articles by this author , Jens UphoffJens Uphoff Oldenburg, Germany More articles by this author , Rolf-Peter HenkeRolf-Peter Henke Oldenburg, Germany More articles by this author , and Friedhelm WawroschekFriedhelm Wawroschek Oldenburg, Germany More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.524AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In penile cancer the absence of lymph node (LN) metastases is the most important prognostic factor. Patients without LN metastases have a long-term survival of up to 90% whereas in the case of LN metastases the 5-year survival rate drops below 30%. Patients with LN metastases and only a small tumor burden can be cured surgically. Therefore, in penile cancer the significance of lymphadenectomy is high. This contrasts with the large morbidity of extended inguinal lymphadenectomy or over-treatment of many patients. The guidelines of the European Association of Urology recommend the minimally invasive sentinel-guided lymphadenectomy from a tumor stage ≥T1G2. We analyzed the reliability of inguinal sentinel lymphadenectomy in our own collective. METHODS 29 patients with penile cancer who had received surgical treatment (circumcision, partial resection of the penis or penectomy, 11/2004 - 06/2010) were included. The tumor stages varied from T1 to T3 (G1-3). 22 patients (mean 63, range 42 - 83 years) with a tumor stage ≥T1G2 received an inguinal sentinel lymphadenectomy and stage adapted additionally a modified inguinal lymphadenectomy. The sentinel tracer (Technetium99mNanocolloid) was injected preoperatively peritumoral (n= 11) or in a two-step procedure in the area of the resection (n= 10). In one patient primary a radical inguinal lymphadenectomy was performed. In this case no sentinel LN could be detected intraoperatively. Patients with positive sentinel LN received a secondary radical inguinal lymphadenectomy in pN1 stage or a inguinal and pelvic lymphadenectomy in pN2 stage. LN negative patients received only an aftercare. RESULTS In 19 of the 22 cases with lymphadenectomy no LN metastases were detected. Of the 3 patients with positive sentinel LN one had a pN1 stage (pN1 (mi) (3/5 LN)) and two a pN2 stage (pN2 (2/5 or 5/23 LN)). In the secondary radical inguinal lymphadenectomy (0/18 LN) or inguinal and pelvic lymphadenectomy (0/31 LN or 0/35 LN) no additional metastases were detected. In the follow-up (median 37 month; range 10 - 78 months) 20 patients were free of recurrence (including one patient with pN1 and pN2) and one patient lost to follow-up. One patient (pN2) died of progressive lymphatic dissemination and two patients of other causes. CONCLUSIONS The minimally invasive sentinel-guided inguinal lymphadenectomy showed reliable results in our collective. By their use the number of extended inguinal lymphadenectomy can be reliably reduced. Patients are spared from higher postoperative morbidity. Thereby the tumor-surgical results are excellent. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e388-e389 Peer Review Report Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alexander Winter Oldenburg, Germany More articles by this author Jens Uphoff Oldenburg, Germany More articles by this author Rolf-Peter Henke Oldenburg, Germany More articles by this author Friedhelm Wawroschek Oldenburg, Germany More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

IL-12p40 Deficiency Leads to Uncontrolled Trypanosoma cruzi Dissemination in the Spinal Cord Resulting in Neuronal Death and Motor Dysfunction

Chagas’ disease is a protozoosis caused by Trypanosoma cruzi that frequently shows severe chronic clinical complications of the heart or digestive system. Neurological disorders due to T. cruzi infection are also described in children and immunosuppressed hosts. We have previously reported that IL-12p40 knockout (KO) mice infected with the T. cruzi strain Sylvio X10/4 develop spinal cord neurodegenerative disease. Here, we further characterized neuropathology, parasite burden and inflammatory component associated to the fatal neurological disorder occurring in this mouse model. Forelimb paralysis in infected IL-12p40KO mice was associated with 60% (p<0.05) decrease in spinal cord neuronal density, glutamate accumulation (153%, p<0.05) and strong demyelization in lesion areas, mostly in those showing heavy protein nitrosylation, all denoting a neurotoxic degenerative profile. Quantification of T. cruzi 18S rRNA showed that parasite burden was controlled in the spinal cord of WT mice, decreasing from the fifth week after infection, but progressive parasite dissemination was observed in IL-12p40KO cords concurrent with significant accumulation of the astrocytic marker GFAP (317.0%, p<0.01) and 8-fold increase in macrophages/microglia (p<0.01), 36.3% (p<0.01) of which were infected. Similarly, mRNA levels for CD3, TNF-α, IFN-γ, iNOS, IL-10 and arginase I declined in WT spinal cords about the fourth or fifth week after infection, but kept increasing in IL-12p40KO mice. Interestingly, compared to WT tissue, lower mRNA levels for IFN-γ were observed in the IL-12p40KO spinal cords up to the fourth week of infection. Together the data suggest that impairments of parasite clearance mechanisms in IL-12p40KO mice elicit prolonged spinal cord inflammation that in turn leads to irreversible neurodegenerative lesions.

Promienica krtani – opis przypadku i przegląd piśmiennictwa

We report a case of a 20-year-old man who presented with discreet dysphagia for several months. Indirect laryngoscopy showed a swollen, reddened, thickened epiglottis and smooth, thickened, injected mucosa of aryepiglottic folds and postcricoid region. Thorough work-up was undertaken to exclude specific and non-specific infectious diseases, neoplasm, vascular disorders, immunodeficiency syndrome. Histology revealed actinomycotic colonies in biopsy specimen taken from the epiglottis. The inflammation was resolving gradually during long-term antibiotic-therapy. Actinomycosis should be considered in the differential diagnosis in unclear long-lasting inflammation of the supraglottis. The course of untreated actinomycosis can be fatal which is connected with progressive dissemination of the process and secondary abscesses formation in the lungs, liver and brain.

Part-whole dissemination of large multimedia contents in opportunistic networks

A common assumption in intermittently-connected (or opportunistic) mobile networks is that any contact has enough capacity to transfer the required amount of data. Although such an assumption is reasonable for analytical purposes and when contents are small, it does not hold anymore when users produce contents that are larger than the capacity of a contact. In such a case, users must slice data and send fragments separately, which allows better use of short contacts and progressive dissemination of large contents data pieces. The main question here is to design the best strategy for deciding which piece(s) to transmit whenever nodes meet. In addition, although small pieces imply a better use of short contacts, they generate more overhead due to the headers required at each piece. In this paper, we investigate these two issues: piece size selection and piece selection strategy. First, we theoretically define the global goodput of the system that defines the tradeoff between the size of the shortest contact that can be considered as useful and piece overhead. Results from real-world traces show that, for reasonable header size, the piece size can be selected out of a large range of values without significantly impacting the results. Second, we present the design and evaluation of PACS (Prevalence-Aware Content Spreading), a completely distributed algorithm that selects pieces to transfer based on their popularity. We evaluate the performance of PACS using both synthetic and real traces from intermittently-connected networks. When compared with sequential and randomized solutions, we show that PACS significantly outperforms these approaches both in terms of latency to achieve full dissemination and ratio of effective contacts. Moreover, PACS achieves performance levels that are extremely close to a centralized oracle-based solution.

Challenges and Opportunities for Promoting Booster Seat Use

Motivating parents to take certain safety precautions when traveling with their children remains challenging for advocates. Caregivers of booster-aged children are particularly difficult to reach because they do not consider their children to be of "safety-seat" age and have inherently low perceptions of vulnerability to crash injury. Unfortunately, most booster seat programs fail to adequately motivate their intended population because they are primarily informational in nature and rely on caregivers to seek out and attend to the information. In this article, interventions using threat appeal tactics and progressive dissemination methods are recommended to effectively target participation and perceptions of vulnerability among this population. Recent research on risk communication indicates that threat appeals are supported when they contain high threat and high efficacy components. Threat appeal tactics are particularly desirable when perception of vulnerability is low, as is the case with parents of booster-aged children. In addition to theoretical arguments for more aggressive intervention approaches, a case example is presented wherein such techniques were used to promote booster seat use. The intervention resulted in significant increases in knowledge, risk-reduction attitudes, sense of efficacy, and observed booster seat use. Through use of progressive dissemination methods, the intervention has reached an audience of 431,600 people and counting.

Gastrointestinal Paracoccidioidomycosis

Paracoccidioidomycosis is the most prevalent mycosis in Latin America. Although the lungs are the primary site of infection, physicians often see patients because of disseminated disease. Imported paracoccidioidomycosis has been described in different regions of the world in patients who lived in endemic areas. Gastrointestinal disease owing to P. brasiliensis is rarely recognized in life because of nonspecific clinical manifestations. Gastrointestinal disease can present as part of progressive dissemination of infection or as a result of local complications from a silent healing process. This review will summarize the salient features of gastrointestinal paracoccidioidomycosis.

Pulmonary sclerosing hemangioma with pleural dissemination: Report of a case

Pulmonary sclerosing hemangioma is relatively rare and is usually considered a benign tumor. There have been no reports of pulmonary sclerosing hemangioma with pleural dissemination. This report presents an extremely rare case of pulmonary sclerosing hemangioma with pulmonary dissemination. A 57-year-old woman was found to have an abnormal shadow in the right lower lung field on chest X-ray. Chest computed tomography (CT) indicated a 2.5-cm mass in the right lower lobe. A bronchoscopic biopsy failed to identify malignant cells, which led to the patient undergoing an excisional lung biopsy. Intraoperative findings showed a tumor in the right lower lobe with multiple small nodules in the pleura. The pathological findings revealed that the tumor was sclerosing hemangioma with pleural dissemination. Annual follow-up CT showed irregular pleural thickness, which suggested progressive dissemination 3 years after the operation. Although pulmonary sclerosing hemangioma is regarded as a benign tumor, the potential for malignancy may be a consideration in this setting.

CHR-2845, a Monocyte/Macrophage Targeted Histone Deacetylase Inhibitor In a First In Man Clinical Trial In Subjects with Advanced Haematological Malignancies

AbstractAbstract 3279CHR-2845 is a novel type of histone deacetylase inhibitor (HDACi) for use in cancer, which is targeted specifically to cells of the monocyte-macrophage lineage. CHR-2845 is a cell-permeant ester that is cleaved to an active acid, CHR-2847, by an intracellular esterase (human carboxylesterase-1, hCE-1) that is primarily found in cells of the monocyte lineage including macrophages, monocytes and Kupffer cells, and also hepatocytes. CHR-2847, being a charged molecule, cannot readily leave cells and, hence, selectively accumulates and is active within hCE-1-expressing cells, resulting in a 20–100 fold increase in anti-proliferative potency of CHR-2845 for monocytic over non-monocytic tumour cells. This selectivity should lead to an increased therapeutic window in haematological malignancies involving cells of the monocyte lineage (AML-M4, AML-M5 and CMML). In addition, there is increasing evidence that macrophages associated with progressive, solid tumours (tumour-associated macrophages (TAMs)) and lymphomas are involved in supporting the growth and spread of the tumour. Circulating monocytes differentiate into resident tissue macrophages and, depending on the local microenvironment, acquire specialised phenotypic characteristics and diverse functions. In tumours, macrophages are reprogrammed by neighbouring tumour cells to induce immune suppression of host defences, facilitating progressive tumour growth and tumour cell dissemination. Targeting TAMs with CHR-2845 could, therefore, also have a beneficial effect in non-monocyte derived tumours. The CHR-2845-001 trial recruited patients with advanced haematological malignancies, who are either refractory to standard therapy or for whom no standard therapy exists. This study is a first in man, open label, dose escalating, multi-centre, phase I study of oral CHR-2845 given once a day over a 28 day course of treatment, with the next cycle started at day 29. Cohorts of 3 to 6 patients were treated at increasing dose levels to establish the MTD. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were taken from all patients in all cohorts. The PD evaluation consisted of a FACS-based assay to compare histone acetylation in monocytes, granulocytes and lymphocytes. 18 patients, 7 F:11 M, median age 73 yrs (51 - 80) were enrolled at doses of 20 (n=3), 40 (n=3), 80 (n=3), 160 (n=3), 320 (n=3) and 640 mg (n=3). Intra-subject dose escalations were allowed, with 2 patients receiving 3 dose levels, and 3 patients receiving 2 different dose levels. The median number of cycles administered was 3 (1 – 9). One patient with AML M2 was treated for 7 cycles, a patient with NHL is ongoing at 7 cycles, and a patient with CMML was on treatment for 9 cycles and achieved a bone marrow response and symptomatic relief, although no impact on peripheral monocytes was seen. Dose limiting toxicities (DLT) have not been observed at any dose, possibly due to the targeted nature of CHR-2845. Dose escalation has been halted at 640 mg. Of 197 AEs reported to date, 54 were considered at least possibly related to CHR-2845. Most were grade 1/2, with only 3 grade 3 (anorexia, asthenia, acute confused state). The most frequent drug-related AEs were nausea (11), anorexia (6) and fatigue (5). No liver enzyme disturbances have been noted. PK analysis of CHR-2845 distribution revealed rapid absorption (Tmax 0.9 – 2.1h) and mean elimination plasma half-life of 2.5 hrs. Cmax and AUC(0-t) increased dose proportionally, although there was high variability between patients. There was no substantial accumulation of CHR-2845 observed on Day 28. Preliminary analysis of histone acetylation in PBMCs shows a pattern of monocyte-specific increases in histone acetylation, with no increase in histone acetylation in granulocytes and lymphocytes. Evaluation of PD samples is continuing and an updated analysis will be presented at the meeting. Conclusions:CHR-2845 is well tolerated, with very few of the drug-related adverse events (like nausea, fatigue, diarrhea) commonly seen with HDACi. Plasma concentrations of CHR-2845 achieved in this trial exceed those required for in vitro anti-proliferative activity in the absence of significant toxicity. Updated results will be presented at the meeting, including an assessment of histone acetylation as a pharmacodynamic biomarker in a FACS based assay which can distinguish between targeted acetylation in monocytes versus granulocytes and lymphocytes. Disclosures:Debnam:Chroma Therapeutics: Employment, Equity Ownership. Needham:Chroma Therapeutics: Employment, Equity Ownership. Bawden:Chroma Therapeutics: Employment, Equity Ownership. Hooftman:Chroma Therapeutics: Employment, Equity Ownership.

Isolation and Propagation of a Human CD133- Colon Tumor-Derived Cell Line with Tumorigenic and Angiogenic Properties

It has been proposed in human colorectal cancers (CRC) a minority subset of cancer cells within tumors able to initiate tumor growth, defined as cancer stem cells (CSC). Solid human primary colonic and its ovarian metastatic cancer tissues were collected from fresh surgical samples and subsequent xenografts were established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. The resulting tumors were disaggregated into single-cell suspensions and a CD133(-) cell line (NANK) was newly established and analyzed by flow cytometry. Surface markers of progenitor cells were immunophenotypically analyzed, and expression of stem cell and cancer-related genes was characterized. Secreted angiogenesis-associated molecules were investigated by proteomic array technology. Finally, different numbers of NANK were implanted and their tumor-initiating properties were investigated in NOD/SCID mice. Intraperitoneal injection of NANK in NOD/SCID mice induced tumors with developing progressive peritoneal dissemination and ascites. NANK cells maintained a differentiated phenotype and reproduced the full morphologic and phenotypic heterogeneity of their parental lesions. Noticeably, NANK lacked the expression of conventional CSC markers CD133 and CD44, self-renewal genes Oct-4 and Nanog, but showed the expression of an important gastrointestinal development marker CDX-2 and BMI-1 that is essential in regulating the proliferative activity of normal and leukemic stem cells. In addition, NANK secreted high amounts of important angiogenic cytokines. These results provide a novel and extensive model in human CSC for studying the generation and maintenance of phenotypic heterogeneity in CRC.

Recognition, Diagnosis, and Treatment of Histoplasmosis Complicating Tumor Necrosis Factor Blocker Therapy

Life-threatening histoplasmosis is one of the most common opportunistic infections in patients receiving tumor necrosis factor (TNF) blockers. Delays in considering the diagnosis may lead to increased morbidity and mortality. Most affected patients present with pneumonitis, usually accompanied by additional signs of progressive dissemination, or with signs of progressive dissemination alone. The diagnosis often can be promptly established using antigen detection or direct examination of bronchoalveolar lavage specimens. If histoplasmosis is diagnosed promptly, antifungal therapy is highly effective. After a favorable clinical response, the safety of both discontinuation of antifungal therapy and the resumption of TNF blocker remains undetermined. The management of the immune reconstitution inflammatory syndrome that may follow discontinuation of TNF blockers also requires investigation. Prescribers should become aware of the recognition, diagnosis, and treatment of histoplasmosis and educate recipients about decreasing their risk of exposure and both recognizing and reporting signs of early infection.

Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge.

The rapid onset of massive, systemic viral replication during primary HIV/SIV infection and the immune evasion capabilities of these viruses pose fundamental problems for vaccines that depend upon initial viral replication to stimulate effector T cell expansion and differentiation1–5. We hypothesized that vaccines designed to maintain differentiated “effector memory” T cell (TEM) responses5,6 at viral entry sites might improve efficacy by impairing viral replication at its earliest stage2, and have therefore developed SIV protein-encoding vectors based on rhesus cytomegalovirus (RhCMV), the prototypical inducer of life-long TEM responses7–9. RhCMV vectors expressing SIV Gag, Rev/Nef/Tat, and Env persistently infected rhesus macaques (RM), regardless of pre-existing RhCMV immunity, and primed and maintained robust SIV-specific, CD4+ and CD8+ TEM responses (characterized by coordinate TNF, IFN-γ and MIP-1β expression, cytotoxic degranulation, and accumulation at extra-lymphoid sites) in the absence of neutralizing antibodies. Compared to control RM, these vaccinated RM showed increased resistance to acquisition of progressive SIVmac239 infection upon repeated, limiting dose, intra-rectal challenge, including four animals that controlled rectal mucosal infection without progressive systemic dissemination. These data suggest a new paradigm for AIDS vaccine development: that vaccines capable of generating and maintaining HIV-specific TEM might decrease the incidence of HIV acquisition after sexual exposure.

A Rare Case of Gastrointestinal Histoplasmosis in a 15-Year-Old Male Patient with a History of Cardiac Transplant and Diarrhea

Purpose: To report this rare finding. Methods: Case: A 15 y/o Caucasian male presents with fever of unknown origin. He has a h/o cardiac transplant in 1992 for Hypoplastic left heart syndrome. His cough symptoms did not improve with a course of azithromycin. The patient had a four-week visit with relatives in Michigan and Illinois approximately 3 months prior to the appearance of these symptoms. He now develops nausea, some vomiting, and slightly increased loose stool while hospitalized. A test for urine Histoplasma Ag was positive. A chest CT and sputum cultures showed no evidence of a fungal infection. An EGD showed several several duodenal bulb erosions. During colonoscopy, there was extensive erythema seen with superficial to deep ulcerations scattered from the cecum to sigmoid colon. Multiple pseudopolyps and inflammatory nodules were seen in the cecum. Biopsies were taken throughout which were significant for non-necrotizing granulomas. Giemsa and PAS special stains were also positive for numerous intracellular small yeast forms with focal narrow-based budding and rare hyphal forms. Duodenal biopsies were similar. These were morphologically consistent with Histoplasma capsulatum. Results: Histoplasma Capsulatum is a dimorphic fungus and found worldwide.1 In North America it is endemic in the major river valleys (Mississippi and Ohio) of the southern and central United States.2 Once the acute infection is spread hematogenously from the lungs to other organs it is generally classified as systemic. In addition to this, findings of positive blood cultures, or positive urine or serum Histoplasma antigens changes its classification to disseminated.2 Most infections are self-limited, but 1 in 2000 infections result in progressive dissemination especially in immunocompromised hosts.4 The symptoms of disseminated histoplasmosis include fever, malaise, anorexia, and weight loss. The gastrointestinal tract is commonly involved (70–90%) during disseminated infection as determined by autopsy studies.4,8 The colon is usually the most involved organ of the gastrointestinal tract followed by the small bowel. Serious gastrointestinal complications include malabsorption from severe diarrhea, ulcerations, strictures, bowel obstruction, gastrointestinal hemorrhage and perforations.7,8 Conclusion: Our case is a unique example of an immunosuppressed patient with recent travel to an endemic area which may have predisposed the duodenum and colon to a Histoplasma Capsulatum infection. Laboratory evidence of dissemination warrants endoscopic exam even when asymptomatic because the gastrointestinal tract is commonly involved. Prompt diagnosis and treatment may reduce the incidence of serious gastrointestinal complications.

Molecular Epidemiology of Imipenem-Resistant Acinetobacter haemolyticus and Acinetobacter baumannii Isolates Carrying Plasmid-Mediated OXA-40 from a Portuguese Hospital

Major outbreaks of multidrug-resistant Acinetobacter baumannii associated with nosocomial infections have been increasingly reported worldwide (1, 10, 12). The endemicity of an OXA-24/40-producing A. baumannii clone associated with mortality events in Portugal has been observed at numerous hospitals within the Iberian Peninsula (5, 6, 10). Inversely, Acinetobacter haemolyticus, isolated only occasionally from clinical samples (9), usually presents susceptibility to different antibiotics, including β-lactams (13). The isolation of two carbapenem-resistant A. haemolyticus strains prompted us to assess the relative contribution of clonal spread to the observed high rate of carbapenem-resistant Acinetobacter spp. in a general hospital in Porto, Portugal. Between January 2001 and October 2004, 224 imipenem-resistant Acinetobacter spp. were collected from several specimen sources and different hospital wards, where A. baumannii was associated with nosocomial infections and colonizations for several months (Table ​(Table1).1). Imipenem resistance significantly increased from 2001 to 2002 and from 2002 to 2003. Macrorestriction analysis of genomic DNA by pulsed-field gel electrophoresis (5) and 16S rRNA gene sequencing, performed for each clone and species representative, showed that, with the exception of two clonally related A. haemolyticus isolates, the remainder were A. baumannii isolates, distributed among three different pulsotypes. Clonal dissemination of two major pulsotypes (A and B), widespread throughout the hospital, contributed to the observed A. baumannii imipenem resistance, which has persisted since at least 2001 despite several elimination attempts, including the use of polymyxin. Pulsotype B was predominant from 2001 to 2002, after which clone A emerged as the dominant type (Table ​(Table1).1). This clone was found to be identical to the previously described Iberian OXA-24/40-producing clone (5). Pulsotype C, with only two isolates, seemed to represent a sporadic event within the observed prevalence of clones A and B. Antimicrobial susceptibilities varied among isolates according to clones (Table ​(Table2).2). A. haemolyticus isolates presented resistance to all β-lactams, with the exception of cefepime, ceftazidime, and aztreonam. All Acinetobacter sp. isolates were resistant to ciprofloxacin, whereas susceptibility to aminoglycosides was variable. Only 11 isolates (including the two A. haemolyticus isolates) showed a colistin MIC of ≥4 μg/ml (2). However, when the recently updated CLSI susceptible interpretative criterion of ≤2 μg/ml (3, 8) was applied, the susceptibility rate dropped from 96.1% to 92.1%. Detection of carbapenemase production, ulteriorly identified as an OXA-24/40 enzyme, was performed as previously described (5) and was positive only for clone A A. baumannii isolates and, for the first time, A. haemolyticus isolates. Hybridization assays after both S1 nuclease digestion and I-CeuI digestion, performed as previously described (7), revealed that although some clone A A. baumannii isolates showed a chromosome-positive signal (ca. 150 kb) for the blaOXA-24/40 probe, most also presented a positive hybridization in plasmidic bands of ca. 180 kb and ca. 30 kb. Similar hybridization signals were observed in the A. haemolyticus isolates. Further studies on plasmid characterization, assessing the homology among different plasmids, are ongoing. TABLE 1. Clinical data for imipenem-resistant Acinetobacter spp.a TABLE 2. In vitro susceptibilities of imipenem-resistant Acinetobacter sp. clinical isolates We describe, for the first time, the presence of an OXA-24/40 enzyme in an A. haemolyticus clinical isolate. Although the spread of OXA-24/40, both in the Iberian Peninsula and in France, has been correlated with the progressive dissemination of a single A. baumannii clone, the observation of this enzyme in a different, previously unreported, genomic species, A. haemolyticus, poses new questions on OXA-24/40 dissemination. It now seems reasonable to suspect a horizontal dissemination of the blaOXA-40 gene between different species, an ability supported by the observation of this enzyme, previously described as chromosomally encoded (7), in a plasmid. Notwithstanding, the dissemination of “successful” clones may possibly contribute to the high rates and persistence of imipenem-resistant A. baumannii isolates (4).

A case of coccidioidal fungemia initially diagnosed as rhinosporidiosis

Coccidioidomycosis, a disease endemic to the southwestern United States, is caused by the dimorphic fungus Coccidioides immitis. This organism, initially categorized as a protozoan, has been known to cause morbidity and mortality for more than 100 years. Coccidioidomycosis is usually a benign, self-limiting respiratory disorder, but may lead to progressive pulmonary disease and dissemination. Manifestations are protean, and coccidioidomycosis is often confused with other disorders. Management of advanced infection is unsatisfactory. When fungemia is identified, prognosis is poor. 1-5 A patient presented with a lesion initially identified as a related fungus, Rhinosporidiosis seeberi. The patient rapidly deteriorated with acute respiratory failure, obtundation, coma, shock, and death. Blood cultures ultimately grew coccidioidomycosis. The clinical features of severe coccidioidomycosis including fungemia, together with a comparison of the key clinical and microbiologic features of coccidioidomycosis and rhinosporidiosis, are discussed.

Gastrointestinal Histoplasmosis

Gastrointestinal histoplasmosis (GIH) is an uncommon disease with protean manifestations. It may occur as a result of mediastinal histoplasmosis or in the setting of progressive dissemination. GIH may be misdiagnosed as inflammatory bowel disease, malignancy, or other intestinal diseases leading to inappropriate therapies and unnecessary surgical interventions. Patients with bowel obstruction, perforation, or bleeding, and systemic findings suggestive of histoplasmosis should be evaluated for GIH. This is especially true for immunosuppressed patients, especially those with AIDS. Diagnosis first requires consideration of histoplasmosis in the differential in patients with the above types of gastrointestinal abnormalities, and second, familiarity with a battery of mycologic and serologic tests. Progressive disseminated histoplasmosis (PDH) is lethal if left untreated, and treatment is highly effective. This review will focus on the clinical and histopathologic features of GIH, the approach to diagnosis, and recommendations for treatment.

Le virus West Nile, un arbovirus émergent

The West Nile virus (family Flaviviridae, genus Flavivirus), first isolated in 1937 in Africa, is an arthropod-borne virus transmitted through Culex mosquitoes bite. Its natural cycle includes a vector (Culex mosquitoes), a reservoir (birds of various species) and humans and large mammals are epidemiological dead-ends. PROGRESSIVE DISSEMINATION: This virus recently drew attention after several epidemics and epizooties were identified in France, Russia, Romania, and Israel. However, the most striking fact is its introduction in 1999 into the north-eastern United States, a country previously West Nile virus-free, and its progressive spread according to North-South and West-East gradients to finally cover the near-totality of the north American territory (USA, Canada and Mexico), in 2002. The year 2002 has been particularly prone to disseminating West Nile virus in the Unites States: more than 4,000 human cases have been recorded and resulted in the death of almost 300. In 2003, around 10,000 cases were recorded. From January to October 2004, around 2,000 human cases have been recorded in the USA. Among infected patients, few develop a symptomatic form, and only a small proportion of the latter will develop a neurological form. REGARDING DIAGNOSIS AND SURVEILLANCE: Although virus isolation remains the technique of reference, routine diagnosis basically relies on serology (detection of increased levels of specific antibodies on two blood tests at 21 days interval, detection of IgM on a single test) and on molecular techniques (detection of the viral genome); the latter have been developed in quantitative and real-time formats that provide results within 24 hours. We describe the situation in France following the equine epizooty that occurred in 2000, and the surveillance modalities initiated at that time.