Improved Protective Efficacy of a Species-Specific DNA Vaccine Encoding Mycolyl-Transferase Ag85A from Mycobacterium ulcerans by Homologous Protein Boosting

Vaccination with plasmid DNA encoding Ag85A from M. bovis BCG can partially protect C57BL/6 mice against a subsequent footpad challenge with M. ulcerans. Unfortunately, this cross-reactive protection is insufficient to completely control the infection. Although genes encoding Ag85A from M. bovis BCG (identical to genes from M. tuberculosis) and from M. ulcerans are highly conserved, minor sequence differences exist, and use of the specific gene of M. ulcerans could possibly result in a more potent vaccine. Here we report on a comparison of immunogenicity and protective efficacy in C57BL/6 mice of Ag85A from M. tuberculosis and M. ulcerans, administered as a plasmid DNA vaccine, as a recombinant protein vaccine in adjuvant or as a combined DNA prime-protein boost vaccine. All three vaccination formulations induced cross-reactive humoral and cell-mediated immune responses, although species-specific Th1 type T cell epitopes could be identified in both the NH2-terminal region and the COOH-terminal region of the antigens. This partial species-specificity was reflected in a higher—albeit not sustained—protective efficacy of the M. ulcerans than of the M. tuberculosis vaccine, particularly when administered using the DNA prime-protein boost protocol

Fatal Case of Toxic Shock-Like Syndrome Due to Group C Streptococcus Associated with Superantigen Exotoxin

Group C streptococci have been reported to cause invasive disease similar to that classically associated with group A streptococcus (GAS). We describe a fatal case of toxic shock-like syndrome due to Streptococcus equi subsp. zooepidemicus. The causative organism did not possess any known GAS superantigen exotoxin genes but did show evidence of superantigen production

Cytokine Profiles of Patients Infected with Mycobacterium ulcerans and Unaffected Household Contacts

Mycobacterium ulcerans, the cause of Buruli ulcer, is an environmental mycobacterium with a distinct geographic distribution. The reasons why only some individuals who are exposed to M. ulcerans develop ulcers are not known but are likely to reflect individual differences in the immune response to infections with this bacterium. In this study, we investigated cytokine profiles of peripheral blood mononuclear cells (PBMC) from 23 Buruli ulcer patients and 25 household contacts in a region of Australia where Buruli ulcer is endemic. The results showed that following stimulation with M. ulcerans or Mycobacterium bovis BCG, PBMC from Buruli ulcer patients mounted a Th2-type response, which was manifested by the production of mRNA for interleukin 4 (IL-4), IL-5, IL-6, and IL-10, whereas unaffected contacts responded mainly with the Th1 cytokines gamma interferon (IFN-γ) and IL-12. For example, mRNA for IL-4 was detected in 18 of 23 patients but in only 3 of 25 control subjects (P < 0.0001). By contrast, PBMC from 21 of 25 unaffected individuals produced IFN-γ compared with 3 of 23 patients (P < 0.0001). IFN-γ release following stimulation with mycobacteria was markedly reduced in affected subjects. Frequencies of antibodies to M. ulcerans in serum samples from affected and unaffected subjects were similar, indicating that many of the control subjects had been exposed to this bacterium. Together, these findings suggest that a Th1-type immune response to M. ulcerans may prevent the development of Buruli ulcer in people exposed to M. ulcerans, but a Th-2 response does not

Intratracheal injection of adenovirus containing the human MNSOD transgene protects athymic nude mice from irradiation-induced organizing alveolitis

Purpose: A dose and volume limiting factor in radiation treatment of thoracic cancer is the development of fibrosis in normal lung. The goal of the present study was to determine whether expression prior to irradiation of a transgene for human manganese superoxide dismutase (MnSOD) or human copper/zinc superoxide dismutase (Cu/ZnSOD) protects against irradiation- induced lung damage in mice. Methods and Materials: Athymic Nude (Nu/J) mice were intratracheally injected with 109 plaque-forming units (PFU) of a replication-incompetent mutant adenovirus construct containing the gene for either human MnSOD, human copper/zinc superoxide dismutase (Cu/ZnSOD) or LacZ. Four days later the mice were irradiated to the pulmonary cavity to doses of 850, 900, or 950 cGy. To demonstrate adenoviral infection, nested reverse transcriptase-polymerase chain reaction (RT-PCR) was carried out with primers specific for either human MnSOD or Cu/ZnSOD transgene on freshly explanted lung, trachea, or alveolar type II cells, and immunohistochemistry was used to measure LacZ expression. RNA was extracted on day 0, 1, 4, or 7 after 850 cGy of irradiation from lungs of mice that had previously received adenovirus or had no treatment. Slot blot analysis was performed to quantitate RNA expression for IL-1, tumor necrosis factor (TNF)-α, TGF-β, MnSOD, or Cu/ZnSOD. Lung tissue was explanted and tested for biochemical activity of MnSOD or Cu/ZnSOD after adenovirus injection. Other mice were sacrificed 132 days after irradiation, lungs excised, frozen in OCT, (polyvinyl alcohol, polyethylene glycol mixture) sectioned, H and E stained, and evaluated for percent of the lung demonstrating organizing alveolitis. Results: Mice injected intratracheally with adenovirus containing the gene for human MnSOD had significantly reduced chronic lung irradiation damage following 950 cGy, compared to control mice or mice injected with adenovirus containing the gene for human Cu/ZnSOD or LacZ. Immunohistochemistry for LacZ protein in adenovirus LacZ (Ad-LacZ)-injected mice demonstrated expression of LacZ in both the upper and lower airway. Nested RT-PCR showed lung expression of MnSOD and Cu/ZnSOD for at least 11 days following infection with each respective adenovirus construct. Nested RT-PCR using primers specific for human MnSOD demonstrated increased expression of the human MnSOD transgene in the trachea and alveolar type II cells 4 days after virus injection on the day of irradiation. At this time point, increased biochemical activity of MnSOD and Cu/ZnSOD respectively, was detected in lungs from these two adenovirus groups, compared to each other or to control or adenovirus LacZ mice. Slot blot analysis of RNA from lungs of mice in each group following 850 cGy irradiation demonstrated decreased expression of mRNA for interleukin-I (IL-1), TNF-α, and transforming growth factor-beta (TGF-β) in the MnSOD adenovirus-injected mice, compared to irradiated control, LacZ, or Cu/ZnSOD adenovirus-injected, irradiated mice. Mice receiving adenovirus MnSOD showed decreased organizing alveolitis at 132 days in all three dose groups, compared to irradiated control or Ad-LacZ, or Ad-Cu/ZnSOD mice. Conclusions: Overexpression of MnSOD in the lungs of mice prior to irradiation prevents irradiation-induced acute and chronic damage quantitated as decreased levels of mRNA for IL-1, TNF-α, and TGF-β in the days immediately following irradiation, and decrease in the percent of lung demonstrating fibrosis or organizing alveolitis at 132 days. These data provide a rational basis for development of gene therapy as a method of protection of the normal lung from acute and chronic sequellae of ionizing irradiation

The state of neuropsychological test norms for Spanish-speaking adults in the United States.

Objective: The present review paper aimed to identify published neuropsychological test norms developed for Spanish-speakers living in the United States (U.S.). Methods: We conducted a systematic review of the literature via an electronic search on PubMed using keywords "Normative data," "Neuropsychological test," "norms", "Hispanic/Latinos," "Spanish Speakers," and "United States." We added other studies and published manuals as identified by citations in papers from the original search. Results Eighteen sources of normative data for Spanish-speakers in the U.S. were identified. Of the 18 citations identified, only four provide normative data on comprehensive batteries of tests for Spanish-Speakers. Two of these are based on persons living in the southwest of the U.S., who tend to be of Mexican origin. Overall, a number of the studies are focused on older persons and although the majority include participants with wide ranges of education, participants in the ends of the education distribution tend to be underrepresented. Conclusion: Here we provide a detailed description of the neuropsychological normative data currently available for Spanish-speakers living in the U.S. While there has been increased attention towards developing norms for neuropsychological batteries in Spanish-speaking countries (e.g., Latin America and Spain), there is still an urgent need to standardize neuropsychological tests among diverse groups of Spanish-speaking adults living in the U.S. The present review presents a list of norms for U.S.-dwelling Spanish-speakers, thus providing an important tool for clinicians and researchers

Introduction to the Neuropsychological Norms for the US-Mexico Border Region in Spanish (NP-NUMBRS) Project

ObjectiveThe present introduction to the Neuropsychological Norms for the U.S.-Mexico Border Region in Spanish (NP-NUMBRS) project aims to provide an overview of the conceptual framework and rationale that guided the development of this project.MethodsWe describe important aspects of our conceptual framework, which was guided by some of the main purposes of neuropsychological testing, including the identification of underlying brain dysfunction, and the characterization of cognitive strengths and weakness relevant to everyday functioning. We also provide our rationale for focusing this norm development project on Spanish-speakers in the United States, and provide an outline of the articles included in this Special Issue focused on the NP-NUMBRS project.ConclusionsThe data presented in this Special Issue represent an important tool for clinicians and researchers working in the neuropsychological assessment of Spanish-speakers in the United States

Introduction to the Neuropsychological Norms for the US-Mexico Border Region&nbsp;in Spanish (NP-NUMBRS) Project.

ObjectiveThe present introduction to the Neuropsychological Norms for the U.S.-Mexico Border Region in Spanish (NP-NUMBRS) project aims to provide an overview of the conceptual framework and rationale that guided the development of this project.MethodsWe describe important aspects of our conceptual framework, which was guided by some of the main purposes of neuropsychological testing, including the identification of underlying brain dysfunction, and the characterization of cognitive strengths and weakness relevant to everyday functioning. We also provide our rationale for focusing this norm development project on Spanish-speakers in the United States, and provide an outline of the articles included in this Special Issue focused on the NP-NUMBRS project.ConclusionsThe data presented in this Special Issue represent an important tool for clinicians and researchers working in the neuropsychological assessment of Spanish-speakers in the United States

The Neuropsychological Norms for the U.S.-Mexico Border Region in Spanish (NP-NUMBRS) Project: Overview and considerations for life span research and evidence-based practice.

ObjectiveThis paper summarizes the findings of the Neuropsychological Norms for the U.S.-Mexico Border Region in Spanish (NP-NUMBRS) Project and offers a roadmap for future research.MethodsThe NP-NUMBRS project represents the largest and most comprehensive co-normed neuropsychological battery to date for native Spanish-speaking healthy adults from the U.S. (California/Arizona)-Mexico borderland region (N = 254; ages 19-60 years). These norms provide demographic adjustments for tests across numerous domains (i.e., verbal fluency, processing speed, attention/working memory, executive function, episodic memory [learning and delayed recall], visuospatial, and fine motor skills).ConclusionsThis project: 1) shows that the NP-NUMBRS norms consistently outperformed previously published norms for English-speaking non-Hispanic (White and African-American) adults in identifying impairment; 2) explores the role of Spanish-English bilingualism in test performance; and 3) provides support for the diagnostic validity of these norms in detecting HIV-associated neurocognitive impairment. Study limitations include the limited assessment of sociocultural variables and generalizability (e.g., other Latina/o populations, age limit [19 - 60 years]). Future research is needed to: 1) investigate these norms with U.S.-dwelling Spanish-speakers of non-Mexican heritage and other clinical subpopulations; 2) expand coverage of cognitive domains (e.g. language, visuospatial); 3) develop large normative datasets for children and older Latina/o populations; 4) examine how sociocultural factors impact performance (e.g., bilingualism, acculturation); 5) investigate these norms' diagnostic and ecological validity; and 6) develop norms for neurocognitive change across time. It is hoped that the NP-NUMBRS norms will aid researchers and clinicians working with U.S.-dwelling Spanish-speakers from the U.S.-Mexico borderland to conduct research and evidence-based neuropsychological evaluations in a more culturally responsive and ethical manner