Limited Protective Role Research Articles

Similar humoral responses but distinct CD4+ T cell transcriptomic profiles in older adults elicited by MF59 adjuvanted and high dose influenza vaccines.

Older age (≥ 65 years) is associated with impaired responses to influenza vaccination, leading to the preferential recommendation of MF59-adjuvanted (MF59Flu) or high-dose (HDFlu) influenza vaccines for this age group in the United States. Herein, we characterized transcriptomic profiles of CD4+ T cells isolated from 234 recipients (≥ 65 years) of either MF59Flu or HDFlu vaccine, prior to vaccination and 28 days thereafter. We identified 412 and 645 differentially expressed genes (DEGs) in CD4+ T cells of older adults after receiving MF59Flu and HDFlu, respectively. DEGs in CD4+ T cells of MF59Flu recipients were enriched in 14 KEGG pathways, all of which were downregulated. DEGs in CD4+ T cells of HDFlu recipients were enriched in 11 upregulated pathways and 20 downregulated pathways. CD4+ T cells in both vaccine groups shared 50 upregulated genes and 75 downregulated genes, all of which were enriched in 7 KEGG pathways. The remaining 287 and 520 DEGs were specifically associated with MF59Flu and HDFlu, respectively. Unexpectedly, none of these DEGs was significantly correlated with influenza A/H3N2-specific HAI titers, suggesting these DEGs at the individual level may have a limited role in protection against influenza. Our findings emphasize the need for further investigation into other factors influencing immunity against influenza in older adults.

Bacterial Contamination in Total Joint Replacement: Should We Change into a New Set of Clean Scrub Suits Whenever Entering the Operating Room?

The aims of this study are as follows: (1) to investigate the level and probability of bacterial contamination on scrub suits over time for medical personnel working inside and/or outside the operating room (OR) area; (2) to discuss the protective role of cover gowns against bacterial contamination; and (3) to consider the necessity of changing into clean suits whenever entering the OR in terms of preventing periprosthetic joint infection (PJI) in total joint replacement (TJR). The bacterial colony count was examined on the chest area of the scrub suits worn during various daily clinical practices. The genus/species of the contaminants were identified by matrix-assisted laser deposition ionization-time of flight mass spectrometry (MALDI-TOF MS). The scrub suits worn outside the OR area showed a greater level of bacterial contamination than those worn inside the OR area, although the colony counts tended to increase over time both in and out of the area. The probability of contamination involving coagulase-negative staphylococci (CNS) (known as the primary cause of PJI) did not increase significantly in the scrubs worn inside the OR area, but did increase significantly after a long-time departure from the OR area. Our results suggest that wearing scrub suits outside and/or the long duration of wearing the same suits can significantly increase the level and probability of any bacterial contamination (including CNS) on scrub suits. We also found that wearing a cover gown over scrub suits outside the OR area may have only a limited protective role against bacterial contamination.

Phenotypic analyses, protein localization, and bacteriostatic activity of Drosophila melanogaster transferrin-1

Transferrin-1 (Tsf1) is an extracellular insect protein with a high affinity for iron. The functions of Tsf1 are still poorly understood; however, Drosophila melanogaster Tsf1 has been shown to influence iron distribution in the fly body and to protect flies against some infections. The goal of this study was to better understand the physiological functions of Tsf1 in D. melanogaster by 1) investigating Tsf1 null phenotypes, 2) determining tissue-specific localization of Tsf1, 3) measuring the concentration of Tsf1 in hemolymph, 4) testing Tsf1 for bacteriostatic activity, and 5) evaluating the effect of metal and paraquat treatments on Tsf1 abundance. Flies lacking Tsf1 had more iron than wild-type flies in specialized midgut cells that take up iron from the diet; however, the absence of Tsf1 had no effect on the iron content of whole midguts, fat body, hemolymph, or heads. Thus, as previous studies have suggested, Tsf1 appears to have a minor role in iron transport. Tsf1 was abundant in hemolymph from larvae (0.4 μM), pupae (1.4 μM), adult females (4.4 μM) and adult males (22 μM). Apo-Tsf1 at 1 μM had bacteriostatic activity whereas holo-Tsf1 did not, suggesting that Tsf1 can inhibit microbial growth by sequestering iron in hemolymph and other extracellular environments. This hypothesis was supported by detection of secreted Tsf1 in tracheae, testes and seminal vesicles. Colocalization of Tsf1 with an endosome marker in oocytes suggested that Tsf1 may provide iron to developing eggs; however, eggs from mothers lacking Tsf1 had the same amount of iron as control eggs, and they hatched at a wild-type rate. Thus, the primary function of Tsf1 uptake by oocytes may be to defend against infection rather than to provide eggs with iron. In beetles, Tsf1 plays a role in protection against oxidative stress. In contrast, we found that flies lacking Tsf1 had a typical life span and greater resistance to paraquat-induced oxidative stress. In addition, Tsf1 abundance remained unchanged in response to ingestion of iron, cadmium or paraquat or to injection of iron. These results suggest that Tsf1 has a limited role in protection against oxidative stress in D. melanogaster.

Protective Role of Folic Acid Versus Atorvastatin on Experimentally Induced Doxorubicin Toxicity on Testes of Adult Albino Rats: Anatomical, Histological and Immunoassay Study

Background: Infertility is a worldwide common health problem that might be induced by many factors and anti-cancerous are among the most common causes. Doxorubicin, and similar drugs are widely used anti cancerous agents mainly in the treatment of solid tumors, lymphoma and leukemia. they are attributable to male infertility due to testicular intoxication, and issue necessitates the concomitant usage of protective agents especially with increase life expectancy of cancer patients associated with better health care.Aim of the work: The current study is designed to compare the possible protective effect of both folic acid and Atorvastatin in doxorubicin induced testicular intoxication in adult male albino rats. Materials and methods: The experiment was conducted on sixty adult animals divided randomly and equally as control group (including three subgroups, 10 rats EACH, received no treatment, 10 rats received Atorvastatin and 10 rats received Folic acid), Doxorubicin treated group and two more groups that received folic acid and Atorvastatin in the second concomitantly as protective agents.Results: The results assessed anatomically (body weight, testicular weight and body: testicular weight ratio), biochemical assay (LH, antioxidant and testosterone serum level), and histologically both by light and Transmission Electron Microscopy (TEM). All results suggest that folic acid has a significant protective role on doxorubicin induced testicular intoxication. Administration of Atorvastatin at the used dose has a limited role in protection. Conclusion: The results recommend the use of folic acid as a routine protective agent for those under doxorubicin treatment especially in males during childhood and young age.

The ameliorative impacts of curcumin on copper oxychloride-induced hepatotoxicity in rats

BackgroundCopper oxychloride (COC) (50% of its component, copper) is copper-based fungicides. The present study aimed to investigate the possible protective effect of 80 mg/kg curcumin against the toxicity of 500, 1000, or 2000 mg COC per kilogram body weight for 90 days on the liver of a rat. Serum glutamic-pyruvic transaminase (SGPT), serum glutamic-oxaloacetic transaminase (SGOT), hepatic glutathione reduced content (GSH), and malondialdehyde (MDA) levels were detected. The histological and ultrastructure changes of the liver tissues as well as the hepatic content of copper, iron, manganese, and zinc were also reported.ResultsCOC-treated rats showed an increase of SGPT and SGOT, with the elevation of copper and zinc content and MDA levels with no change in GSH level. The liver showed a significant increase in the copper and iron contents. The liver of COC-treated rats showed histological and ultrastructural damage that increased with increasing the COC dose. Conversely, curcumin supplementation potentially recovered liver function enzymes in only low doses of COC, reduced MDA level, increased GSH content, and improved the hepatic lesions. These findings revealed that subchronic exposure to even low levels of COC may have potential hazards and harmful effects on the liver, and the curcumin markedly attenuated the COC biochemical, histological, and cellular alterations in liver tissues, best with the low dose of COC.ConclusionsIt is concluded that curcumin has a limited protective role against COC liver toxicity.

Depletion of Alveolar Macrophages Does Not Prevent Hantavirus Disease Pathogenesis in Golden Syrian Hamsters.

ABSTRACTAndes virus (ANDV) is associated with a lethal vascular leak syndrome in humans termed hantavirus pulmonary syndrome (HPS). The mechanism for the massive vascular leakage associated with HPS is poorly understood; however, dysregulation of components of the immune response is often suggested as a possible cause. Alveolar macrophages are found in the alveoli of the lung and represent the first line of defense to many airborne pathogens. To determine whether alveolar macrophages play a role in HPS pathogenesis, alveolar macrophages were depleted in an adult rodent model of HPS that closely resembles human HPS. Syrian hamsters were treated, intratracheally, with clodronate-encapsulated liposomes or control liposomes and were then challenged with ANDV. Treatment with clodronate-encapsulated liposomes resulted in significant reduction in alveolar macrophages, but depletion did not prevent pathogenesis or prolong disease. Depletion also did not significantly reduce the amount of virus in the lung of ANDV-infected hamsters but altered neutrophil recruitment, MIP-1α and MIP-2 chemokine expression, and vascular endothelial growth factor (VEGF) levels in hamster bronchoalveolar lavage (BAL) fluid early after intranasal challenge. These data demonstrate that alveolar macrophages may play a limited protective role early after exposure to aerosolized ANDV but do not directly contribute to hantavirus disease pathogenesis in the hamster model of HPS.IMPORTANCE Hantaviruses continue to cause disease worldwide for which there are no FDA-licensed vaccines, effective postexposure prophylactics, or therapeutics. Much of this can be attributed to a poor understanding of the mechanism of hantavirus disease pathogenesis. Hantavirus disease has long been considered an immune-mediated disease; however, by directly manipulating the Syrian hamster model, we continue to eliminate individual immune cell types. As the most numerous immune cells present in the respiratory tract, alveolar macrophages are poised to defend against hantavirus infection, but those antiviral responses may also contribute to hantavirus disease. Here, we demonstrate that, like in our prior T and B cell studies, alveolar macrophages neither prevent hantavirus infection nor cause hantavirus disease. While these studies reflect pathogenesis in the hamster model, they should help us rule out specific cell types and prompt us to consider other potential mechanisms of disease in an effort to improve the outcome of human HPS.

Environmental control of tuberculosis

The premise of this article is that it is possible to reduce but not eliminate the risk of TB infection in many institutional settings through environmental interventions--as supplements to conventional public health TB control efforts. Of the environmental means available to reduce the concentration of infectious droplet nuclei, ventilation, isolation strategies, and personal respirators have received the most attention, but each has inherent limitations. Ventilation and other air-moving strategies (i.e., fan-filter and fan-UV room units) are limited by the large volume of air that must be moved to dilute and remove already dilute droplet nuclei. Isolation assumes that potential transmitters are suspected, whereas negative pressure in isolation rooms is difficult to achieve and maintain in many hospitals. The use of well-designed small enclosures for sputum induction and other high-risk procedures, however, should provide highly effective source control. Personal respirators have a limited protective role because they cannot be worn by all workers at all times, and cannot reasonably be issued to other patients and visitors. Germicidal UV irradiation of upper room air is widely misunderstood, but offers practical air disinfection that can be safely and efficiently deployed in a variety of high-risk environments. Although there are theoretical and experimental bases for these recommendations, there are no clinical field trials preventing TB using any of the available environmental interventions, primarily because of the highly variable nature of TB transmission.

High‐frequency vaccine‐induced CD8+ T cells specific for an epitope naturally processed during infection with Mycobacterium tuberculosis do not confer protection

Relatively few MHC class I epitopes have been identified from Mycobacterium tuberculosis, but during the late stage of infection, CD8+ T‐cell responses to these epitopes are often primed at an extraordinary high frequency. Although clearly available for recognition during infection, their role in resistance to mycobacterial infections still remain unclear. As an alternative to DNA and viral vaccination platforms, we have exploited a novel CD8+ T‐cell‐inducing adjuvant, cationic adjuvant formulation 05 (dimethyldioctadecylammonium/trehalose dibehenate/poly (inositic:cytidylic) acid), to prime high‐frequency CD8 responses to the immunodominant H2‐Kb‐restricted IMYNYPAM epitope contained in the vaccine Ag tuberculosis (TB)10.4/Rv0288/ESX‐H (where ESX is mycobacterial type VII secretion system). We report that the amino acid C‐terminal to this minimal epitope plays a decisive role in proteasomal cleavage and epitope priming. The primary structure of TB10.4 is suboptimal for proteasomal processing of the epitope and amino acid substitutions in the flanking region markedly increased epitope‐specific CD8+ T‐cell responses. One of the optimized sequences was contained in the closely related TB10.3/Rv3019c/ESX‐R Ag and when recombinantly expressed and administered in the cationic adjuvant formulation 05 adjuvant, this Ag promoted very high CD8+ T‐cell responses. This abundant T‐cell response was functionally active but provided no protection against challenge, suggesting that CD8+ T cells play a limited role in protection against M. tuberculosis in the mouse model.

Allogeneic Stem Cell Transplantation For Acute Myeloid Leukemia With Normal Cytogenetics (CN-AML): Outcome, Risk Factors and Role Of Molecular Subgroups In 752 Patients – A Report From The Acute Leukemia Working Party Of EBMT

BackgroundAllogeneic stem cell transplantation (alloSCT) is the only curative treatment for most patients with CN AML. It is now well established that some relevant molecular markers can allow for the definition of risk groups after conventional chemotherapy. However, the role of these markers among other factors influencing outcome after alloSCT remains to be defined. Hence, we conducted an EBMT registry-based analysis aiming to define the exact prognostic role of molecular subgroups in conjunction with other classical risk factors after alloSCT for CN-AML. Patients, Methods and Results752 adults (375 males) fulfilled the inclusion criteria, i.e. first alloSCT for CN-AML between 2000 and 2011, matched sibling (MSD) or unrelated (MUD) donor, and known mutational status of FLT3-ITD and NPM1, the two most frequently observed molecular markers in CN-AML. Median age was 51y (range, 18-71), disease status at time of alloSCT was CR1 (n=554), CR2/3 (n=90), primary induction failure (PIF, n=39), relapsed disease (n=62) and unknown (n=7). Myeloablative and reduced-intensity conditioning regimens were used in 371 and 378 patients, respectively. 597 received allogeneic PBSCs.With a median follow-up of 27 months, The 2-year estimates of overall survival (OS) and leukemia-free survival (LFS) were respectively 68±2% and 61±6% after alloSCT in CR1, 63±2% and 53±6% in CR2/3, 36±7% and 33±8% in PIF, and 28±7% and 25±6% in relapsed disease. In 554 patients transplanted in CR1, OS, LFS, cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were calculated according to molecular subgroups. Whereas NPM1mut had no influence on outcome, FLT3-ITD was associated with increased CIR (p<0.0001), decreased LFS (p=0.0002) and OS (p=0.0006) Outcome after alloSCT of subgroups based on mutational status of NPM1 and FLT3-ITD is shown in table 1Table 1Table 1OS (%)LFS (%)CIR (%)NRM (%)NPM1WT/FLT3-ITDneg(n=221)75±369±316±215±2NPM1WT/FLT3-ITD(n=59)47±744±736±719±6NPM1mut/FLT3-ITD(n=215)64±458±428±313±2NPM1mut/FLT3-ITDneg(n=59)80±577±613±411±4Global p-value0.00080.00060,00030,85.A multivariate Cox model of predefined risk factors including age, WBC at diagnosis, time to reach CR1, donor type, conditioning type (reduced vs. standard), and presence of NPM1mut and FLT3-ITD, was performed. Age >=50 years was the only risk factor for NRM (HR= 2.40, 95%CI: 1.32-4.37), while the presence of FLT3-ITD was the only risk factor for CIR (HR=2.85; 95%CI; 1.76-4.60). Both age >=50 years and FLT3-ITD were associated with inferior LFS (HR=1.65, 95%CI: 1.14-2.39, p=0.01 for age, HR=2.08, 95%CI: 1.43-3.01, p=0.001 for FLT3-ITD) and, most importantly, OS (HR=1,76; 95%CI: 1.19-2.61, p=0.005 for age, and HR=2.19; 95%CI: 1.48-3.26, p=0.0001 for FLT3-ITD). The latter data allowed to identify 3 prognostic groups with 2-years OS of 83±4% (younger age and FLT3-ITDneg), 70±4% (older age OR FLT3-ITD) and 48±5% (older age and FLT3-ITD), p<0.0001; Figure 1). On the contrary, donor type (sibling vs. MUD) or intensity of the conditioning regimen (standard vs. reduced) did not play any significant role in any molecular subgroup. [Display omitted] ConclusionIn the largest study on CN-AML performed thus far, we identified age >=50 years and FLT3-ITD as the major risk factors for OS after alloSCT in CR1, independently from other risk factors such as type of donor or conditioning. In patients harboring FLT3-ITD, a limited protective role for NPM1 mutation could be observed. These results underscore the importance of post-transplant strategies to prevent relapse in AML with FLT3-ITD. Encouraging results were observed after SCT in PIF, relapse or advanced CR. Disclosures:Schmid:Novartis: Honoraria, Research Funding, travel grant Other; Roche: travel grant, travel grant Other; MSD: Honoraria. Rambaldi:Novartis: Honoraria; Sanofi: Honoraria; Italfarmaco: Honoraria.

Limited protective role of V-PYRRO/NO against cholestasis produced by alpha-naphthylisothiocyanate in mice

O 2 -vinyl 1-(pyrrolidin-1-yl)diazen-1-ium-1,2-diolate (V-PYRRO/NO) is a liver-selective nitric oxide donor that has been shown to protect against hepatotoxic effects of endotoxin, acetaminophen and cadmium. This study examined the effects of V-PYRRO/NO on alpha-naphthylisothiocyanate (ANIT)-induced hepatotoxicity in mice. Mice were given V-PYRRO/NO via osmotic pumps (5.4 mg/ml; 0.5 μl/h) starting 24 h before receiving a hepatotoxic dose of ANIT (150 mg/kg in olive oil, i.g.), and continuing for additional 48 h (3-day pumps). V-PYRRO/NO administration partially ameliorated ANIT-induced hepatotoxicity, as evidenced by reduced serum alanine aminotransferase and alkaline phosphatase, markers of liver cell death, and by improved liver pathology. However, V-PYRRO/NO had no effect on ANIT-induced cholestasis, as ANIT-increased serum bilirubin levels and gamma-glutamyl transpeptidase activity were not ameliorated. Microarray and real time RT-PCR analysis revealed that ANIT intoxication altered expression of various genes, including genes encoding metabolic enzymes, transporter proteins, acute phase proteins, inflammation- and, apoptosis-related genes, as well as other genes related to liver injury. V-PYRRO/NO treatment attenuated ANIT-induced elevations in certain inflammation- and apoptosis-related genes, but had no effect on ANIT-induced disturbance on the expression of genes related to metabolism, transport, and acute phase proteins. Thus, the liver-selective NO donor, V-PYRRO/NO, was partially protective against ANIT-induced liver injury, without affecting ANIT-induced cholestasis and cholestasis-related gene expression.

An Intravaginal Live Candida Challenge in Humans Leads to New Hypotheses for the Immunopathogenesis of Vulvovaginal Candidiasis

Acute and recurrent vulvovaginal candidiasis (VVC) remains a significant problem in women of childbearing age. While clinical studies of women with recurrent VVC (RVVC) and animal models have provided important data about a limited protective role of adaptive immunity, there remains a paucity of information on the protective mechanisms or factors associated with susceptibility to infection. In the present study, an intravaginal live Candida challenge in healthy adult women showed a differential susceptibility to symptomatic VVC, where 3 (15%) of 19 women with no history of VVC acquired a symptomatic infection compared to 6 (55%) of 11 women with an infrequent history of VVC. Furthermore, these studies revealed that protection against infection is noninflammatory while symptomatic infection correlates with a vaginal infiltration of polymorphonuclear neutrophils (PMNs) and a high vaginal fungal burden. Thus, the presence of symptomatic infection appears more dependent on host factors than on properties of the organism. Finally, vaginal lavage fluid from women with a symptomatic infection, but not those asymptomatically colonized, promoted the chemotaxis of PMNs. These results suggest that rather than RVVC/VVC being caused by an aberrant adaptive immune response, symptoms that define infection appear to be due to an aggressive innate response by PMNs.

Effect of Photorespiratory C2Acids on CO2Assimilation, PS II Photochemistry and the Xanthophyll Cycle in Maize

The photorespiration cycle plays an important role in avoiding carbon drainage from the Calvin cycle and in protecting plants from photoinhibition. The role of photorespiration is frequently underestimated in C(4) plants, since these are characterized by low photorespiration rates. The aim of this work was to study the relationship between CO(2) assimilation, PS II photochemistry and the xanthophyll cycle when the photorespiratory cycle is disrupted in Zea mays L. To this end, the photorespiration inhibitor phosphinothricin (PPT) was applied individually or together with the photorespiratory C(2) acids, glycolate and glyoxylate to maize leaves. Application of PPT alone led to the inhibition of CO(2) assimilation. Moreover, feeding with glycolate or glyoxylate enhanced the effect of PPT on CO(2) assimilation. Our results confirm that the avoidance of the accumulation of the photorespiratory metabolites glycolate, glyoxylate or phosphoglycolate, is of vital importance for coordinated functioning between the glycolate pathway and CO(2) assimilation. Relatively early changes in PS II photochemistry also took place when the photorespiratory cycle was interrupted. Thus, fluorescence photochemical quenching (qP) was slightly reduced (10%) due to the application of PPT together with glycolate or glyoxylate. A decrease in the efficiency of excitation-energy capture by open PS II reaction centres (F'v/F'm) and an increase in thermal energy dissipation (non-photochemical quenching, NPQ) were also measured. These observations are consistent with a limitation of activity of the Calvin cycle and a subsequent lower demand for reduction equivalents. The increase in NPQ is discussed on the basis of changes in the xanthophyll cycle in maize, which seem to provide a limited protective role to avoid photoinhibition when the glycolate pathway is blocked. We conclude that C(2) photorespiratory acids can act as physiological regulators between the photorespiratory pathway and the Calvin cycle in maize.

Multiple experimental designs to evaluate the role of T-cell-mediated immunity against experimental vaginalCandida albicansinfection

Studies to date suggest a limited protective role for Candida-specific Th1-type cell-mediated immunity (CMI) against Candida albicans vaginitis, despite protection against other mucosal Candida infections. Recent evidence suggests this may be due to immunoregulatory mechanisms that inhibit a more profound CMI response against C. albicans vaginal infections. The present study was designed to conduct an evaluation of the protective role of CMI against experimental C. albicans vaginitis using multiple approaches, including the use of T-cell-immunodeficient (SCID, Nude) and knockout (CD4) mice and several immunization designs in immunocompetent mice. Results showed, with few exceptions, that most T-cell-immunodeficient or knockout mice had a vaginal fungal burden similar to that of wild-type strains throughout the observation period. In addition, no correlation was observed between vaginal T-helper and proinflammatory cytokines and fungal burden, suggesting a generalized state of immunoregulation. Evaluation of the effects of various immunization designs that included different Candida antigens, routes of delivery and strains of mice yielded no protection against vaginal candidiasis. These studies provide further evidence of a lack of a protective role of T cells against C. albicans vaginitis, and continue to support the concept of immunoregulation against vaginal CMI responses.

Impaired macrophage listericidal and cytokine activities are responsible for the rapid death of Listeria monocytogenes-infected IFN-gamma receptor-deficient mice.

IFN-gamma receptor-deficient (IFN-gammaR -/-) mice were used to study the innate immune responses during infection with Listeria monocytogenes. Mutant mice were unable to limit bacterial growth and died of sepsis even with an infection dose of 70 Listeria. At day 2, they showed an exacerbated listeriosis and mice succumbed to infection before the onset of an effective specific immunity, demonstrating a defective innate immunity. Recruitment and extravasation of phagocytic cells to infected organs was present and dominated by neutrophils. However, during the early course of infection, mutant mice responded by an elevated inflammatory type 1 cytokine response, as determined by IL-12, IFN-gamma, TNF-alpha, and IL-1alpha-specific RNA expression. Induction of inducible nitric oxide synthase was present and also increased in mutant mice. Interestingly, IFN-gammaR -/- neutrophils expressed substantial TNF-alpha- and IL-1alpha-specific RNA, suggesting a substantial contribution in the overall inflammatory cytokine response. In contrast, IFN-gammaR -/- macrophages showed reduced MHC class II surface expression levels and impaired TNF-alpha and IL-1alpha but normal IL-6 production after restimulation with heat-killed L. monocytogenes. Moreover, IFN-gammaR -/- macrophages showed defective listericidal activities. In contrast to normal macrophages, Listeria escaped rapidly from the phagosome in IFN-gammaR -/- macrophages to the cytoplasm, where they productively survived. In conclusion, these data suggest that IFN-gammaR signaling activates yet unknown functions in macrophages, preventing Listeria-induced escape from the phagosome and consequent killing of the invader. Together with the impaired cytokine responses, these macrophage defects seem to be responsible for the dramatic susceptibility during innate immunity, whereas predominant neutrophil responses mediate limited protective role in mutant mice.

The role of a mutant CCR5 allele in HIV-1 transmission and disease progression.

A 32-nucleotide deletion (delta 32) within the beta-chemokine receptor 5 (CCR5) gene has been described in subjects who remain uninfected despite extensive exposure to HIV-1. This allele was found to be common in the Caucasian population with a frequency of 0.0808, but was not found in people of African or Asian ancestry. To determine its role in HIV-1 transmission and disease progression, we analyzed the CCRS genotype of 1252 homosexual men enrolled in the Chicago component of the Multicenter AIDS Cohort Study (MACS). No infected participant was found to be homozygous for the delta 32 allele, whereas 3.6% of at-risk but uninfected Caucasian participants were homozygous, showing the highly protective role of this genotype against sexual acquisition of HIV-1. No evidence was found to suggest that heterozygotes were protected against HIV-1 infection, but a limited protective role against disease progression was noted. The delta 32 allele of CCR5 is therefore an important host factor in HIV-1 transmission and pathogenesis.

Environmental control of tuberculosis

The premise of this article is that it is possible to reduce but not eliminate the risk of TB infection in many institutional settings through environmental interventions--as supplements to conventional public health TB control efforts. Of the environmental means available to reduce the concentration of infectious droplet nuclei, ventilation, isolation strategies, and personal respirators have received the most attention, but each has inherent limitations. Ventilation and other air-moving strategies (i.e., fan-filter and fan-UV room units) are limited by the large volume of air that must be moved to dilute and remove already dilute droplet nuclei. Isolation assumes that potential transmitters are suspected, whereas negative pressure in isolation rooms is difficult to achieve and maintain in many hospitals. The use of well-designed small enclosures for sputum induction and other high-risk procedures, however, should provide highly effective source control. Personal respirators have a limited protective role because they cannot be worn by all workers at all times, and cannot reasonably be issued to other patients and visitors. Germicidal UV irradiation of upper room air is widely misunderstood, but offers practical air disinfection that can be safely and efficiently deployed in a variety of high-risk environments. Although there are theoretical and experimental bases for these recommendations, there are no clinical field trials preventing TB using any of the available environmental interventions, primarily because of the highly variable nature of TB transmission.

Discovery of a Late Triassic basin north of Boston and some implications as to post-Paleozoic tectonics in northeastern Massachusetts

IFN-gamma receptor-deficient (IFN-gammaR -/-) mice were used to study the innate immune responses during infection with Listeria monocytogenes. Mutant mice were unable to limit bacterial growth and died of sepsis even with an infection dose of 70 Listeria. At day 2, they showed an exacerbated listeriosis and mice succumbed to infection before the onset of an effective specific immunity, demonstrating a defective innate immunity. Recruitment and extravasation of phagocytic cells to infected organs was present and dominated by neutrophils. However, during the early course of infection, mutant mice responded by an elevated inflammatory type 1 cytokine response, as determined by IL-12, IFN-gamma, TNF-alpha, and IL-1alpha-specific RNA expression. Induction of inducible nitric oxide synthase was present and also increased in mutant mice. Interestingly, IFN-gammaR -/- neutrophils expressed substantial TNF-alpha- and IL-1alpha-specific RNA, suggesting a substantial contribution in the overall inflammatory cytokine response. In contrast, IFN-gammaR -/- macrophages showed reduced MHC class II surface expression levels and impaired TNF-alpha and IL-1alpha but normal IL-6 production after restimulation with heat-killed L. monocytogenes. Moreover, IFN-gammaR -/- macrophages showed defective listericidal activities. In contrast to normal macrophages, Listeria escaped rapidly from the phagosome in IFN-gammaR -/- macrophages to the cytoplasm, where they productively survived. In conclusion, these data suggest that IFN-gammaR signaling activates yet unknown functions in macrophages, preventing Listeria-induced escape from the phagosome and consequent killing of the invader. Together with the impaired cytokine responses, these macrophage defects seem to be responsible for the dramatic susceptibility during innate immunity, whereas predominant neutrophil responses mediate limited protective role in mutant mice.

Attempts to Immunize Monkeys Against Plasmodium knowlesi by using Heat-Stable, Serum-Soluble Antigens

Thirty-six Macaca mulatta monkeys were immunized with different concentrations and regimens of heat-stable, serum-soluble (S-) antigens of Plasmodium knowlesi prior to challenge with the homologous parasite via sporozoite inoculation. Fewer deaths and reduced maximum parasitemias occurred in those animals inoculated with 10 to 40 mg of S-antigen compared to nonimmunized monkeys or those receiving only Freund's adjuvant. Protection was incomplete, however, suggesting that atibodies to S-antigens may have a limited role in protection of hosts to malarial infection.

Systemic and urinary immune response in experimental E. coli pyelonephritis of mice.

Serum and urinary immunoglobulin concentrations were determined in mice with experimental &lt;i&gt;Escherichia coli&lt;/i&gt; pyelonephritis; and the results compared to those present in appropriate control animals. A significant increase in serum IgG and IgM concentrations was observed in animals with proven pyelonephritis at four weeks after bladder inoculation. This increase reflected in part an IgG antibody response to &lt;i&gt;E. coli&lt;/i&gt; which did not appear to be protective. No significant increase of urinary immunoglobulin concentrations, including secretory IgA levels, was detected. Specific antibody to &lt;i&gt;E. coli&lt;/i&gt; was not demonstrated in the urines or kidney eluates from the infected or control groups. The results suggest that antibodies within the urinary tract play only a limited protective role in ascending pyelonephritis of mice. These observations might explain the failure of local immunization in protecting mice against ascending &lt;i&gt;E. coli&lt;/i&gt; urinary tract infection.