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Asthma is a syndrome with different inflammatory phenotypes. Animal models have shown that, after sensitization and allergen challenge, Th2 and Th1 cells contribute to the development of allergic airway disease. We have previously demonstrated that naturally occurring regulatory T cells (nTregs) can only marginally suppress Th2-induced airway inflammation and airway hyperresponsiveness. In this study, we investigated nTreg-mediated suppression of Th2-induced and Th1-induced acute allergic airway disease. We demonstrate in vivo that nTregs exert their suppressive potency via cAMP transfer on Th2- and Th1-induced airway disease. A comparison of both phenotypes revealed that, despite similar cAMP transfers, Th1-driven airway hyperresponsiveness and inflammation are more susceptible to nTreg-dependent suppression, suggesting that potential nTreg-based therapeutic strategies might be more effective in patients with predominantly neutrophilic airway inflammation based on deregulated Th1 response.

Previous work has suggested that the LIGHT-TR2 costimulatory pathway plays a role in the acute and chronic stages of dextran sulfate sodium (DSS)-induced colitis [Steinberg et al. (2008); Wang et al. (2005)]. To clarify the role of TNFR-related 2 (TR2) signaling in the maintenance of intestinal homeostasis, we generated a TR2 knock-out (KO) mouse. Using DSS to induce colitis, we compared the colitic symptoms and pathological changes in wild type (WT) and TR2 KO mice, and the production of cytokines by the diseased colons. We also studied the role of TR2 in suppressing innate and adaptive immunity in the DSS model. TR2 deficient mice were characterized by reduced symptoms of intestinal inflammation compared with wild-type mice, and reduced production of cytokines. We therefore generated a monoclonal antibody against mouse TR2 which was specific to TR2 and capable of blocking TR2 signals. With this antibody, we demonstrated that antagonizing TR2 during the development of DSS-induced colitis reduced the symptoms of inflammation. Our findings suggest that TR2 is an important mediator in colitis, and may serve as a therapeutic target in inflammatory bowel disease.

Cyclin-dependent kinase (CDK) inhibitors have been considered as excellent drug candidates for cancer therapy owing to their potential capacity to restore cell cycle control. The first generation of CDK inhibitors showed modest clinical advantages that could be attributed to off-target effects preventing them from reaching therapeutic concentrations. A phase I dose-escalation study using the second generation multi-CDK inhibitor PHA-793887 was conducted on a total of 19 patients with advanced refractory malignancies in two sites in Europe: the University of Leeds and St. James's Institute of Oncology, Leeds, UK, and the Institut Gustave Roussy, Villeujf, France (IGR). Fifteen patients were treated at IGR. Six among these patients manifested the reactivation of herpes virus replication. In vitro experiments revealed that PHA-793887 severely impaired signaling by toll-like receptors (such as TLR3, TLR4 and TLR9) in dendritic cells (DC), thus suppressing the production of multiple cytokines (type 1 interferon, interleukin-6,-10, -12, and tumor necrosis factorα) by mature DC, as well as the DC-stimulated production of interferon-γ by natural killer cells. Pharmacological inhibition of glycogen synthase-3β (GSK-3β), one of the off-targets of PHA-793887, did not cause such immunological defects. Altogether, these data underscore a hitherto unsuspected immunosuppressive effect of PHA-793887.

Formation of germ cell derived teratomas occurs in mice of the 129/SvJ strain, but not in C57Bl/6 inbred or CD1 outbred mice. Despite this, there have been few comparative studies aimed at determining the similarities and differences between teratoma susceptible and non-susceptible mouse strains. This study examines the entry of fetal germ cells into the male pathway and mitotic arrest in 129T2/SvJ mice. We find that although the entry of fetal germ cells into mitotic arrest is similar between 129T2/SvJ, C57Bl/6 and CD1 mice, there were significant differences in the size and germ cell content of the testis cords in these strains. In 129T2/SvJ mice germ cell mitotic arrest involves upregulation of p27(KIP1), p15(INK4B), activation of RB, the expression of male germ cell differentiation markers NANOS2, DNMT3L and MILI and repression of the pluripotency network. The germ-line markers DPPA2 and DPPA4 show reciprocal repression and upregulation, respectively, while FGFR3 is substantially enriched in the nucleus of differentiating male germ cells. Further understanding of fetal male germ cell differentiation promises to provide insight into disorders of the testis and germ cell lineage, such as testis tumour formation and infertility.

Background: Following damage to the intestinal epithelium, restoration of epithelial barrier integrity is triggered by a robust proliferative response. In other tissues, focal adhesion kinase (FAK) regulates many of the cellular processes that are critical for epithelial homeostasis and restitution, including cell migration, proliferation and survival. However, few studies to date have determined how FAK contributes to mucosal wound healing in vivo., Methodology and Principal Findings: To examine the role of FAK in intestinal epithelial homeostasis and during injury, we generated intestinal epithelium (IE)-specific conditional FAK knockout mice. Colitis was induced with dextran-sulfate-sodium (DSS) and intestinal tissues were analyzed by immunohistochemistry and immunoblotting. While intestinal development occurred normally in mice lacking FAK, FAK-deficient animals were profoundly susceptible to colitis. The loss of epithelial FAK resulted in elevated p53 expression and an increased sensitivity to apoptosis, coincident with a failure to upregulate epithelial cell proliferation. FAK has been reported to function as a mechanosensor, inducing cyclin D1 expression and promoting cell cycle progression under conditions in which tissue/matrix stiffness is increased. Collagen deposition, a hallmark of inflammatory injury resulting in increased tissue rigidity, was observed in control and FAK knockout mice during colitis. Despite this fibrotic response, the colonic epithelium in FAK-deficient mice exhibited significantly reduced cyclin D1 expression, suggesting that proliferation is uncoupled from fibrosis in the absence of FAK. In support of this hypothesis, proliferation of Caco-2 cells increased proportionally with matrix stiffness in vitro only under conditions of normal FAK expression; FAK depleted cells exhibited reduced proliferation concomitant with attenuated cyclin D1 expression., Conclusions: In the colon, FAK functions as a regulator of epithelial cell survival and proliferation under conditions of mucosal injury and a mechanosensor of tissue compliance, inducing repair-driven proliferation in the colonic epithelium through upregulation of cyclin D1.

Background: The influence of gender in the clinical expression of COPD has received important attention. Limited information exists regarding gender differences in the skeletal muscle characteristics in COPD subjects. The present study was aimed to determine the differences in the skeletal muscle characteristics in men and women with and without COPD., Methods: For comparison we studied 24 female (61 ± 9 years) and 30 male (65 ± 8 years) COPD patients with similar disease severity. In addition healthy subjects, 17 women (58 ± 8 years), and 9 men (57 ± 8 years) were studied. Pulmonary function, health status, six minute walk distance test (6MWD) and vastus lateralis muscle biopsy were assessed. Fiber type proportion, fiber type cross sectional area (CSA), capillary counts, and activity of citrate synthase (CS), 3-hydroxyacyl-CoA-dehydrogenase (HAD) and lactate-dehydrogenase (LDH) were determined., Results: Pulmonary function, health status and 6MWD were similar in male and female COPD patients. Fiber type distribution was similar between women (I = 42 ± 9%, IIA = 39 ± 13%, IIX = 19 ± 7%) and men (I = 39 ± 13%, IIA = 38 ± 9%, IIX = 29 ± 10%) with COPD, as well as CSA, capillarity and enzymes (CS 8.59 ± 1.6 vs.9.74 ± 2.6, HAD 9.03 ± 1.9 vs. 9.84 ± 2.5, LDH 124 ± 48 vs. 151 ± 68 μmol min(-1) g(-1)). In normal subjects a decrease in type IIX fibers CSA was found in women compared with men (3703 ± 1478 vs. 5426 ± 1386 μm(2), respectively)., Conclusions: Female and male with COPD have similar skeletal muscle characteristics; it is possible that the disease blurs the gender differences. On the other hand, there seems to be fewer differences in muscle characteristics between older men and women, perhaps due to lower male testosterone levels and physical inactivity., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Hepatitis C virus (HCV) is a global problem. To better understand HCV infection researchers employ in vitro HCV cell-culture (HCVcc) systems that use Huh-7 derived hepatoma cells that are particularly permissive to HCV infection. A variety of hyper-permissive cells have been subcloned for this purpose. In addition, subclones of Huh-7 which have evolved resistance to HCV are available. However, the mechanisms of susceptibility or resistance to infection among these cells have not been fully determined. In order to elucidate mechanisms by which hepatoma cells are susceptible or resistant to HCV infection we performed genome-wide expression analyses of six Huh-7 derived cell cultures that have different levels of permissiveness to infection. A great number of genes, representing a wide spectrum of functions are differentially expressed between cells. To focus our investigation, we identify host proteins from HCV replicase complexes, perform gene expression analysis of three HCV infected cells and conduct a detailed analysis of differentially expressed host factors by integrating a variety of data sources. Our results demonstrate that changes relating to susceptibility to HCV infection in hepatoma cells are linked to the innate immune response, secreted signal peptides and host factors that have a role in virus entry and replication. This work identifies both known and novel host factors that may influence HCV infection. Our findings build upon current knowledge of the complex interplay between HCV and the host cell, which could aid development of new antiviral strategies.

The authors have defined some specific features of performance of the immune and lipid-transporting systems in their association with serum cortisol levels in frequently ill children when the signs of an infectious process are absent. The possible links of a pathological process, which give rise to enhanced susceptibility to acute respiratory infections in this patient group, are described.

The following functions of mononuclear phagocytes of 24 patients with rheumatoid arthritis, 24 their relatives, and 24 women, not hereditary tainted with autoimmune diseases (control) were compared: (1) engulfment and digestion (radioisotope method); (2) release of lysosomal glucuronidase during the interaction of cells with opsonized zymosan (fluorescent method). In rheumatoid arthritis the slowed down process of engulfment and preliminary extracellular digestion was combined with accelerated digestive potential. In relatives, the delayed and suppressed engulfment was associated with the decelerated digestive mononuclear phagocyte potential. The congenital peculiarity of the cell functioning was suggested, being due to the imperfect anti infectious defense in predisposed to the disease individuals, on one hand, and to the excessive damage of the surrounding tissues and to the provocation of autoimmune processes.

Nerve agents are acetylcholinesterase inhibitors, exposure to which causes brain damage, primarily by inducing intense seizure activity. Knowledge of the brain regions that are most vulnerable to nerve agent-induced brain damage can facilitate the development of drugs targeting the protection of these regions. Both the amygdala and the hippocampus have been shown to suffer significant damage after nerve agent exposure, but the amygdala appears to be the more severely affected structure. However, damage in the amygdala has generally been compared with damage in the dorsal hippocampus, whereas there is evidence that the ventral hippocampus is significantly more susceptible to seizures than the dorsal region and, therefore, it may also be more susceptible to nerve agent-induced neuropathology. Here, we report that after status epilepticus induced by soman administration to rats, neuronal degeneration as assessed by Fluoro-Jade C staining was more extensive in the ventral than the dorsal hippocampal subfields, 1 day after soman exposure. Seven days later, the difference between dorsal and ventral regions was not statistically significant. In the amygdala, soman-induced neurodegeneration was more severe in the posteroventral regions of the lateral, basolateral, and medial nuclei compared to the anterodorsal regions of these nuclei. In contrast, the basomedial nucleus was more severely affected in the anterodorsal region. The extent of neurodegeneration in the amygdala was not significantly different from that in the ventral hippocampus. However, when compared with the whole hippocampus, the amygdala displayed more severe neurodegeneration, on both day 1 and day 7 after soman exposure. Testing the protective efficacy of drugs against nerve agent-induced brain damage should include examination of the ventral hippocampus and the posteroventral regions of the amygdala, as these areas are most vulnerable to nerve agent-induced neurodegeneration., (Published by Elsevier B.V.)

Purpose: Central nervous system infections greatly increase the risk for the development of seizures and epilepsy (recurrent unprovoked seizures). We have previously shown that Theiler's murine encephalomyelitis virus (Theiler's virus or TMEV) infection causes acute symptomatic seizures in C57BL/6 (B6) mice. The objective of the present study was threefold: (1) to assess pathologic changes associated with acute TMEV infection and infection-induced seizures, (2) to determine whether Theiler's virus infection and associated acute seizures lead to chronically altered seizure susceptibility, and (3) to determine whether genetic background influences seizure susceptibility following Theiler's virus infection., Methods: Immunohistochemical techniques were used to assess Theiler's virus antigen localization in the brain and associated neuronal cell death. A battery of electroconvulsive threshold (ECT) tests and corneal kindling studies were conducted to assess whether there were chronic alterations in seizure susceptibility and kindling development. Studies were conducted in both B6 and SJL/J mice to assess strain-dependent effects., Results: Histopathologic analyses indicate that TMEV has specific tropism for limbic structures and causes widespread cell death in these regions. Results from ECT studies demonstrate that B6 mice that displayed acute symptomatic seizures have significantly reduced seizure thresholds and kindle faster than either control mice or infected mice without acute seizures. Furthermore, these effects were mouse-strain dependent, since SJL/J mice displayed a different seizure threshold spectrum., Discussion: These findings indicate that Theiler's virus infection leads to chronically altered seizure susceptibility in mice. It is important to note that Theiler's virus infection of B6 mice represents a novel model to study postinfection hyperexcitability., (Wiley Periodicals, Inc. © 2009 International League Against Epilepsy.)

Type 1 diabetes is inhibited in diabetes-prone BioBreeding (BBdp) rats fed a low-antigen hydrolyzed casein (HC) diet. In cereal-fed BBdp rats, islet expansion is defective accompanied by a futile upregulation of islet neogenesis without increased islet mass, due to a subtle blockage in islet cell cycle. We hypothesized that islet growth is enhanced before insulitis in HC-fed young BBdp rats and that islet neogenesis could be stimulated by a trophic factor, islet neogenesis-associated protein (INGAP). beta-Cell homeostasis was analyzed using immunohistochemistry, morphometry, laser capture microdissection and RT-PCR in BBdp rats fed HC or cereal diets. beta-cell proliferation in small and medium islets, and the number and area fraction of medium and large islets were increased in HC-fed animals. In situ islet cell cycle analysis revealed an increased proportion of proliferating S + G2 cells in medium and large islets of 25-45 day HC-fed rats. Expression of the cell cycle inhibitor, p16(INK4a) correlated with islet size and the percentage of p16(INK4a+) beta-cells increased in HC-fed BBdp rats, likely reflecting an increase in large islet area fraction. In HC-fed rats, extra-islet insulin(+) clusters (EIC), insulin(+) duct cells, large islet area fraction, and beta-cell mass were increased. Neurogenin-3 and Pdx-1, markers of beta-cell progenitors, were increased in EIC of weanling HC-fed rats. Daily injection of INGAP (30-45 days) increased the number of small islets, total islets, and insulin(+) cells in small ducts. Thus, in BBdp rats fed a protective HC diet, beta-cell expansion is enhanced through increased beta-cell proliferation and stimulation of islet neogenesis.

A20 is a nuclear factor kappaB (NF-kappaB) target gene that encodes a ubiquitin-editing enzyme that is essential for the termination of NF-kappaB activation after tumor necrosis factor (TNF) or microbial product stimulation and for the prevention of TNF-induced apoptosis. Mice lacking A20 succumb to inflammation in several organs, including the intestine, and A20 mutations have been associated with Crohn's disease. However, ablation of NF-kappaB activity, specifically in intestinal epithelial cells (IECs), promotes intestinal inflammation. As A20 deficiency sensitizes cells to TNF-induced apoptosis yet also promotes NF-kappaB activity, it is not clear if A20 deficiency in IECs would exacerbate or ameliorate intestinal inflammation. We generated mice lacking A20 specifically in IECs. These mice did not show spontaneous intestinal inflammation but exhibited increased susceptibility to experimental colitis, and their IECs were hypersensitive to TNF-induced apoptosis. The resulting TNF-driven breakdown of the intestinal barrier permitted commensal bacterial infiltration and led to systemic inflammation. These studies define A20 as a major antiapoptotic protein in the intestinal epithelium and further indicate that defects in A20 might contribute to inflammatory bowel disease in humans.

Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis, which is crucial for development and metastasis of tumors including hepatocellular carcinoma (HCC), and elevated VEGF levels in serum and tissues have been known to be related with poor prognosis in patients with HCC. Polymorphisms in VEGF may alter VEGF protein concentrations, influence the process of angiogenesis, and may relate to interindividual variation in tumorigenesis. In this study, we carried out a case-control study in a Chinese population (206 cases and 302 controls) to estimate the susceptibility to HCC associated with an 18-bp insertion/deletion polymorphism (rs35569394) in the promoter region of VEGF. After adjusting the data by gender, age, smoking status, drinking status, and hepatitis B virus (HBV) infection using logistic regression model, we found that rs35569394 was not associated with HCC, at both the allele and genotype levels. Thus, rs35569394 should not be viewed as a major contributor to the development of HCC in Chinese.

Cardiac hypertrophy is a common response to hemodynamic stress in the heart and can progress to heart failure. To investigate whether the transcription factor cardiovascular basic helix-loop-helix factor 1/hairy/enhancer of split related with YRPW motif 2 (CHF1/Hey2) influences the development of cardiac hypertrophy and progression to heart failure under conditions of pressure overload, we performed aortic constriction on 12-wk-old male wild-type (WT) and heterozygous (HET) mice globally underexpressing CHF1/Hey2. After aortic banding, WT and HET mice showed increased cardiac hypertrophy as measured by gravimetric analysis, as expected. CHF1/Hey2 HET mice, however, demonstrated a greater increase in the ventricular weight-to-body weight ratio compared with WT mice (P < 0.05). Echocardiographic measurements showed a significantly decreased ejection fraction compared with WT mice (P < 0.05). Histological examination of Masson trichrome-stained heart tissue demonstrated extensive fibrosis in HET mice compared with WT mice. TUNEL staining demonstrated increased apoptosis in HET hearts (P < 0.05). Exposure of cultured neonatal myocytes from WT and HET mice to H(2)O(2) and tunicamycin, known inducers of apoptosis that work through different mechanisms, demonstrated significantly increased apoptosis in HET cells compared with WT cells (P < 0.05). Expression of Bid, a downstream activator of the mitochondrial death pathway, was expressed in HET hearts at increased levels after aortic banding. Expression of GATA4, a transcriptional activator of cardiac hypertrophy, was also increased in HET hearts, as was phosphorylation of GATA4 at Ser(105). Our findings demonstrate that CHF1/Hey2 expression levels influence hypertrophy and the progression to heart failure in response to pressure overload through modulation of apoptosis and GATA4 activity.

Seventeen striped dolphins (Stenella coeruleoalba) displaying swimming disorders compatible with neurological syndromes were investigated for Brucella infection. Sixteen dolphins had meningoencephalomyelitis. Serum antibody against Brucella antigen was detected in all 14 animals tested and Brucella ceti was isolated from eight out of nine animals. Brucella antigen was detected in the brain by immunofluorescence, but not by immunohistochemical labelling. By contrast, Brucella antigen was demonstrated by immunohistochemistry in the trophoblast of animals with severe placentitis and in the mitral valve of animals with myocarditis. The microscopical lesions observed in the tissues of the infected dolphins were similar to those of chronic brucellosis in man. The severity of brucellosis in S. coeruleoalba indicates that this dolphin species is highly susceptible to infection by B. ceti., (Copyright 2009 Elsevier Ltd. All rights reserved.)

The recent epidemic caused by H5N1 highly pathogenic avian influenza (HPAI) viruses has spread over many parts of Asia, Europe and Africa. Wild birds, particularly waterfowl, are considered to play a role in viral dissemination. However, detailed information on whether wild terrestrial birds act as carriers is currently unavailable. To investigate the susceptibility of terrestrial birds to HPAI viruses, two species of wild bird (great reed warbler and pale thrush) that are common in East Asia were infected with H5N1 HPAI virus. The results showed that both species were highly susceptible to the virus. The great reed warbler showed fatal infection with 100% mortality, but the pale thrush survived for longer periods (>8 days) with viral shedding. These findings suggest that there is variation in clinical outcome after infection of wild terrestrial birds, and that some bird species could become subclinical excretors of the H5N1 virus.

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system characterized by relapses and remissions. The risk of acquiring this complex disease is associated with exposure to environmental factors in genetically susceptible individuals. The epidemiology of MS has been extensively studied. We review the geographic epidemiology of the disease, the influence of immigration, age at immigration, clustering and epidemics. Various presumptive risk factors are discussed such as ultraviolet radiation, vitamin D, Epstein-Barr virus and infectious mononucleosis, other infectious agents and non-infectious factors. Two different hypotheses, the hygiene hypothesis and the prevalence hypothesis, were proposed to explain these environmental risk factors for MS. The epidemiological data, combined with pathological and immunological data, may contribute to the debate whether MS is an autoimmune disease, a latent or persistent viral disease, or a neurodegenerative disease., (2009 Elsevier B.V. All rights reserved.)

Limited experimental models exist to assess drug toxicity in pediatric populations. We recently reported how a multi-age rat model could be used for pre-clinical studies of comparative drug toxicity in pediatric populations. The objective of this study was to expand the utility of this animal model, which previously demonstrated an age-dependent sensitivity to the classic nephrotoxic compound, gentamicin, to another nephrotoxicant, namely cisplatin (Cis). Sprague-Dawley rats (10, 25, 40 and 80 days old) were injected with a single dose of Cis (0, 1, 3 or 6 mg kg(-1) i.p.). Urine samples were collected prior and up to 72 h after treatment in animals that were >or= 25 days old. Several serum, urinary and 'omic' injury biomarkers as well as renal histopathology lesions were evaluated. Statistically significant changes were noted with different injury biomarkers in different age groups. The order of age-related Cis-induced nephrotoxicity was different than our previous study with gentamicin: 80 > 40 > 10 > 25 day-old vs 10 >or= 80 > 40 > 25-day-old rats, respectively. The increased levels of kidney injury molecule-1 (Kim-1: urinary protein/tissue mRNA) provided evidence of early Cis-induced nephrotoxicity in the most sensitive age group (80 days old). Levels of Kim-1 tissue mRNA and urinary protein were significantly correlated to each other and to the severity of renal histopathology lesions. These data indicate that the multi-age rat model can be used to demonstrate different age-related sensitivities to renal injury using mechanistically distinct nephrotoxicants, which is reflected in measurements of a variety of metabolite, gene transcript and protein biomarkers.

Influenza viral infection is well-known to predispose to subsequent bacterial superinfection in the lung but the mechanisms have remained poorly defined. We have established a murine model of heterologous infections by an H1N1 influenza virus and Staphylococcus aureus. We found that indeed prior influenza infection markedly increased the susceptibility of mice to secondary S. aureus superinfection. Severe sickness and heightened bacterial infection in flu and S. aureus dual-infected animals were associated with severe immunopathology in the lung. We further found that flu-experienced lungs had an impaired NK cell response in the airway to subsequent S. aureus bacterial infection. Thus, adoptive transfer of naive NK cells to the airway of prior flu-infected mice restored flu-impaired antibacterial host defense. We identified that TNF-alpha production of NK cells played an important role in NK cell-mediated antibacterial host defense as NK cells in flu-experienced lungs had reduced TNF-alpha expression and adoptive transfer of TNF-alpha-deficient NK cells to the airway of flu-infected mice failed to restore flu-impaired antibacterial host defense. Defected NK cell function was found to be an upstream mechanism of depressed antibacterial activities by alveolar macrophages as contrast to naive wild-type NK cells, the NK cells from flu-infected or TNF-alpha-deficient mice failed to enhance S. aureus phagocytosis by alveolar macrophages. Together, our study identifies the weakened NK cell response in the lung to be a novel critical mechanism for flu-mediated susceptibility to bacterial superinfection.

Mammographic density for age and body mass index (BMI) is a heritable risk factor for breast cancer. We aimed to determine if recently identified common variants associated with small gradients in breast cancer risk are associated with mammographic density. We genotyped 497 monozygotic and 330 dizygotic twin pairs and 634 of their sisters from 903 families for 12 independent variants. Mammographic dense area, percent dense area, and nondense area were measured by three observers using a computer-thresholding technique. Associations with mammographic density measures adjusted for age, BMI, and other determinants were estimated (a) cross-sectionally using a multivariate normal model for pedigree analysis (P(x)), (b) between sibships, and (c) within sibships using orthogonal transformations of outcomes and exposures. A combined test of association (P(c)) was derived using the independent estimates from b and c. We tested if the distributions of P values across variants differed from the uniform distribution (P(u)). For dense area and percent dense area, the distributions of P(c) values were not uniform (both P(u) <0.007). Consistent with their breast cancer associations, rs3817198 (LSP1) and rs13281615 (8q) were associated with dense area and percent dense area (all P(x) and P(c) <0.05), and rs889312 (MAP3K1), rs2107425 (H19), and rs17468277 (CASP8) were marginally associated with dense area (some P(x) or P(c) <0.05). All associations were independent of menopausal status. At least two common breast cancer susceptibility variants are associated with mammographic density measures that predict breast cancer. These findings could help elucidate how those variants and mammographic density measures are associated with breast cancer susceptibility.

Background: The anthracycline doxorubicin is an effective chemotherapeutic agent used to treat pediatric cancers but is associated with cardiotoxicity that can manifest many years after the initial exposure. To date, very little is known about the mechanism of this late-onset cardiotoxicity., Methods and Results: To understand this problem, we developed a pediatric model of late-onset doxorubicin-induced cardiotoxicity in which juvenile mice were exposed to doxorubicin, using a cumulative dose that did not induce acute cardiotoxicity. These mice developed normally and had no obvious cardiac abnormalities as adults. However, evaluation of the vasculature revealed that juvenile doxorubicin exposure impaired vascular development, resulting in abnormal vascular architecture in the hearts with less branching and decreased capillary density. Both physiological and pathological stress induced late-onset cardiotoxicity in the adult doxorubicin-treated mice. Moreover, adult mice subjected to myocardial infarction developed rapid heart failure, which correlated with a failure to increase capillary density in the injured area. Progenitor cells participate in regeneration and blood vessel formation after a myocardial infarction, but doxorubicin-treated mice had fewer progenitor cells in the infarct border zone. Interestingly, doxorubicin treatment reduced proliferation and differentiation of the progenitor cells into cells of cardiac lineages., Conclusions: Our data suggest that anthracycline treatment impairs vascular development as well as progenitor cell function in the young heart, resulting in an adult heart that is more susceptible to stress.

Absolute quantification of cerebral blood flow, cerebral blood volume and mean transit time is desirable in the determination of tissue viability thresholds and tissue at risk in acute ischaemic stroke, as well as in cases where a global reduction in cerebral blood flow is expected, for example, in patients with dementia or depressive disorders. Absolute values are also useful when comparing sequential examinations of tissue perfusion parameters, for example, in the monitoring and follow-up of various kinds of therapy. Regardless of the method employed, a number of assumptions and approximations must be made to obtain absolute measures of perfusion. Furthermore, the different stages of data acquisition and processing are associated with various degrees of uncertainty. In this review, the problems of particular relevance to absolute quantification of cerebral perfusion parameters using dynamic susceptibility contrast magnetic resonance imaging are discussed, and possible solutions are outlined.

Susceptibility weighted imaging provides diagnostic information in strokes, hemorrhages, and cerebral tumors and has proven to be a valuable tool in imaging venous vessels in the cerebrum. The SWI principle is based on the weighting of T(2)* weighted magnitude images with a phase mask, therewith improving image contrast of veins or neighbouring structures of different susceptibility, in general. T(2)* weighted MRI is already used for assessment of kidney function. In this paper, the feasibility of SWI on kidneys was investigated. Translation of SWI from the brain to the kidneys comes along with two main challenges: (i) organ motion due to breathing and (ii) a higher oxygenation level of renal veins compared to the brain. To handle these problems, the acquisition time has been cut down to allow for breath-hold examinations, and different post-processing methods including a new phase mask were investigated to visualize renal veins. Results showed that by a new post-processing strategy SWI contrast was enhanced on average by a factor of 1.33 compared to the standard phase mask. In summary, initial experiences of SWI on the kidneys demonstrated the feasibility. However, further technical developments have to be performed to make this technology applicable in clinical abdominal MRI., (2010. Published by Elsevier GmbH.)

Background: Chinook, or föhn, is a weather phenomenon characterized by a rapid influx of warm, high-pressured winds into a specific location. Pressure changes associated with chinook winds induce facial pain similar to acute sinusitis. The purpose of this study was to determine the relationship between sinonasal anatomy and chinook headaches., Methods: Retrospective computed tomography (CT) sinonasal anatomy analysis of 38 patients with chinook headaches and 27 controls (no chinook headaches). The chinook headache status was blinded from the CT reviewer. Forty-one sinonasal anatomy variants, Lund-Mackay status, and sinus size (cm(3)) were recorded., Results: There were three statistically significant sinonasal anatomy differences between patients with and without chinook headaches. The presence of a concha bullosa and sphenoethmoidal cell (Onodi cell) appeared to predispose to chinook headaches (p = 0.004). Chinook headache patients had larger maxillary sinus size (right, p = 0.015, and left, p = 0.002). The Lund-Mackay score was higher in the control patients (p = 0.003) indicating that chronic sinusitis does not play a role in chinook headaches., Conclusion: Chinook winds are a common source of facial pain and pressure. This is the first study to show that sinonasal anatomic variations may be a predisposing factor. Anatomic variants may induce facial pain by blocking the natural sinus ostia, thus preventing adequate pressure equilibrium.

In our previous studies, WBN/KobSlc was characterized as a rat strain in which only males began to develop pancreatitis, and then presented with diabetic symptoms. In the course of studying their pancreatic inflammation, we detected molar caries in prediabetic males feeding on a standard diet (CRF-1) widely used for experimental animals. The purpose of this study is to confirm whether the WBN/KobSlc strain is caries-susceptible to the diet reported to be non-cariogenic, and to examine the effect of a prediabetic condition on their dental caries. For a morphological study, 25 male WBN/KobSlc rats aged 3.2-7.8 months and 24 females of the same strain aged 3.3-6.6 months were used, along with 10 males and 10 females of 8.2-month-old F344 rats. Marked dental caries were detected in the mandibular molars of male and female WBN/KobSlc rats regardless of pancreatitis, although no similar changes were observed in any teeth of the F344 strain fed the same diet. Soft X-ray examination revealed that the caries began in the crown and progressed horizontally and vertically, and that a severe radiolucent lesion extensively expanded to the entire crown, corresponding to a macroscopically deleted molar. The caries had gradually developed mainly in the second mandibular molar from more than 3.5 months of age, while none were seen in any rats before that time. The WBN/KobSlc rats were caries-susceptible even to the standard laboratory diet, and pancreatitis was not directly associated with the onset of dental caries in this strain.

Background: Structural brain abnormalities have been described in individuals with an at-risk mental state for psychosis. However, the neuroanatomical underpinnings of the early and late at-risk mental state relative to clinical outcome remain unclear., Aims: To investigate grey matter volume abnormalities in participants in a putatively early or late at-risk mental state relative to their prospective clinical outcome., Method: Voxel-based morphometry of magnetic resonance imaging data from 20 people with a putatively early at-risk mental state (ARMS-E group) and 26 people with a late at-risk mental state (ARMS-L group) as well as from 15 participants with at-risk mental states with subsequent disease transition (ARMS-T group) and 18 participants without subsequent disease transition (ARMS-NT group) were compared with 75 healthy volunteers., Results: Compared with healthy controls, ARMS-L participants had grey matter volume losses in frontotemporolimbic structures. Participants in the ARMS-E group showed bilateral temporolimbic alterations and subtle prefrontal abnormalities. Participants in the ARMS-T group had prefrontal alterations relative to those in the ARMS-NT group and in the healthy controls that overlapped with the findings in the ARMS-L group., Conclusions: Brain alterations associated with the early at-risk mental state may relate to an elevated susceptibility to psychosis, whereas alterations underlying the late at-risk mental state may indicate a subsequent transition to psychosis.

Rationale: Myocardial infiltrating macrophages play an important role in the pathogenesis of viral myocarditis in male BALB/c mice following coxsackievirus B3 (CVB3) infection. Interestingly, comparable macrophage numbers were observed in the myocardium of female mice during acute myocarditis., Objective: Given CVB3 infection causes severe myocarditis in male but not female mice, we postulated that macrophages infiltrating the myocardium of female mice may display distinct functional properties that contribute to differential susceptibility to CVB3 myocarditis., Methods and Results: Here, we found that myocardial infiltrating macrophages from CVB3-infected male mice expressed high levels of classically activated macrophages (M1) markers, including inducible nitric oxide synthase, interleukin-12, tumor necrosis factor-alpha, and CD16/32, whereas those of females showed enhanced expression of arginase 1, interleukin-10, macrophage mannose receptor (MMR) and macrophage galactose type C-type lectin (MGL) that were associated with alternatively activated macrophage (M2) phenotype. Moreover, distinct myocardial-derived cytokines were found to play a critical role in differential macrophage polarization between sexes after CVB3 infection. Adoptive transfer of ex vivo programmed M1 macrophages, as expectedly, significantly increased myocarditis in both male and female mice. Strikingly, transfer of M2 macrophages into susceptible male mice remarkably alleviated myocardial inflammation by modulating local cytokine profile and promoting peripheral regulatory T cell (Treg) differentiation., Conclusions: Taken together, this study may facilitate the understanding of the mechanism underlying gender bias in susceptibility to CVB3 myocarditis and the development of therapeutic strategies based on macrophage polarization for inflammatory heart disease.

Dupuytren's disease has a high rate of recurrence after treatment. In this study we have assessed the usefulness of histological staging in the prediction of recurrence. We have also verified whether there is a correlation between histological staging and features of Dupuytren's diathesis. We studied 139 hands in 124 Caucasian patients treated between 1997 and 2004. There was a significant difference in the recurrence rate between the three histological types (P = 0.04). Histological staging was independent of features of Dupuytren's diathesis. This study confirms that histological staging is a reliable method for predicting recurrence. However, it should be used in association with clinical data to determine precisely the prognosis of patients suffering from Dupuytren's contracture.

The objective of this study was to compare foot skin patterns from cadavers of 98 men who died from a drug overdose and 50 male suicide victims (as confirmed postmortem inquiries) with those in control samples (from 166 cadavers of men who died from other causes). Dermatoglyphic patterns of the sole and toes in the two former groups were found to have a number of specific and unidirectional features that allowed them to be distinguished from controls. Both drug addicts and self-murderers showed reduced occurrence of fibular loops and higher frequency of whorl patterns on the third toe of the right foot. The frequency of main sole line A termini in the two study groups was reduced in field 1' on either foot and in field 7 on the right one. The same proved true of line E in field 1" on the left foot. An increased ridge count was documented on the first toe of the right foot and on the second toe of the left foot.

Objective: To investigate whether the severity and location of cerebral white matter hyperintensities (WMHs) and brain infarcts are correlated with the signs of retinal microvascular abnormalities in the elderly., Methods: The study included 4,176 men and women (mean age, 76 years) who participated in the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. Digital retinal images of both dilated eyes were taken and evaluated for the presence of retinal focal arteriolar signs (focal arteriolar narrowing and arteriovenous nicking) and retinopathy lesions (retinal blot hemorrhages and microaneurysms). Brain magnetic resonance imaging scans were acquired and evaluated for the presence and distribution of cerebral infarcts and WMHs. Logistic and multinomial logistic models were constructed to estimate the association of retinal microvascular signs to brain lesions., Results: Controlling for demographic and major cardiovascular risk factors, we found that retinal focal arteriolar signs, but not retinopathy lesions, were significantly associated with an increasing load of subcortical and periventricular WMHs. The strongest association was found between retinal arteriolar signs and a heavier WMH load, specifically in the subcortical frontal lobe, and periventricular frontal and parietal caps. There was a tendency toward bilateral retinal focal arteriolar narrowing being more strongly associated with the heavier load of subcortical WMHs. Arteriovenous nicking was significantly associated with subcortical infarcts., Interpretation: In older adults, retinal focal arteriolar signs, but not retinopathy lesions, are correlated with the load of diffuse WMHs, particularly those located in the subcortical frontal lobe, and the periventricular frontal and parietal caps of the brain.

The brain disturbances that place a person at risk for developing depression are unknown. We imaged the brains of 131 individuals, ages 6 to 54 years, who were biological descendants (children or grandchildren) of individuals identified as having either moderate to severe, recurrent, and functionally debilitating depression or as having no lifetime history of depression. We compared cortical thickness across high- and low-risk groups, detecting large expanses of cortical thinning across the lateral surface of the right cerebral hemisphere in persons at high risk. Thinning correlated with measures of current symptom severity, inattention, and visual memory for social and emotional stimuli. Mediator analyses indicated that cortical thickness mediated the associations of familial risk with inattention, visual memory, and clinical symptoms. These findings suggest that cortical thinning in the right hemisphere produces disturbances in arousal, attention, and memory for social stimuli, which in turn may increase the risk of developing depressive illness.

Objective: To analyze a hypothesis regarding the pathogenesis of endometriosis., Design: Retrospective study., Setting: Two academic endometriosis referral centers., Patient(s): We evaluated operative and pathologic reports of 251 women who underwent laparoscopic or laparotomy treatment of endometrioma from August 1996 to February of 2002 at Yale University School of Medicine and at the University of Crete Department of Obstetrics and Gynecology., Intervention(s): Laparascopic examination., Main Outcome Measure(s): Statistical methods included chi(2) and Mann-Whitney U tests measuring incidence of right- vs. left-sided endometria., Result(s): One hundred seventy patients from Yale University and 81 Greek patients participated in this study. Endometrioma was significantly more frequent in the left ovary (139 of 206 [67.4%]) than in the right ovary (67 of 206 [32.6%]; odds ratio [OR] = 4.3; 95% confidence interval [CI) 2.9-6.5; chi(2) = 48.9) and significantly different from the expected proportion of 50% (chi(2) = 25.2). When bilateral endometriomas were included, 62.1% (184 of 296) were left-sided and 37.15 (112 of 296) were right-sided (OR = 17.5; 95% CI 1.9-3.8; chi(2) = 34.1). Dilated ovarian veins in were found in 22 (68.7%) of 32 Greek cases with endometrioma. All 20 women with left endometrioma had left ovarian vein dilated., Conclusion(s): We suggest a new mechanical theory of implication, the female varicocele theory, which could play an important role in the development of ovarian endometriosis or endometriomas.

In a cross-sectional, population-based study in Tromsø, Norway, the authors investigated correlations between lumen diameter in the right common carotid artery (CCA) and the diameters of the femoral artery and abdominal aorta and whether CCA lumen diameter was a risk factor for abdominal aortic aneurysm (AAA). Ultrasonography was performed in 6,400 men and women aged 25-84 years during 1994-1995. An AAA was considered present if the aortic diameter at the level of renal arteries was greater than or equal to 35 mm, the infrarenal aortic diameter was greater than or equal to 5 mm larger than the diameter of the level of renal arteries, or a localized dilation of the aorta was present. CCA lumen diameter was positively correlated with abdominal aortic diameter (r = 0.3, P < 0.01) and femoral artery diameter (r = 0.2, P < 0.01). In a multivariable adjusted model, CCA lumen diameter was a significant predictor of AAA in both men and women (for the fifth quintile vs. the third, odds ratios were 1.9 (95% confidence interval: 1.2, 2.9) and 4.1 (95% confidence interval: 1.5, 10.8), respectively). Thus, CCA lumen diameter was positively correlated with femoral and abdominal aortic artery diameter and was an independent risk factor for AAA.

Transcription factors, including the basic helix-loop-helix (bHLH) family, regulate numerous genes and play vital roles in controlling gene expression. Consequently, transcription factor mutations can lead to phenotypic pleiotropy, and may be a candidate mechanism underlying the complex genetics and heterogeneous phenotype of schizophrenia. Neurogenin1 (NEUROG1; a.k.a. Ngn1 or Neurod3), a bHLH transcription factor encoded on a known schizophrenia linkage region in 5q31.1, induces glutamatergic and suppresses GABAergic neuronal differentiation during embryonic neurodevelopment. The goal of this study is to investigate NEUROG1 effects on schizophrenia risk and on phenotypic features of schizophrenia. We tested 392 patients with schizophrenia or schizoaffective disorder and 226 healthy normal volunteers for association with NEUROG1. Major alleles on two NEUROG1-associated SNPs (rs2344484-C-allele and rs8192558-G-allele) were significantly more prevalent among patients (p

The rise of immunocompromised individuals in our society has provoked a significant emergence in the number of patients affected by opportunistic pathogenic yeast. The microorganisms with a major clinical incidence are species from the genera Candida (especially Candida albicans) and Cryptococcus (particularly Cryptococcus neoformans), although there has been a significant increase in other pathogenic yeasts, such as Trichosporon spp. and Rhodotorula spp. In addition, there are an increasing number of patients infected by yeasts that were not previously considered as pathogenic, such as Saccharomyces cerevisiae. The management of these infections is complicated and is highly dependent on the susceptibility profile not only of the species but also of the strain. The available antifungal compounds belong mainly to the polyene, azole and candin families, which show a distinct spectrum of activity. This review summarizes the current knowledge about the use of the main antifungals for treating infections caused by the yeast species with the most significant clinical relevance, including the susceptibility profiles exhibited by these species in vitro.

The present study was aimed at isolation and characterization of the pathogenic bacterium from diseased freshwater prawn. The effect of the bacterial pathogen on hepatopancreas, gills and exoskeleton was also investigated. Diseased freshwater prawn, Macrobrachium rosenbergii were collected from commercial hatchery in Behera Governorate, Egypt. The diseased prawn showed dark brown focal lesions and necrosis of appendage tips. The causative bacterial pathogen was isolated from haemolymph and hepatopancreas of the diseased prawn. Based on the morphological, biochemical and physiological characteristics, in addition EPI 20E test, the isolated pathogen was characterized as Vibrio vulnificus. Histopathology, hepatopancreas showed haemocytic infiltration in the interstitial sinuses, thickening and ruptures of the basal lamina and necrosis of its tubules. Similarly, the accumulation of haemocytes in the haemocoelic space, swelling, fusion of lamellae and abnormal gill tips. Also, the cuticular layers of the exoskeleton of diseased prawn had a rough or wrinkled surface and were disrupted and separated from the epidermis. The pathogen, V. vulnificus showed different degrees of sensitivity to different antimicrobial agents. It was highly sensitive to each of the antibiotics rifadin, virbamycin, oflaxcin, garamycin, flummox and trimethoprim/sulfamethoxzole) and resistant to nalidixic acid, unasyn, velosef, claforan, negram and amoxicillin. The minimal inhibitory concentration of trimethoprin/sulfamethoxzole for the studied pathogen, V. vulnificus was 0.31/5.93 microg.

Purpose: The effects of maternal systemic lupus erythematosus (SLE) on neonatal prognosis were examined by comparing clinical features of full-term babies born to lupus mothers and age- and parity-matched controls., Patients and Methods: From January 2000 to December 2005, 39 singletons were born to 37 SLE women. Excluding 11 cases of prematurity and preeclampsia, 28 full-term neonates formed the lupus group. The control group included 66 full-term babies. The retrospective study examined medical records and compared gestational age, birth weight, days of hospital stay, small for gestational age (SGA) frequency, Apgar scores < 7, and parity. Lupus neonates were tested for anti-nuclear antibody (ANA) and platelet count, and electrocardiogram was performed., Results: Average gestational age (38 vs. 39 weeks, p < 0.05) and birth weight (2,775 vs. 3,263g, p < 0.05) were significantly different between the SLE and control groups. SGA frequency was higher in the SLE group (25% vs. 4.5%, p < 0.05). No significant difference was observed in Apgar score, birth weight, gestational age, SGA frequency, and platelet count between lupus subgroups formed based on anti-dsDNA antibody levels and antiphospholipid antibody status., Conclusion: The association of maternal ANAs, antiphospholipid antibodies, and drug history with neonatal prognosis could not be elucidated. However, even in uncomplicated pregnancies, maternal lupus is disadvantageous for gestational age, birth weight, and SGA frequency.

Th cells can be subdivided into IFN-gamma-secreting Th1, IL-4/IL-5-secreting Th2, and IL-17-secreting Th17 cells. We have evaluated the capacity of fully differentiated Th1, Th2, and Th17 cells derived from a mouse bearing a transgenic TCR specific for the gastric parietal cell antigen, H(+)K(+)-ATPase, to induce autoimmune gastritis after transfer to immunodeficient recipients. We have also determined the susceptibility of the disease induced by each of the effector T cell types to suppression by polyclonal regulatory T cells (Treg) in vivo. Each type of effector cell induced autoimmune gastritis with distinct histological patterns. Th17 cells induced the most destructive disease with cellular infiltrates composed primarily of eosinophils accompanied by high levels of serum IgE. Polyclonal Treg could suppress the capacity of Th1 cells, could moderately suppress Th2 cells, but could suppress Th17-induced disease only at early time points. The major effect of the Treg was to inhibit the expansion of the effector T cells. However, effector cells isolated from protected animals were not anergic and were fully competent to proliferate and produce effector cytokines ex vivo. The strong inhibitory effect of polyclonal Treg on the capacity of some types of differentiated effector cells to induce disease provides an experimental basis for the clinical use of polyclonal Treg in the treatment of autoimmune disease in humans.

We used an in vitro model of differentiated tracheobronchial epithelium to analyze the susceptibility of different cell types to infection with rhinoviruses (RVs). Primary cells from control subjects were cultured in an air-liquid interface to form differentiated epithelia. Suprabasal and basal fractions were separated after trypsin digestion, and cell suspensions were infected with serotypes RV16 and RV1A. These cell fractions were analyzed for expression of viral capsid protein VP2 (flow cytometry), viral replication (real-time PCR), cytokeratin-14, and intercellular adhesion molecule-1 (ICAM-1). Compared with suprabasal fraction, basal cells had increased percentages of cells staining positive for VP2 (RV1A: 37.8% versus 9.1%, P < 0.01; RV16: 12.0 versus 3.0%, P < 0.05). The average number of viral RNA copies per cell was also higher in basal cells (2.2- and 2.4-fold increase in RV1A- and RV16-infected cells, respectively) compared with suprabasal cells. Furthermore, ICAM-1 was expressed by 33.3% of basal cells, compared with 8.1% of suprabasal cells (P < 0.05). Finally, in culture models of epithelial injury (detached suprabasal cells or scratched surface), there was significantly greater replication of RV1A compared with intact cell layer. These findings demonstrate that basal cells are more susceptible to RV infection than suprabasal cells. For major group RV, this may be in part due to increased expression of ICAM-1; however, minor group RV also replicated more effectively in basal cells. These results suggest the possibility that epithelial cell differentiation is associated with the maturation of antiviral defense mechanisms.

Leishmaniases are a major international public health problem, and macrophages are crucial for host resistance to this parasite. To determine if phosphatase and tensin homologue deleted on chromosome ten (Pten), a negative regulator of the PI3K pathway, plays a role in macrophage-mediated resistance to Leishmania, we generated C57BL/6 mice lacking Pten specifically in macrophages (LysMCrePten(flox/flox) mice). Examination of lesions resulting from Leishmania major infection showed that LysMCrePten(flox/flox) mice were more susceptible to the parasite than wild-type (WT) mice in the early phase of the infection, but were eventually able to eliminate the pathogen. In vitro Pten-deficient macrophages showed a reduced ability to kill parasites in response to IFN-gamma treatment, possibly because the mutant cells exhibited decreased TNF secretion that correlated with reductions in inducible nitric oxide synthase expression and nitric oxide production. In response to various TLR ligands, Pten-deficient macrophages produced less TNF and IL-12 but more IL-10 than WT cells. However, analysis of cells in the lymph nodes draining L. major inoculation sites indicated that both LysMCrePten(flox/flox) and WT mice developed normal Th1 responses following L. major infection, in line with the ability of LysMCrePten(flox/flox) mice to eventually eliminate the parasite. Our results indicate that the efficient clearance of intracellular parasites requires Pten in macrophages.

Previous studies have provided evidence that a quantitative trait locus (QTL) on the distal part of chromosome 18 (chr18) is a major determinant of vulnerability to hippocampal neurodegeneration following kainic acid (KA)-induced seizures in inbred mouse strains. We assessed excitotoxic vulnerability in two congenic, "genome tagged" mouse strains carrying segments of either distal or proximal/medial chr18 from vulnerable DBA/2J mice on a resistant C57BL/6 background. Systemic KA injections triggered brain-wide neurodegeneration in the distal chr18 congenic strain, and specifically in the hilus of the dentate gyrus, but not in CA3. In contrast, the proximal/medial chr18 congenic strain exhibited enhanced degeneration in CA1 and CA3, but little neurodegeneration elsewhere. Both strains exhibited low levels of QUIN-induced striatal neurodegeneration comparable to what is seen in C57BL/6 mice. These results suggest that gene(s) on distal chr18 are important determinants of vulnerability to KA-induced hippocampal neurodegeneration, but not QUIN-induced striatal neurodegeneration.

Adoptive cellular immunotherapy inducing a graft-versus-tumor (GVT) effect is the therapeutic mainstay of allogeneic hematopoietic stem cell transplantation (ASCT) for high-risk leukemias. Autologous immunotherapies using vaccines or adoptive transfer of ex vivo-manipulated lymphocytes are clinically explored in patients with various cancer entities. Main reason for failure of ASCT and cancer immunotherapy is progression of the underlying malignancy, which is more prevalent in patients with advanced disease. Elucidating the molecular mechanisms contributing to immune escape will help to develop strategies for the improvement of immunologic cancer treatment. To this end, we have undertaken functional screening and expression cloning of factors mediating resistance to antigen-specific cytotoxic T lymphocytes (CTLs). We have identified Cdc42, a GTPase regulating actin dynamics and growth factor signaling that is highly expressed in invasive cancers, as determinator of cancer cell susceptibility to antigen-specific CTLs in vitro and adoptively transferred immune effectors in vivo. Cdc42 prevents CTL-induced apoptosis via mitogen-activated protein kinase (MAPK) signaling and posttranscriptional stabilization of Bcl-2. Pharmacologic inhibition of MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK) overcomes Cdc42-mediated immunoresistance and activation of Bcl-2 in vivo. In conclusion, Cdc42 signaling contributes to immune escape of cancer. Targeting Cdc42 may improve the efficacy of cancer immunotherapies.

In this paper, we report an inhibitor antibody to factor XI (FXI) in a woman with severe inherited FXI deficiency, induced by FXI present in an Rh immune globulin preparation. The patient is homozygous for the Glu117Stop mutation, associated with a FXI level of less than 1 U/dL. Unlike all previously described patients with severe FXI deficiency and an inhibitor, the patient had never been exposed to blood products. Following 3 injections of Rh immune globulin during pregnancy, she developed an inhibitor to FXI (8 Bethesda units) that was shown to bind specifically to FXI and inhibit factor IX cleavage by purified FXIa. The administered Rh immune globulin and 2 other similar products were shown to contain FXI. Clinicians should be aware of the potential for immunization of severely FXI-deficient patients by FXI present in Rh immune globulin preparations.

Extraocular muscle (EOM) is susceptible to neuromuscular junction disorders, in particular, myasthenia gravis (MG). While EOM physiological characteristics and the ocular motor system requirements contribute to the propensity of ocular motor deficits observed among patients with MG, the authors propose that EOM have immunological features that place the muscles at risk for immune attack. Genomic profiling studies have demonstrated that genes associated with the immune response are differentially expressed in EOM, with particular differences in both classical and alternative complement-mediated immune response pathways. Intrinsic complement regulators are expressed at lower levels at rodent EOM neuromuscular junctions, which would put them at risk for the complement-mediated injury that occurs in MG. In fact, systemic C inhibition in experimental autoimmune MG (EAMG) induced by administration of acetylcholine receptor (AChR) antibodies or immunization with AChR will eliminate complement deposition at junctions of other skeletal muscle, but not EOM. Also, EOM junctions have greater injury in active and passive EAMG by several measures, suggesting that the lack of complement inhibition puts the EOM at risk. Among ocular myasthenia patients, serum AChR antibody levels are low, which would support the concept that EOM junctions are more susceptible to antibody injury than are other junctions. These observations suggest that complement inhibitory therapies may prove to be particularly effective in treatment of ocular myasthenia.

Breast cancer is a first magnitude problem of public health worldwide. There is increasing evidence that this cancer is originated in and maintained by a small population of undifferentiated cells with self-renewal properties. This small population generates a more differentiated pool of cells which represents the main mass of the tumor, resembling the hierarchical tissue organization of the normal breast. These cancer stem cells seem to share a similar phenotype with their normal counterparts but they display dysfunctional patterns of proliferation and differentiation, and they no longer respond to normal physiological controls that ensure a balanced cellular turnover. The origin of these cancer stem cells is controversial; it is not well known if they are originated from normal stem cells or from more differentiated progenitors where a de novo stem cell program is activated by the oncogenic insult. Here we review the origin of breast cancer stem cells and their role in the pathogenesis of cancer development, together with their implications in breast cancer progression, treatment and prognosis.

Background: Cockroach exposure is a major risk factor for the development of asthma. Inhalation of fecal remnants (frass) is the likely sensitizing agent; however isolated frass has not been tested for its ability to induce experimental asthma in mice., Methods: Mice (Balb/c or C57Bl/6) were sensitized and challenged with GC frass or GC frass devoid of proteases and measurements of airway inflammation and hyperresponsiveness were performed (interleukin (IL)-5, -13, and interferon gamma (IFNgamma) levels in bronchoalveolar lavage fluid, serum IgE levels, airway hyperresponsiveness, cellular infiltration, and mucin production)., Results: Sensitization and challenge of Balb/c mice with GC frass resulted in increased airway inflammation and hyperresponsiveness. C57Bl/6 mice were not susceptible to this model of sensitization; however they were sensitized to GC frass using a more aggressive sensitization and challenge protocol. In mice that were sensitized by inhalation, the active serine proteases in GC frass played a role in airway hyperresponsiveness as these mice had less airway hyperresponsiveness to acetylcholine and less mucin production. Proteases did not play a role in mediating the allergic inflammation in mice sensitized via intraperitoneal injection., Conclusion: While both strains of mice were able to induce experimental asthma following GC frass sensitization and challenge, the active serine proteases in GC frass only play a role in airway hyperresponsiveness in Balb/c mice that were susceptible to sensitization via inhalation. The differences in the method of sensitization suggest genetic differences between strains of mice.

During the second postnatal week in rats, the hippocampus exhibits a transient period of hyperexcitability. To systematically assess the relationship between the onset and end of this period and spontaneous hippocampal activity, we used silicon depth electrodes in unanaesthetized head-fixed rats from postnatal day (P)2 to P18. At all ages, hippocampal sharp waves (SPWs) were prominent in the EEG. Beginning at P6, however, marked changes in SPWs and associated oscillations were detected. SPW-related 'gamma tails' (60-100 Hz) and 'ripples' (140-200 Hz) were first observed at P6 and P7, respectively, and both oscillations persisted up to P18. Transiently, between P6 and P11, SPW duration decreased and the occurrence of SPW doublets increased. In addition, between P8 and P11, a subset of rats exhibited 'spontaneous potentiated SPWs' characterized by double polarity reversals, enhanced likelihood of gamma tails, and population spikes. Having identified a suite of transient hippocampal features consistent with a window of increased excitability, we next assessed whether electrographic seizure activity would be most easily induced during this period. To do this, kainic acid (KA; 200 ng/infusion) was infused into the hippocampus contralateral to the recording probe. KA did not induce seizure activity until P7 and reached peak effectiveness at P9. Thereafter, sensitivity to KA declined. All together, these findings provide in vivo neurophysiological support for the notion of a developmental window of heightened seizure susceptibility during the second postnatal week, and also suggest that spontaneous nonpathological hippocampal activity can be used to mark the onset and end of this period.

Growth Arrest Specific Gene 1 (Gas1) has long been regarded as a cell cycle inhibitor of the G(0) to S phase transition. How GAS1, a GPI-anchored plasma membrane protein, directs intracellular changes without an extracellular ligand or a transmembrane protein partner has been puzzling. A recent series of biochemical and molecular genetic studies assigned the mammalian Hedgehog (HH) growth factor to be a ligand for GAS1 in vitro and in vivo. HH has enjoyed considerable attention for its profound role in embryonic patterning as a classic morphogen, i.e. inducing various cell types in a concentration-dependent manner. GAS1 appears to help transform the HH concentration gradient into its morphogenic activity gradient by acting cooperatively with the HH receptor, the 12-transmembrane protein Patched 1 (PTC1). These findings provoke intriguing thoughts on how HH and GAS1 may coordinate cell proliferation and differentiation to create biological patterns. The role of HH extends to human genetic diseases, stem cell renewal, and cancer growth, and we consider the possibility of GAS1's involvement in these processes as well.