Growth inhibition of Candida albicans by human vaginal epithelial cells.

Vulvovaginal candidiasis (VVC) is a common mucosal infection caused by Candida species in women of childbearing age. Although acute VVC affects a large number of women and is often precipitated by hormonal fluctuations involving high estrogen levels, recurrent VVC (RVVC) affects another 5%-10% of women without any known predisposing factors. We have recently reported that vaginal epithelial cells from nonhuman primates and mice inhibit the growth of Candida albicans in vitro, which may represent an innate host defense mechanism against C. albicans at the vaginal mucosa. In the present study, we show that vaginal epithelial cells collected from healthy women with no history of VVC also exhibit anti-Candida activity, with no differences in activity at various stages of the menstrual cycle. Women diagnosed with RVVC, on the other hand, have reduced epithelial cell anti-Candida activity. These results are further evidence that vaginal epithelial cells provide an innate host resistance mechanism against Candida and that reduced activity may contribute to RVVC.     

Vaginal microbiological flora and sexually transmitted diseases in women with recurrent or current vulvovaginal candidiasis

Summary A history of recurrent vulvovaginal candidiasis (RVVC) was reported by 102 women, while current vulvovaginal candidiasis (VVC) was diagnosed in 83 of the same 996 women. They had all attended two family planning and one youth clinic, respectively. Two women, without RVVC or VVC, matched for age for each case of RVVC, were selected as a comparison group (COMP). Recurrent, but not current VVC, was associated with a history of sexually transmitted disease. Those with current, but not with recurrent, VVC had significantly more often genital warts and bacteriuria (> 10⁵ bacteria/ml), but significantly less often bacterial vaginosis than the COMP women. Both VVC and RVVC were inversely correlated to a vaginal flora change with a mixed anaerobic vaginal flora. Those with VVC had a greater number of lactobacilli on vaginal cultures, than those with RVVC and the women in the COMP group. VVC and a history of RVVC both occurred more frequently in women with a lactobacilli-predominated vaginal flora, as compared with those with a flora change with a mixture of anaerobic and facultative anaerobic bacteria.

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Vaginale Flora und venerische Erkrankungen bei Frauen mit rezidivierender oder akuter vulvovaginaler Kandidose

Zusammenfassung In einer Gruppe von insgesamt 996 Frauen wurde in 102 Fällen eine rezidivierende und in 83 Fällen eine akute vulvovaginale Kandidose diagnostiziert. Alle Frauen hatten zwei Familienplanungskliniken und eine Klinik für Jugendmedizin aufgesucht. Zwei altersgleiche Frauen ohne rezidivierende oder aktuelle vulvovaginale Kandidose wurden für jeden Fall von rezidivierender Kandidose als Kontrollen in die Vergleichsgruppe aufgenommen. Eine Assoziation zu venerischen Krankheiten ergab sich für die rezidivierende aber nicht für die aktuelle Kandidosc. Genitale Warzen und Bakteriurie (> 10⁵ Bakterien/ml) fanden sich im Vergleich zu den Kontrollen signifikant häufiger bei Frauen mit aktueller, aber nicht bei den Frauen mit rezidivierender Kandidose. Zwischen beiden Formen der Kandidose fand sich eine inverse Beziehung zu Veränderungen der vaginalen Flora zu gemischter anaerober Flora. Frauen mit akuter vulvovaginaler Kandidose hatten in den Scheidenkulturen eine größere Zahl an Laktobazillen als Frauen mit rezidivierender Kandidose und Frauen der Vergleichsgruppe. Sowohl die aktuelle Kandidose als auch eine Vorgeschichte von rezidivierender vulvovaginaler Kandidose waren bei Frauen mit einer von Laktobazillen bestimmten Vaginalflora häufiger zu finden als bei Frauen, bei denen sich eine veränderte Mischflora aus anaeroben und fakultativ anaeroben Bakterien eingestellt hatte.

     

Vulvovaginal candidiasis: a comparison of HIV-positive and -negative women

Although considerable information has accumulated in the last decade regarding rates of both vaginal colonization and vulvovaginal candidiasis (VVC) in HIV-positive women, gaps in our knowledge remain, particularly with regard to pathophysiology of clinical disease. Unfortunately, early and possibly premature conclusions were reached in the late 1980s which resulted in the widespread dissemination of information indicating that recurrent VVC (RVVC) was a manifestation of HIV infection and that women with RVVC should be tested for HIV. Unfortunately, subsequent data from cohort studies involving HIV-positive women failed to determine attack rates of symptomatic Candida vaginitis requiring therapy. Recent studies indicate that Candida vaginitis, even if more frequent in HIV infected women, is clinically similar to that experienced in HIV-negative women and does not appear to be of increased clinical severity. VVC in HIV-positive women can be treated by conventional methods including the use of maintenance suppressive antifungal therapy and most importantly RVVC in women is not in itself a sentinel of HIV infection. Ongoing concerns include vaginal acquisition of non-albicans Candida species and the development of antimycotic drug resistance in C. albicans vaginal isolates.     

Candida species isolated from the vaginal mucosa of HIV-infected women in Salvador,Bahia, Brazil

BackgroundVulvovaginal candidiasis (VVC) is the second most common vaginal infection. HIV-infection is a risk factor for this infection.ObjectiveTo determine the frequency of VVC and to describe the main Candida species isolated and their susceptibility to antifungal drugs in HIV-infected patients, compared to HIV-uninfected women in Salvador, Brazil.MethodsCross-sectional study including a group of 64 HIV-infected women and 76 uninfected women, followed up at the AIDS reference center and at the Gynecological Clinic of Escola Bahiana de Medicina e Saúde Pública (Salvador, Bahia, Brazil).ResultsFrequency of Candida spp. was higher in HIV-infected women (29.7%) than in HIV-uninfected controls (14.5%) (p = 0.02). The odds ratio value for vulvovaginal candidiasis in HIV-infected patients was 2.6 (95% CI: 1.07 ? 6.32 p = 0.03). Candida albicans was the most commonly isolated species in both HIV-infected (52.3%) and uninfected women (85.7%), followed by C. parapsolis in 17.6% and 14.3%, respectively. In HIV-infected women, C. glabrata, C. parapsilosis, and a coinfection of C. albicans and C. glabrata were also identified. There was no significant difference between Candida species isolated from the vaginal mucosa of women with VVC and colonization of the vaginal mucosa of HIV-infected and HIV-uninfected women. One C. glabrata isolate from an HIV-infected patient was resistant to fluconazole and other two isolates exhibited a dose-dependent susceptibility.ConclusionOur results confirm a higher frequency of Candida spp. isolated from the vaginal mucosa of HIV-infected women and a broader spectrum of species involved. Only Candida glabrata isolates showed decreased susceptibility to fluconazole.     

Pathogenesis of sarcoidosis

Many improvements have been obtained in understanding the immune and genetic mechanisms of sarcoidosis. Main immune abnormalities in this disease involve T lymphocytes, macrophages and dendritic cells. Interactions between these various immune cells through the immune synapse are tight. Environmental factors and genetic polymorphisms interact at molecular level in these immune targets. Recent pangenomic studies highlight some regions of the genome such as 6p21 where are located important immune genes: MHC, BTNL2 and TNF-α. Gene-environment interactions are important in this polymorphic disease. They need accurate clinical analysis for a better definition of patient subgroups and familial disease studies to progress in the role of genetic determinants.     

Facts and myths on recurrent vulvovaginal candidosis--a review on epidemiology,clinical manifestations,diagnosis, pathogenesis and therapy

Approximately three-quarters of all women will experience an episode of vulvovaginal candidosis at least once in their life and 5-10% of them will have more than one attack. Women suffering from three to four attacks within 12 months will be diagnosed with recurrent vulvovaginal candidosis (RVVC). This review covers the large number of proposed aetiological factors for RVVC. The diagnosis of the condition made by conventional means by health providers is often false and is also often misdiagnosed by the affected woman herself. The review covers various methods of diagnosing RVVC and the current knowledge on potential pathogenetic mechanisms proposed for genital candida infections. Treatment of RVVC, including local and systemic antimicrobial therapy and behaviour modification to decrease the risk of recurrences, are discussed. Recent knowledge on drug resistance in candida is also included.     

EFFECT OF HIGHLY ACTIVE ANTIRETROVIRAL THERAPY ON VAGINAL Candida spp. ISOLATION IN HIV-INFECTED COMPARED TO HIV-UNINFECTED WOMEN

 Vulvovaginal candidiasis (VVC) in HIV-infected women contributed to the impairment of their quality of life. The aim of this study was to evaluate the effect of highly active antiretroviral therapy (HAART) use on the vaginal Candida spp. isolation in HIV-infected compared to HIV-uninfected women. This cross-sectional study included 178 HIV-infected (HIV group) and 200 HIV-uninfected women (control) that were studied at the Specialized Assistance Service (SAE) for sexually transmitted diseases (STD)/AIDS of the city of Maringá, Brazil, from April 1 to October 30, 2011. The yeasts were isolated and identified by phenotypic and molecular methods. The in vitro antifungal susceptibility to fluconazole, itraconazole, nystatin and amphotericin B was tested by the reference microdilution method. Higher frequencies of total vaginal Candida spp. isolation were found in the HIV-infected group than in the control group. However, both groups showed a similar frequency of colonization and VVC. Although C. albicans was the most frequent and sensitive to azolics and polyenes in both HIV-infected and uninfected women, the emerging resistance of C. glabrata to amphotericin B in the HIV-infected women was observed. Although higher frequency of vaginal Candida spp. isolation had been observed in the HIV-infected than in HIV-uninfected women, colonization and VVC showed similar frequency in both groups, indicating that HAART appears to protect against vaginal colonization and VVC.     

Genome-wide association study identifies BTNL2 associated with atopic asthma in children

Asthma is a heterogeneous disease characterized by chronic airway inflammation with a genetic predisposition. Butyrophilin-like 2 (BTNL2) is a member of the immunoglobulin superfamily that plays an important role in regulating T cell activation and immune homeostasis. Here, we aimed to investigate the association of the genetic variants of BTNL2 with childhood asthma and asthma-related traits by utilizing extreme asthma phenotypes and employing a genome-wide association study. Our study included 243 children with well-defined moderate to severe atopic asthma and 134 healthy children with no history of allergic diseases and allergic sensitization. DNA from these subjects was genotyped using Axiom^TM Genome-Wide Array Plates. Although no single nucleotide polymorphisms (SNPs) reached a genome-wide threshold of significance, 3 SNPs, rs3817971, rs41355746, and rs41441651, at BTNL2 were significantly associated with moderate to severe atopic asthma after performing Bonferroni correction. These SNPs were also associated with the risk of allergic sensitization toward house dust mites and the presence and degree of bronchial hyperresponsiveness. Thus, we identified that BTNL2 was associated with atopic moderate to severe persistent asthma in Korean children, and this may play an important role in disease development and susceptibility.     

Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families.

Segregation analysis of breast cancer in families can provide the logical basis and the specific genetic models for mapping and identifying genes responsible for human breast cancer. Patterns of breast cancer occurrence in families were investigated by complex segregation analysis. In a sample of 1579 nuclear families ascertained through a population-based series of probands, an autosomal dominant model with a highly penetrant susceptibility allele fully explained disease clustering. From the maximum-likelihood Mendelian model, the frequency of the susceptibility allele was 0.0006 in the general population, and lifetime risk of breast cancer was 0.82 among susceptible women and 0.08 among women without the susceptibility allele. Inherited susceptibility affected only 4% of families in the sample: multiple cases of this relatively common disease occurred in other families by chance. The same genetic models, with higher gene frequency, explained disease clustering in an extended kindred at high risk of breast cancer. Evidence for a highly penetrant, autosomal dominant susceptibility allele for breast cancer in a high-risk family and the general population suggests that high-risk families can serve as models for understanding breast cancer in the population as a whole.     

New aspects in celiac disease

Celiac disease (CD) is a common autoimmune disorder characterized by an immune response to ingested gluten and has a strong HLA association with HLA- DQ2 and HLA-DQ8 molecules, but human HLA-DQ risk factors do not explain the entire genetic susceptibility to gluten intolerance. CD is caused by the lack of immune tolerance (oral tolerance) to wheat gluten. In this sense, the expression of soluble HLA-G in CD is of special interest because the molecule plays an important role in the induction of immune tolerance. The enhanced expression of soluble HLA-G found in CD may be part of a mechanism to restore the gluten intolerance. In this editorial, we review recent progress in understanding CD in relation to its prevalence, diagnosis and possible mechanisms of pathogenesis.     

Epidemiology, genes and inflammatory bowel diseases in childhood

There is evidence that inflammatory bowel disease is immunologically mediated and that genetic factors play an important aetiological role. The identification of disease susceptibility genes has led to significant progress in our understanding of the pathogenesis of Crohn's disease. Genes linked to Crohn's disease play critical roles in the normal function of the innate immune system, and genes linked to epithelial integrity may play a role in the pathogenesis of inflammatory bowel disease as well. However, the dynamic epidemiology of both Crohn's disease and ulcerative colitis suggests that extrinsic environmental factors acting at the population level may be involved in their pathogenesis. These environmental factors may be responsible for the rising incidence of inflammatory bowel disease.     

Role of host genes in sporadic gastric cancer

Gastric cancer remains a major health problem particularly in the developing world. Helicobacter pylori (H. pylori) infection is the most recognised aetiological risk factor for this malignancy. The infection causes a chronic gastritis that is the precursor to all the pathophysiological abnormalities characteristic of gastric carcinogenesis. Genetic polymorphisms have emerged in recent years as important determinants of disease susceptibility and severity. In the case of H. pylori-induced gastric cancer, host genetic polymorphisms play an important role both in the precancerous stages and in the transition to cancer. In particular, polymorphic genes of the adaptive and innate immune response are involved in all stages of the neoplastic process. This field is rapidly expanding and many other genetic determinants are currently being defined. The ultimate value of host genetics should be in understanding the pathogenesis of the disease, which would offer a true opportunity to defeat this global killer.     

Prevention of cardiovascular events in early menopause: a possible role for hormone replacement therapy

Heart disease is a major cause of illness and death in women. It is well known that there is an increase in cardiovascular disease and cardiovascular risk factors after the menopause, but it is still unclear whether the change in risk factors after the menopause is only related to the aging process or is principally due to estrogen deprivation. Observational studies suggest a protective role for estrogens, whereas recent randomized controlled trials report a negative effect of oral estrogens on primary and secondary prevention of cardiovascular events. The role of inflammation in the process of atherogenesis and in determining the cardiovascular disease risk in postmenopausal women has been focused only recently as well as the role of the estrogen receptor system in different tissues and the role of genetic susceptibility to adverse events during estrogen therapy. The objective of this work was to review the current understanding of the relationships between cardiovascular disease risk factors and hormonal age-related changes in postmenopausal women and particularly in early and surgical postmenopausal women, for a more appropriate evaluation of the expected effects of therapy with exogenous estrogens in a specific sample of the large population of postmenopausal women.     

Genes or environment to determine alcoholic liver disease and non-alcoholic fatty liver disease.

While the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome will have steatosis, only a minority will ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and non-alcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of fibrosis. For ALD, the dose and pattern of alcohol intake, along with obesity are the most important environmental factors determining disease risk. For NAFLD, dietary saturated fat and antioxidant intake and small bowel bacterial overgrowth may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the alcohol dehydrogenases and aldehyde dehydrogenase alcohol metabolising genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, TNF-alpha, transforming growth factor-beta, and angiotensinogen may be associated with steatohepatitis and/or fibrosis.     

Genetic Backgrounds of Asthma and COPD

Asthma and COPD are complex diseases with strong genetic and environmental components. These common pulmonary diseases have both different and similar clinical features. Molecular genetic techniques are being used to improve understanding of these common late onset disorders. Recently, several genes and genetic loci associated with increased susceptibility to asthma and COPD have been described. Many of these genes are expressed in the lung tissues, indicating that events in lung tissues might drive disease processes. Lung tissues are rich sources of innate danger signals, and an increased understanding of how the lung tissues communicate with the immune system to maintain healthy tissue might provide new insights into the pathogenesis of chronic inflammatory lung diseases in which injury and repair are in disequilibrium. Given that the innate immune system is at the interface between the airways and environmental insults, genetic polymorphisms in genes related to the innate immune system are likely to affect susceptibility to both asthma and CopD. In addition, some findings from genetic studies provide molecular support for the point of view proposed in the Dutch hypothesis regarding the relationship between asthma and COPD, which highlights the complexity of the pathways that can induce small airway disease and suggests that there is a continuum between asthma and COPD.     

Genetics of acute and chronic pancreatitis: An update

Progress made in identifying the genetic susceptibility underlying acute and chronic pancreatitis has benefitted the clinicians in understanding the pathogenesis of the disease in a better way. The identification of mutations in cationic trypsinogen gene(PRSS1 gene; functional gain mutations) and serine protease inhibitor kazal type 1(SPINK1 gene; functional loss mutations) and other potential susceptibility factors in genes that play an important role in the pancreatic secretory functions or response to inflammation during pancreatic injury has changed the current concepts and understanding of a complex multifactorial disease like pancreatitis. An indi-vidual's susceptibility to the disease is governed by ge-netic factors in combination with environmental factors. Candidate gene and genetic linkage studies have iden-tified polymorphisms in cationic trypsinogen(PRSS1), SPINK1, cystic fibrosis trans-membrane conductance regulator(CFTR), Chymotrypsinogen C(CTRC), Ca-thepsin B(CTSB) and calcium sensing receptor(CASR). Individuals with polymorphisms in the mentioned genes and other as yet identified genes are at an enhanced risk for the disease. Recently, polymorphisms in genes other than those involved in "intra-pancreatic trypsin regulatory mechanism" namely Claudin-2(CLDN2) andCarboxypeptidase A1(CPA1) gene have also been iden-tified for their association with pancreatitis. With ever growing number of studies trying to identify the genetic susceptibility in the form of single nucleotide polymor-phisms, this review is an attempt to compile the avail-able information on the topic.     

Genetic variation in toll-like receptor 9 and susceptibility to systemic lupus erythematosus

OBJECTIVE: Autoantibodies produced by differentiated B cells play an important role in the pathogenesis of systemic lupus erythematosus (SLE). The Toll-like receptor 9 (TLR-9) gene has recently emerged as an important costimulatory molecule for both B cells and dendritic cells that respond to chromatin immune complexes. Genetic variation affecting the function of TLR-9 may therefore increase or decrease the threshold of B cell or dendritic cell activation. This variability in activation threshold may, in turn, affect an individual's susceptibility to SLE. This study assessed the role of genetic variation within the TLR-9 gene in susceptibility to SLE. METHODS: We genotyped 362 SLE-affected subject/parent trios for 10 single-nucleotide polymorphisms (SNPs) covering a 68,742-bp genomic segment that contains the TLR-9 gene and approximately 60 kb of flanking sequence. We analyzed the data using the transmission disequilibrium test. RESULTS: There was no association of susceptibility to SLE with any of the 9 SNPs that generated usable data or the 8 haplotypes found at a frequency of >0.05 in this population. When analyzing the subset of 143 subjects with lupus nephritis, there was also no evidence of association between disease susceptibility and any SNP or haplotype. CONCLUSION: These results indicate that there is no evidence that common (frequency higher than 5%) alleles of the TLR-9 gene contribute significantly to the genetic risk involved in susceptibility to SLE or lupus nephritis.     

Genetics of alcoholic liver disease and nonalcoholic fatty liver disease

Although the vast majority of heavy drinkers and individuals with obesity, insulin resistance, and the metabolic syndrome have steatosis, only a minority ever develop steatohepatitis, fibrosis, and cirrhosis. Genetic and environmental risk factors for advanced alcoholic liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD) seem likely to include factors that influence the severity of steatosis and oxidative stress, the cytokine milieu, the magnitude of the immune response, and/or the severity of liver fibrosis. For ALD, the dose and pattern of alcohol intake, coffee intake, and dietary and other lifestyle factors leading to obesity are the most important environmental determinants of disease risk. For NAFLD, dietary saturated fat and antioxidant intake, small bowel bacterial overgrowth, and obstructive sleep apnea syndrome may play a role. Family studies and interethnic variations in susceptibility suggest that genetic factors are important in determining disease risk. For ALD, functional polymorphisms in the ADH and ALDH alcohol metabolizing genes play a role in determining susceptibility in Oriental populations. No genetic associations with advanced NAFLD have been replicated in large studies. Preliminary data suggest that polymorphisms in the genes encoding microsomal triglyceride transfer protein, superoxide dismutase 2, the CD14 endotoxin receptor, tumor necrosis factor alpha, transforming growth factor beta, and angiotensinogen may be associated with steatohepatitis or hepatic fibrosis or both.     

Genetic and exposure risks for chronic beryllium disease

Exposure to beryllium results in beryllium sensitization, or development of a beryllium-specific, cell-mediated immune response, in 2% to 19% of exposed individuals. Sensitization usually precedes the development of the scarring lung disease, chronic beryllium disease. The development of granulomatous inflammation in patients with CBD is associated with the production of numerous inflammatory cytokines, including IFN-gamma, IL-2, and TNF-alpha (see Fig. 1). In some individuals this can result in increased granulomatous inflammation and a more severe form of the disease. Although the exposure response relationship in sensitization and disease is nonlinear, in some studies, higher exposures were associated with higher rates of sensitization and CBD. Machinists usually have higher levels of beryllium exposure and increased risk of developing sensitization and disease. The impact of the physicochemical properties of beryllium, such as form, solubility, and particle size, on the risk of sensitization and disease are less well understood. It is clear from numerous studies that genetic susceptibility affects risk of beryllium-related health effects. The role of HLA-DPB1 Glu69 in the proliferative response to beryllium and risk of sensitization has been the most well-studied. Some genes, such as Glu69, are important in the development of an antigen-specific, cell-mediated immune response to beryllium or sensitization, whereas others may be important in the development of beryllium-specific granulomatous inflammation or CBD (see Fig. 1). Two copies of the Glu69 gene may be a disease-specific genetic risk factor. The TNF-alpha -308 A variant is associated with beryllium-stimulated TNF-alpha production, which, in turn, is associated with more severe CBD. Whether the TNF-alpha -308 A is a genetic risk factor in CBD, sensitization, or more severe disease still needs to be determined. It is likely that sensitization and CBD are multigenetic processes, and that these genes interact with exposure to determine risk of disease. Current genetic markers are not ready for clinical use as a screening test for beryllium-related health effects because of the low specificity of the markers and the low prevalence of BeS and CBD.     

Understanding rheumatic fever

Through a comprehensive review of the recent findings on rheumatic fever, we intend to propose a new physiopathologic model for this disease. A Medline search was performed for all articles containing the terms rheumatic fever or rheumatic heart disease in title or abstract from 1970 to 2011. Best evidence qualitative technique was used to select the most relevant. The scientific interest on rheumatic fever has notably diminished throughout the twentieth century as evidenced by the comparison of the proportion of articles in which RF was a subject in 1950 (0.26%) and today (0.03%) [Pubmed]. However, RF remains a major medical and social problem in the developing world and in the so-called hotspots, where it still causes around 500.000 deaths each year, not too different from the pre-antibiotic era. The role of genetic factors in RF susceptibility is discussed. Familiar aggregation, similarity of disease patterns between siblings, identical twin, and HLA correlation studies are evidence for a genetic influence on RF susceptibility. The suspect-involved genes fall mainly into those capable of immunologic mediation. Molecular mimicry explains the triggering of RF, but an intense and sustained inflammation is needed to cause sequels. Also, RF patients vary greatly in terms of symptoms. It is likely that a genetic background directing immune response towards a predominantly Th1 or Th2 pattern contributes to these features. The recent findings on rheumatic fever provide important insight on its physiopathology that helps understanding this prototype post-infectious autoimmune disease giving insights on other autoimmune conditions.