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The diagnosis of genital lichen sclerosus (LS) is often confirmed by obtaining a skin biopsy, which can lead to unwanted complications and is uncomfortable in the sensitive genital area. Thus, there is a need of finding novel, non-invasive techniques that can rapidly and accurately diagnose LS. The present study investigated the potential for reflectance confocal microscopy (RCM) to diagnose LS compared with healthy penile skin and other common penile skin disorders in males. A total of 30 male patients, including patients with LS, nonspecific balanoposthitis, plasma cell balanitis and psoriasis, and healthy individuals were included and were subject to non-invasive RCM investigation. Prominent fiber-like structures, representing hyaline sclerosis, were observed in the RCM images for almost half of the patients. Differences between healthy penile skin and LS were confirmed by identifying the edged papillae on healthy skin and their absence or obscureness in patients with LS. Notably, RCM could detect the atypical honeycomb pattern referring to dysplasia in 1 patient with LS with penile intraepithelial neoplasia. In conclusion, the present study demonstrated that RCM can detect sclerosis in penile LS. RCM can potentially become a valuable tool for monitoring patients with LS for dysplasia providing a useful non-invasive diagnostic tool for genital disorders.

The incidence of syphilis was decreasing during the last decades of the 20th century, partly due to the awareness and fear of hiv. However, an increase is now apparent in many countries. It is still uncommon in Sweden compared to chlamydia and gonorrhoea, and the incidence is 4.6/100.000 inhabitants. The infection can be latent and without symptoms, but also manifest itself as a painless genital ulcer, with rash and fever, or as neurosyphilis. Congenital infection due to transmission of the syphilis spirochete from an infected mother to her fetus is still a problem in many parts of the world. In order to prevent congenital syphilis it is important for all pregnant women to have access to maternal care during their pregnancy, and to get efficient treatment if diagnosed with syphilis.

IFN-γ–inducible protein 16 (IFI16) is an immunological DNA sensor proposed to act in the cyclic GMP–AMP synthase–stimulator of IFN genes pathway. Because mice do not have a clear ortholog of IFI16, this system is not suitable for genetic studies of IFI16. In this study, we have compared the dependency on IFI16, cyclic GMP–AMP synthase, and stimulator of IFN genes for type I IFN induction by a panel of pathogenic bacteria and DNA viruses. The IFN response induced by HSV-2 was particularly dependent on IFI16. In a cohort of patients with genital herpes and healthy controls, the minor G allele of the IFI16 single nucleotide polymorphism rs2276404 was associated with resistance to infection. Furthermore, the combination of this allele with the C allele of rs1417806 was significantly overrepresented in uninfected individuals. Cells from individuals with the protective GC haplotype expressed higher levels of IFI16 and induced more IFN-β upon HSV-2 infection. These data provide genetic evidence for a role for IFI16 in protection against genital herpes.

The modern medical treatment of HIV with antiretroviral therapy (ART) has drastically reduced the morbidity and mortality in patients infected with this virus. ART has also been shown to reduce the transmission risk from individual patients as well as the spread of the infection at the population level. This position statement from the Public Health Agency of Sweden and the Swedish Reference Group for Antiviral Therapy is based on a workshop organized in the fall of 2012. It summarizes the latest research and knowledge on the risk of HIV transmission from patients on ART, with a focus on the risk of sexual transmission. The risk of transmission via shared injection equipment among intravenous drug users is also examined, as is the risk of mother-to-child transmission. Based on current knowledge, the risk of transmission through vaginal or anal intercourse involving the use of a condom has been judged to be minimal, provided that the person infected with HIV fulfils the criteria for effective ART. This probably also applies to unprotected intercourse, provided that no other sexually transmitted infections are present, although it is not currently possible to fully support this conclusion with direct scientific evidence. ART is judged to markedly reduce the risk of blood-borne transmission between people who share injection equipment. Finally, the risk of transmission from mother to child is very low, provided that ART is started well in advance of delivery.

Lichen sclerosus (LS) is a chronic dermatosis mainly localised to the anogenital area. The aim of this study was to investigate the clinical features of LS in adult men. A retrospective analysis of records from 771 patients diagnosed with LS was made and a questionnaire was sent to all patients. The results showed that the clinical spectrum was wide. Itch, tenderness and pain were frequently reported and more than half of the patients reported that LS had a negative impact on their sexual health. Phimosis was common and almost 1/3 of the patients were circumcised before or during the study period. Eight cases (1%) of penile squamous cell carcinoma were recorded. This emphasises the need for follow-up of male patients with LS.

Lichen sclerosus is a chronic inflammatory disease associated with substantial morbidity. Knowledge of the aetiology and progression of lichen sclerosus is therefore needed. In this cross-sectional study, 100 male patients diagnosed with lichen sclerosus were interviewed and examined. Since there is a possible link between lichen sclerosus and autoimmunity, blood tests were analysed for thyroid disease, antinuclear antibodies and antibodies to extracellular matrix protein 1, but autoimmunity was found to be infrequent. In 72 participants active genital lichen sclerosis was observed and complications were common; 27 patients had preputial constriction and 12 meatal engagement. In total, 13 patients needed a referral to the Department of Urology, including 1 patient with suspected penile cancer. In conclusion, despite available treatment with ultra-potent steroids and circumcision, lichen sclerosus in males is frequently complicated by phimosis and meatal stenosis. However, the disease can also go into remission, as seen in 27% of our patients.

Commentary on "Phimosis with Preputial Fissures as a Predictor of Undiagnosed Type 2 Diabetes in Adults"

Herpes simplex virus type 1 (HSV-1) is a ubiquitous pathogen infecting most individuals worldwide. The majority of HSV-1-infected individuals have no clinical symptoms but shed HSV-1 asymptomatically in saliva. Recent phylogenetic analyses of HSV-1 have defined three genetic clades (A–C) and recombinants thereof. These data have all been based on clinical HSV-1 isolates and do not cover genetic variation of asymptomatically shed HSV-1. The primary goal of this study was to investigate such variation. A total of 648 consecutive saliva samples from five HSV-1-infected volunteers was collected. Asymptomatic shedding was detected on 7.6 % of the days from four subjects. The HSV-1 genome loads were quantified with real-time PCR and varied from 1×102to 2.8×106 copies of virus DNA (ml saliva)−1. Phylogenetic network analyses and bootscanning were performed on asymptomatically shed HSV-1. The analyses were based on DNA sequencing of the glycoprotein I gene, and also of the glycoprotein E gene for putative recombinants. For two individuals with clinical HSV-1 infection, the same HSV-1 strain was shed asymptomatically as induced clinical lesions, and sequence analyses revealed that these strains clustered distinctly to clades A and B, respectively. For one of the subjects with no clinical HSV-1 infection, a recombinant strain was identified. The other truly asymptomatic individual shed evolutionarily distinct HSV-1 strains on two occasions. The first strain was classified as a recombinant and the other strain clustered in clade A. High replication rates of different strains in the same person may facilitate the creation of recombinant clinical HSV-1 strains.

High estimates of herpes simplex virus-2 (HSV-2) seroprevalence have been reported for women who were pregnant in Sweden in the 1980s, probably reflecting sexual risk-taking during the 1960s and 1970s. The aim of the present study was to evaluate the HSV-2 seroprevalence in pregnant women and in the female attendees at a clinic for sexually transmitted infections in Sweden at the beginning of the 21st century and to compare the results with those of earlier Swedish studies. Sera were collected during the period 2000 to 2002 from 299 pregnant women at an antenatal clinic and from 290 female attendees at a clinic for sexually transmitted infections in Gothenburg. To enable comparison with earlier seroprevalence data the same test method was used; Helix pomatia antigen in an enzyme-linked immunoassay. The overall HSV-2 prevalence was 10.4% for the pregnant women and 25.2% for the female attendees at the clinic for sexually transmitted infections. The seroprevalence of HSV-2 in pregnant women appears to have decreased in Sweden during the past decade, which may reflect changes in sexual behaviour.

It was recently shown that the transcription factor T-bet is crucial for adequate innate and acquired immune responses to genital herpes simplex virus type 2 (HSV-2) infection in mice. To test the possible genetic influence of variations in the TBX21 gene encoding T-bet on susceptibility to infection, this study evaluated the frequencies of five different single-nucleotide polymorphisms (SNPs) in the human TBX21 gene in 159 HSV-2-infected individuals and compared them with those in 186 healthy HSV-2-seronegative controls. The data showed that one variation (rs17244587) in the 3′-untranslated region of TBX21 was strongly associated with the incidence of genital HSV-2 infection. The frequency of the A allele at this position was 0.19 in the group of HSV-2-infected individuals compared with 0.05 in the group of uninfected controls (P=9.3×10−8). Furthermore, a homozygous AA genotype was found only among HSV-2-infected individuals and not in seronegative controls. These results indicate that the host genetic background may affect susceptibility to HSV-2 infection in humans, with TBX21 as a strong candidate gene.

T-cell recognition of the secreted and membrane-bound portions of the herpes simplex virus type 2 (HSV-2) glycoprotein G (sgG-2 and mgG-2, respectively) was compared in symptomatic and asymptomatic HSV-2-infected individuals and in HSV-2-seronegative controls and the responses with HSV-1 glycoproteins C and E (gC-1 and gE-1) were compared. CD4+T cells from HSV-2-infected individuals specifically recognized both sgG-2 and mgG-2, whereas HSV-1-infected and HSV-seronegative controls did not respond to these glycoproteins. The responses to gC-1 and gE-1, on the other hand, were not type specific, as blood mononuclear cells from both HSV-1- and HSV-2-infected individuals respondedin vitro. There was an association between the status of the infection (symptomatic versus asymptomatic) and the CD4+T-cell responsiveness. Symptomatic HSV-2-seropositive individuals responded with significantly lower Th1 cytokine production to sgG-2 and mgG-2 than did asymptomatic HSV-2-infected carriers, especially within the HSV-1-negative cohort. No differences in T-cell proliferation were observed between asymptomatic and symptomatic individuals. The results have implications for studies of HSV-2-specific CD4+T-cell reactivity in general and for analysis of immunological differences between asymptomatic and symptomatic individuals in particular.

Serological diagnosis of herpes simplex virus (HSV) infections requires assays based on antigens that expose type-specific determinants. This study was designed to outline the B-cell epitopes of the type-specific glycoprotein G-1 (gG-1) of HSV type 1 (HSV-1), by investigating the reactivity of human anti-gG-1 antibodies, purified from 21 HSV-1-isolation-proven patient sera, to cellulose-bound synthetic peptides spanning the entire gG-1 sequence. The epitope mapping demonstrated that these antibodies bound preferentially to antigenic determinants that localized to regions with a high degree of amino acid similarity to the corresponding glycoprotein in HSV-2, gG-2. In spite of this, the purified anti-gG-1 antibodies were found to be non-reactive to native gG-2 antigen, as well as to overlapping gG-2 peptides, thus supporting the role of gG-1 as a prototype HSV-1 type-specific antigen. One immunodominant region, delimited by amino acids 112-127, reacted with all purified anti-gG-1 antibodies and may be of interest for the further development of a peptide-based HSV-1 type-specific seroassay.

Glycoprotein G (gG) of herpes simplex virus type 1 (HSV-1) has been used as a prototype antigen for HSV-1 type-specific serodiagnosis, but data on the sequence variability of the gene coding for this protein in wild-type strains are lacking. In this study, direct DNA sequencing of the gG-1 genes from PCR products was performed with clinical HSV-1 isolates from 11 subjects as well as with strains Syn 17 + , F, and KOS 321. The reference strains Syn 17 + and F showed a high degree of conservation, while KOS 321 carried 13 missense mutations and, in addition, 12 silent mutations. Three clinical isolates showed mutations leading to amino acid alterations: one had a mutation of K 122 to N, which is a gG-1–to–gG-2 alteration; another contained all mutations which were observed in KOS 321 except two silent mutations; and the third isolate carried five missense mutations. Two clinical isolates as well as strain KOS 321 showed a mutation (F 111 →V) within the epitope of a gG-1-reactive monoclonal antibody (MAb). When all viruses were tested for reactivity with the anti-gG-1 MAb, the three strains with the F 111 →V mutation were found to be unreactive. Furthermore, gG-1 antibodies purified from sera from the two patients carrying strains mutated in this epitope were less reactive when they were tested by an HSV-1-infected-cell assay. Therefore, our finding that the sequence variability of the gG-1 gene also affects B-cell epitope regions of this protein in clinical isolates may have consequences for the use of this protein as a type-specific antigen for serodiagnosis.

Chlamydia trachomatis is among the most prevalent genital infections and is an important cause of tubal factor infertility. The majority of infected females are asymptomatic. Evidence on the reliability of signs of inflammation used to predict chlamydia in female patients is inconsistent. This study examined associations between criteria routinely used in many Scandinavian sexually transmitted infection (STI) clinics and a positive chlamydia test in a high-prevalence population. Clinical and microscopic signs of cervicitis and urethritis were recorded in 99 women attending due to chlamydia infection in a sexual partner. Mucopurulent cervical discharge, easily induced bleeding from the cervix, and more polymorpho-nuclear cells than epithelial cells in vaginal wet smear all correlated significantly with a positive Chlamydia trachomatis test (odds ratios: 3.4, 4.0 and 4.8, respectively). Increased numbers of polymorphonuclear leucocytes (>30 and ≥ 5 respectively) in stained cervical and urethral smears were not significantly correlated with chlamydia infection. Hence, routine collection of cervical and urethral smears in female STI patients is questionable.

Lack of Toll-like receptor 3 (TLR3) functional activity predisposes children to human herpesvirus 1 (HSV-1) encephalitis. In this study, we have investigated whether there is any link between TLR3 and adult HSV-2 infection by studying genetic variations in TLR3. The frequency of four single-nucleotide polymorphisms (SNPs) in the TLR3 gene in 239 patients with genital HSV-2 infection and 162 healthy controls, as well as the impact of these variants on TLR3 gene-expression levels, were compared. Two SNPs in the TLR3 gene (rs13126816 and rs3775291) were associated with a reduced incidence of HSV-2 infection. The minor allelic variants at both rs13126816 and rs3775291 were more common among healthy HSV-2-seronegative subjects than among HSV-2-infected individuals. This was even more apparent in HSV-1-seronegative individuals. There was, however, no association between any of the four TLR3 SNPs and HSV-2 disease severity, as they were expressed at similar proportions in asymptomatic and symptomatic HSV-2-infected patients alike. Furthermore, when assessing TLR3 mRNA expression in a limited number of HSV-2-infected individuals, we found that individuals carrying the homozygous genotypes for the minor alleles had significantly higher levels of TLR3 mRNA expression in peripheral blood mononuclear cells in response to HSV-2 stimulation than individuals that were homozygous for the major allele variants. Taken together, these results suggest that genetic variations in TLR3 may affect the susceptibility to HSV-2 infection in humans.

Herpes simplex virus type 1 (HSV-1) encodes 11 envelope glycoproteins, of which glycoprotein G-1 (gG-1) induces a type-specific antibody response. Variability of the gG-1 gene among wild-type strains may be a factor of importance for a reliable serodiagnosis and typing of HSV-1 isolates. Here, we used a gG-1 type-specific monoclonal antibody (MAb) to screen for mutations in the immunodominant region of this protein in 108 clinical HSV-1 isolates. Of these, 42 isolates showed no reactivity to the anti-gG-1 MAb. One hundred five strains were further examined by DNA sequencing of the middle part of the gG-1 gene, encompassing 106 amino acids including the immunodominant region and epitope of the anti-gG-1 MAb. By phylogenetic comparisons based on the sequence data, we observed two (main) genetic variants of the gG-1 gene among the clinical isolates corresponding to reactivity or nonreactivity to the anti-gG-1 MAb. Furthermore, four strains appeared to be recombinants of the two gG-1 variants. In addition, one strain displayed a gG-1-negative phenotype due to a frameshift mutation, in the form of insertion of a cytosine nucleotide. When immunoglobulin G reactivity to HSV-1 in sera from patients infected with either of the two variants was investigated, no significant differences were found between the two groups, either in a type-common enzyme-linked immunosorbent assay (ELISA) or in a type-specific gG-1 antigen-based ELISA. Despite the here-documented existence of two variants of the gG-1 gene affecting the immunodominant region of the protein, other circumstances, such as early phase of infection, might be sought for explaining the seronegativity to gG-1 commonly found in a proportion of the HSV-1-infected patients.

Herpes simplex virus type 1 (HSV-1) has been associated with orofacial infections and HSV type 2 (HSV-2) with genital infections. This tropism of the virus seems to have changed and in clinical reports an increasing number of genital herpes infections caused by HSV-1 have been recognized. The aim of this study was to estimate the proportion of HSV-1 and HSV-2, respectively, among isolates from different anatomical sites typed in our laboratory during the years 1994-1998. Out of a total of 3,085 anogenital isolates, 29% were typed as HSV-1 and 71% as HSV-2. The highest prevalence of HSV-1 was registered among isolates from young women. Of 631 orofacial isolates, 4% were typed as HSV-2 and 96% as HSV-1. Of 69 finger/hand isolates, 54% were typed as HSV-1 and 46% as HSV-2, and of 95 isolates from other regions (abdomen, foot, etc.), 60% were typed as HSV-1 and 40% as HSV-2. It was found that HSV-2 was as common as HSV-1 in the extra-genital regions with the exception of the orofacial area, in which HSV-2 was seldom detected. Furthermore, the study showed an increasing proportion of HSV-1 among anogenital isolates during the study period. Taken together, these results suggest that a clear HSV type-related tropism might be limited to the permissiveness of the orofacial region for HSV-1, and that both serotypes may readily establish infections below the neck.

The majority of herpes simplex virus type 2 (HSV-2) genital infections are asymptomatic. We wanted to evaluate the acceptance of HSV-2 antibody testing among people attending an STD clinic and to estimate, after counselling, the percentage of recognized and unrecognized HSV-2 infections. First visitors to an STD clinic were invited to participate by answering a questionnaire and taking a blood test for HSV-2 antibodies. HSV-2 seropositive individuals, who were unaware of having genital herpes, were offered an HSV-2 counselling visit and follow-up. Of 1769 patients offered testing, 57% accepted. Of 152 (15%) HSV-2 seropositive individuals, 41% had a self-reported history of genital herpes, approximately 30% had genital symptoms and 30% had no genital symptoms. The percentage of patients reporting genital symptoms was much higher in HSV-2 seropositives (45%) without a history of genital herpes than in an HSV-2 seronegative group (28%). HSV-2 antibody testing should be performed generously in all cases of uncharacteristic genital symptoms.

Acid exposure of the duodenal mucosa increased duodenal HCO 3 post− secretion by ~60%. When the acid exposure was performed simultaneously with an arterial bleeding of 0.6 ml/100 g body wt (10% of the total blood volume), the increase in duodenal HCO 3 post− secretion was totally abolished. When the acid exposure and bleeding procedures were performed at the same time in rats with bilaterally cut splanchnic nerves, alkaline secretion increased by 60%, as it did in the unbled rats. Direct electrical stimulation of the splanchnic nerves (10 Hz, supramaximal intensity) inhibited the stimulatory effect of duodenal acid exposure on alkaline secretion. Taken together, the data suggest that the sympathetic nervous system, because of splanchnic nerve activation, inhibits the acid-induced increase in duodenal HCO 3 post− secretion.