Inhibition of DAMP signaling as an effective adjunctive treatment strategy in pneumococcal meningitis.

BACKGROUND: Pneumococcal meningitis remains a potentially lethal and debilitating disease, mainly due to brain damage from sustained inflammation. The release of danger-associated molecular patterns (DAMPs), like myeloid-related protein 14 (MRP14) and high mobility group box 1 protein (HMGB1), plays a major role in persistence of inflammation. In this study, we evaluated if paquinimod, an MRP14-inhibitor, and an anti-HMGB1 antibody can improve clinical outcome as adjunctive therapeutics in pneumococcal meningitis. METHODS: We tested the adjuvant administration of paquinimod and the anti-HMGB1 antibody in our pneumococcal meningitis mouse model assessing clinical (clinical score, open-field-test, temperature) and pathophysiological parameters (intracranial pressure, white blood cell count in CSF, bleeding area) as well as bacterial titers in blood and brain 24 h after administration and 48 h after infection. Furthermore, we explored the interactions of these two agents with dexamethasone, the standard adjuvant treatment in pneumococcal meningitis (PM), and daptomycin, a non-bacteriolytic antibiotic preventing pathogen-associated molecular pattern (PAMP) release. RESULTS: Adjunctive inhibition of MRP14 or HMGB1 reduced mortality in mice with PM. This effect was lost when the two anti-DAMP agents were given simultaneously, possibly due to excessive immunosuppression. Combining anti-PAMP (daptomycin) and anti-DAMP treatments did not produce synergistic results; instead, the anti-DAMP treatment alone was sufficient and superior. The combination of anti-HMGB1 with dexamethasone did not diminish the effect of the former. CONCLUSIONS: DAMP inhibition possesses good potential as an adjuvant treatment approach in PM, as it improves clinical outcome and can be given together with the standard adjuvant dexamethasone without drug effect loss in experimental PM.

Specific behaviour, mood and personality traits may contribute to obesity in patients with craniopharyngioma.

INTRODUCTION: Patients with craniopharyngioma (CP) often suffer from obesity, but the underlying causes are still not fully understood. We compared CP to patients with nonfunctioning pituitary adenoma (NFPA) and to a control group (CG) using standardized questionnaires to investigate whether behavioural, mood or personality traits contribute to obesity. METHODS: We compared 31 patients with CP (42% male, 53 ± 15·1 years) to 26 patients with NFPA (71% male, 63·2 ± 10·3 years) and to age- and gender-matched local CG (ratio 2:1). Normative data from the literature are included for reference. Patients were asked to complete eleven standardized questionnaires. Two questionnaires were used to evaluate eating disorders (FEV, EDE-Q), one depression (BDI), one anxiety (STAI), three health-related quality of life (SF-36, EuroQoL, QoL-AGHDA), one sleepiness (Epworth Sleepiness Scale), two personality (EPQ-RK, TPQ) and one body image (FKB-20). RESULTS: Patients with CP scored significantly higher in conscious hunger perception (FEV, CP 5·8 ± 3·2 scores, NFPA 3·6 ± 3·3 scores, CG 3·0 ± 2·5, P < 0·001). They had similar scores for BDI compared with NFPA, but higher scores to CG (P < 0·001, CP 10·6 ± 8·3, NFPA 7·5 ± 5·7, CG 4·96 ± 4·2). CP and NFPA scored higher than CG for anxiety and personality traits such as harm avoidance, fatigability and asthenia and slightly higher for neuroticism. No differences were seen for EDE-Q, quality of life, daytime sleepiness and body image between CP and NFPA. However, differences could be observed to normative data from the literature. CONCLUSION: Obesity in patients with CP might be influenced by eating disorders, negative mood alterations and increased anxiety-related personality traits.

Early identification of renal transplant recipients with high risk of polyomavirus-associated nephropathy.

Polyomavirus BK (BKPyV) is ubiquitous among humans. Following primary infection, the virus remains latent predominantly in the hosts' uroepithelial cells. Up to 10 % of renal transplant recipients show a viral reactivation that can lead to polyomavirus-associated nephropathy (PyVAN). In the absence of early treatments, the risk of graft loss is up to 80 %. Monitoring viral load in urine and plasma by real-time PCR after transplantation is the most common diagnostic tool to detect viral reactivation. In the present retrospective study, BKPyV-DNA loads in urine and plasma by quantitative real-time PCR were associated with clinical data, including HLA haplotype, blood parameters and viral genotype, of 40 renal transplant recipients at the University Clinics of Cologne. Seventeen out of 329 patients screened for BKPyV from January 2009 to October 2013 were detected BKPyV positive in urine only, whereas in 23 patients the virus became additionally detectable in plasma. Among these, ten patients progressed to PyVAN. Overall, the present study showed that the detection from the third month onwards after transplantation of a first viruric episode with a median viral load of 1 × 10(8) copies/mL, followed after few days by a first viremic episode with a median viral load of >1 × 10(4) copies/mL, was strongly associated with the development of PyVAN. In conclusion, the viral load and the temporal profile of the first viruric and viremic episode post-transplantation, in combination with specific features of the host immune response, should be considered as relevant clinical determinants of the risk of renal transplant recipients to progress to PyVAN.

Anxious and non-anxious forms of major depression: familial, personality and symptom characteristics.

BACKGROUND: Earlier clinical studies have suggested consistent differences between anxious and non-anxious depression. The aim of this study was to compare parental pathology, personality and symptom characteristics in three groups of probands from the general population: depression with and without generalized anxiety disorder (GAD) and with other anxiety disorders. Because patients without GAD may have experienced anxious symptoms for up to 5 months, we also considered GAD with a duration of only 1 month to produce a group of depressions largely unaffected by anxiety. METHOD: Depressive and anxiety disorders were assessed in a 10-year prospective longitudinal community and family study using the DSM-IV/M-CIDI. Regression analyses were used to reveal associations between these variables and with personality using two durations of GAD: 6 months (GAD-6) and 1 month (GAD-1). RESULTS: Non-anxious depressives had fewer and less severe depressive symptoms, and higher odds for parents with depression alone, whereas those with anxious depression were associated with higher harm avoidance and had parents with a wider range of disorders, including mania. CONCLUSIONS: Anxious depression is a more severe form of depression than the non-anxious form; this is true even when the symptoms required for an anxiety diagnosis are ignored. Patients with non-anxious depression are different from those with anxious depression in terms of illness severity, family pathology and personality. The association between major depression and bipolar disorder is seen only in anxious forms of depression. Improved knowledge on different forms of depression may provide clues to their differential aetiology, and guide research into the types of treatment that are best suited to each form.

Neuroinfectious diseases at a European neurological tertiary care center: one-third of patients require treatment in the neurological intensive care unit.

BACKGROUND AND PURPOSE: Studies on the impact of infectious diseases affecting the nervous system are sparse. METHODS: All patients with neuroinfectious diseases (NIDs) who were treated at our Department of Neurology from 2005 until 2009 were retrospectively analyzed. RESULTS: Patients with NIDs required treatment at the intensive care unit in 34.8%. The mortality rate of patients with NIDs was significantly higher than that of other inpatients with neurological diseases (5.1% vs. 3.0%, respectively, P = 0.018). CONCLUSION: In summary, this study shows that patients with NIDs are severely ill and mortality is high.

[Lyme borreliosis]. / Lyme-Borreliose.

Lyme borreliosis is a multisystem infectious disease affecting mainly the skin, nervous system, joints and heart. It is caused by spirochetes of the Borrelia burgdorferi sensu lato complex which are transmitted by ticks. The diagnosis of Lyme borreliosis is based primarily on typical clinical symptoms and signs with serological confirmation. Antibiotic therapy is beneficial for all manifestations and treatment refractory cases are rare. The diagnosis "chronic Lyme borreliosis" is increasingly being misused for all conceivable medically unexplained symptoms.

Increased prevalence of anxiety-associated personality traits in patients with Cushing's disease: a cross-sectional study.

BACKGROUND/AIMS: Chronic hypercortisolism in Cushing's disease (CD) has been suggested to contribute to an altered personality profile in these patients. We aimed to test this hypothesis and attempted to determine the effects of disease- and treatment-related factors that might moderate an altered personality in CD. METHODS: We assessed 50 patients with CD (74% biochemically controlled) and compared them to 60 patients with non-functioning pituitary adenomas (NFPA) and 100 age- and gender-matched mentally healthy controls. Personality was measured by two standardized personality questionnaires, TPQ (Cloninger personality questionnaire) and EPQ-RK (Eysenck personality questionnaire-RK). RESULTS: Compared to mentally healthy controls, CD patients reported significantly less novelty-seeking behaviour, including less exploratory excitability and less extravagance. On harm avoidant subscales, they presented with more anticipatory worries and pessimism, higher fear of uncertainty, shyness with strangers, fatigability and asthenia. Moreover, CD patients appeared to be less extraverted, more neurotic and socially desirable. CD patients differed from NFPA patients in terms of higher neuroticism scores, and NFPA patients did not show altered novelty-seeking behaviour or extraversion. In the subgroup analysis, CD patients with persistent hypercortisolism displayed significantly higher fear of uncertainty, fatigability and asthenia, indicating high harm avoidance in total, than those in biochemical remission. CONCLUSION: Patients with CD showed a distinct pattern of personality traits associated with high anxiety in combination with traits of low externalizing behaviour. Such personality changes should be taken into account in the diagnosis and treatment of CD patients, as they might interfere with the patient-physician communication and/or challenge the patients' social and psychological functioning.

Factors associated with the seroprevalence of 26 cutaneous and two genital human papillomavirus types in organ transplant patients.

Viral skin infections are commonly present in organ transplant recipients (OTR). In this study, we aimed to identify factors associated with human papillomavirus (HPV) infections in OTR. Patients with solid-organ transplants were recruited from the outpatient nephrology and dermatology clinics in five European countries. Only patients with no current or past skin cancer were included in this analysis. Serum samples were analysed for antibodies to the L1 proteins of 26 cutaneous and two genital HPV types from five phylogenetic genera (α, ß, γ, µ and ν). The most consistent association was found between recreational sun exposure and the seroprevalence of all tested genera, except α. The antibody presence of any ß type was higher among people who had been transplanted at least 23 years prior to participation than in those who had been transplanted for less than 7 years. The prevalence of two γ-HPV types (60 and 65) and three ß-HPV types (15, 38 and 49) was associated with time since transplantation. The presence of a high number of warts was associated with the presence of any µ-PV or ν-PV types, and having greater than 50 keratotic skin lesions was almost significantly associated with the presence of antibodies to two or more γ-PV. Discrepancies in the results of the present study, as well as in previous reports, may depend on different methodologies and on geographical variations. Our results also indicate that further research with more standardized methods is needed to clarify the role of cutaneous HPV in OTR.

TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies.

The lifetime prevalence of panic disorder (PD) is up to 4% worldwide and there is substantial evidence that genetic factors contribute to the development of PD. Single-nucleotide polymorphisms (SNPs) in TMEM132D, identified in a whole-genome association study (GWAS), were found to be associated with PD in three independent samples, with a two-SNP haplotype associated in each of three samples in the same direction, and with a P-value of 1.2e-7 in the combined sample (909 cases and 915 controls). Independent SNPs in this gene were also associated with the severity of anxiety symptoms in patients affected by PD or panic attacks as well as in patients suffering from unipolar depression. Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex. In parallel, using a mouse model of extremes in trait anxiety, we could further show that anxiety-related behavior was positively correlated with Tmem132d mRNA expression in the anterior cingulate cortex, central to the processing of anxiety/fear-related stimuli, and that in this animal model a Tmem132d SNP is associated with anxiety-related behavior in an F2 panel. TMEM132D may thus be an important new candidate gene for PD as well as more generally for anxiety-related behavior.

Distinct dopaminergic personality patterns in patients with prolactinomas: a comparison with nonfunctioning pituitary adenoma patients and age- and gender-matched controls.

INTRODUCTION: Personality patterns such as extraversion and novelty seeking have been associated with an altered dopaminergic activity in healthy subjects. Patients with prolactinomas have been described as exhibiting an altered dopaminergic tone and are often treated with dopamine agonists. Little is known about the personality traits of this patient group. Hence, we aimed at examining whether patients with prolactinomas exhibit modified personality patterns compared to patients with nonfunctioning pituitary adenomas and healthy controls. SUBJECTS/METHODS: In this cross-sectional study, 86 patients with prolactinomas and 58 patients with nonfunctioning pituitary adenomas (NFPA) were compared with 172 mentally healthy age- and gender-matched controls. To assess personality traits, standardized personality questionnaires (Eysenck personality questionnaire-EPQ-RK and Tridimensional Personality Questionnaire devised by Cloninger-TPQ) were administered. RESULTS: Patients with either prolactinomas or NFPA showed a distinct personality profile compared to the normal population, characterized by increased neuroticism and they also answered in a socially desirable mode. On harm-avoidant total and subscales, they presented with a higher fear of uncertainty and also increased fatigability and asthenia. The prolactinoma patients, when contrasted with the 'clinical' control group of patients with NFPA and after post hoc tests for multiple comparisons following the Bonferroni-Holm procedure showed significantly reduced extraversion (p = 0.044) and increased shyness with strangers (p = 0.044), tending to be more neurotic and present lower scores in the novelty seeking subscale impulsiveness. CONCLUSION: This is, to our knowledge, the first study providing new evidence of an altered personality profile of prolactinoma patients which might affect the patient-doctor relationship, treatment and patient's quality of life.

Cognitive function in acromegaly: description and brain volumetric correlates.

In acromegaly, we reported on increased rates of affective disorders such as dysthymia and depression, as well as structural brain changes. Objective of this study was to determine if cognitive impairments in patients with acromegaly exist and whether such impairments are associated with structural brain alterations defined by magnetic resonance imaging (MRI). In this cross-sectional study, 55 patients with biochemically confirmed acromegaly were enrolled. MRI data were compared with 87 control subjects. Main outcome measures were performance levels in 13 cognitive tests covering the domains of attention, memory and executive function, with performance below the cut-off level of the 16th percentile rated as impaired. In addition, individual global and hippocampal volume changes were defined for each patient in reference to a normative sample. We found that up to 33.3% of the patients were impaired in the attention, up to 24.1% in the memory, and up to 16.7% in the executive function domain. 67.3% of the patients failed to reach the cut-off level in at least one subtest. MRI demonstrated increased global, left and right hippocampal grey matter and white matter, particularly early in the disease course. Rather few positive than expected negative correlations could be established between the hippocampal grey matter gain and cognitive performance. Cognitive dysfunction, particularly attentional deficits, are common in acromegaly, rendering neuropsychological testing essential in the diagnostic work-up.

A case-control study of betapapillomavirus infection and cutaneous squamous cell carcinoma in organ transplant recipients.

We examined the association between betapapillomavirus (betaPV) infection and cutaneous squamous cell carcinoma (SCC) in organ transplant recipients. A total of 210 organ transplant recipients with previous SCC and 394 controls without skin cancer were included. The presence of 25 betaPV types in plucked eyebrow hairs was determined using a human papillomavirus (HPV) DNA genotyping assay, and antibodies for the 15 most prevalent betaPV types were detected using multiplex serology. We used multivariate logistic regression models to estimate associations between various measures of betaPV infection and SCC. BetaPV DNA was highly prevalent (>94%) with multiple types frequently detected in both groups. We found a significant association between SCC and the concordant detection of both antibodies and DNA for at least one betaPV type (adjusted OR 1.6; 95% CI 1.1;2.5). A borderline-significant association with SCC was found for HPV36 (adjusted OR 2.4; CI 1.0;5.4), with similar associations for HPV5, HPV9 and HPV24. These data provide further evidence of an association between betaPV infection and SCC in organ transplant recipients. Confirmation of a betaPV profile predictive of risk for SCC may pave the way for clinically relevant pretransplant HPV screening and the development of preventive and therapeutic HPV vaccination.

Somatization in major depression--clinical features and genetic associations.

OBJECTIVE: To identify clinical variables and genetic variations within monoaminergic genes known to be implicated in pain perception that are associated with the occurrence of somatization symptoms in patients with major depression. METHOD: Somatization was evaluated using the respective subscale of the Symptom Checklist SCL-90-R. Six monoaminergic genes were identified showing an involvement in pain perception and somatization according to the literature: COMT, HTR2A, SLC6A2, SLC6A4, DRD4, and TPH1. One hundred and eighteen single nucleotide polymorphisms (SNPs) within these genes were genotyped using Illumina BeadChips in a sample of 398 at least moderately to severely depressed in-patients participating in the Munich Antidepressant Response Signature (MARS) project. RESULTS: Thirty SNPs exhibit nominally significant associations with somatization. One SNP (rs9534505) located in intron 2 of the HTR2A gene withstood correction for multiple testing. Clinical data provide further evidence for strong impact of somatization on the presentation of depressive symptoms and description of a patient subgroup with unfavorable clinical outcome. CONCLUSION: Our results demonstrate the influence of a HTR2A polymorphism on aspects of somatization in major depression, which co-occurs with an unfavorable antidepressant treatment outcome. These results confirm and expand previous findings on somatization as a risk factor for treatment outcome in major depression.

More CLEC16A gene variants associated with multiple sclerosis.

OBJECTIVES: Recently, associations of several single-nucleotide polymorphisms (SNPs) within the CLEC16A gene with multiple sclerosis (MS), type-I diabetes, and primary adrenal insufficiency were reported. METHODS: We performed linkage disequilibrium (LD) fine mapping with 31 SNPs from this gene, searching for the region of highest association with MS in a German sample consisting of 603 patients and 825 controls. RESULTS: Four SNPs located in intron 19 of the CLEC16A gene were found associated. We could replicate the finding for SNP rs725613 and were able to show for the first time the association of rs2041670, rs2080272 and rs998592 with MS. CONCLUSION: All described base polymorphisms are mapping to one LD block of approximately 50 kb within intron 19 of the CLEC16A gene, suggesting a pivotal role of this region for susceptibility of MS and possibly also for other autoimmune diseases.

[Biology of epidermodysplasia verruciformis-associated HPV]. / Biologie der Epidermodysplasia-verruciformis-assoziierten HPV.

The genus betapapillomavirus (betaPV) presently comprises more than 40 virus types including the so-called epidermodysplasia verruciformis (EV)-associated HPV, which were originally detected in EV-patients by Southern blot hybridization. BetaPV are ubiquitous in the general population and frequently establish themselves already during the first weeks of life. Hair follicles are regarded as natural reservoir. About 25% of betaPV detected in adults persist for at least 9 months. Due to very low virus production, seroconversion against betaPV starts sluggishly. Hyperproliferation of keratinocytes in psoriasis patients or after severe burns stimulates virus replication. Massive virus replication only occurs in EV-patients, associated with the induction of disseminated skin lesions with a high risk of malignant conversion. In 75% of EV-patients this can be put down to homozygous, inactivating mutations in the genes EVER1 or EVER2. A transgenic mouse model substantiated the crucial role of increased HPV8 oncogene expression, induced by UV-irradiation or wounding, for tumor induction.

Listeria meningitis: identification of a cerebrospinal fluid inhibitor of macrophage listericidal function as interleukin 10.

The killing of bacteria gaining access to the central nervous system is insufficient and requires bactericidal antibiotics for treatment. The inefficient host response in cerebrospinal fluid (CSF) is thought to be due to impaired phagocytosis in CSF, and low local concentration of antibody and complement. In addition, the CSF may contain inhibitors, disabling phagocytes to eliminate bacteria. We have assessed the bactericidal activity of macrophages in the presence of CSF from mice infected intracerebrally with Listeria monocytogenes (LM). Pretreatment of J774A.1 macrophages with interferon gamma (IFN-gamma) resulted in high levels of nitric oxide-dependent intracellular killing of LM. CSF taken from mice 24 h after infection (CSF-LM 24) contained IFN-gamma and induced killing of LM by macrophages. However, pulsing J774A.1 cells with IFN-gamma in the presence of CSF obtained from mice at later time points (48 h) rendered macrophages partly permissive for intracellular Listeria growth. The inhibitor detected in CSF-LM 48 was identified as IL-10 since: (a) IL-10 dose dependently impaired the listericidal activity of IFN-gamma-activated macrophages; (b) anti-IL-10 antibodies abrogated the bacterial growth permissive effect of CSF-LM 48; and (c) IL-10 was detected in CSF-LM 48 but not in CSF-LM 24 or CSF of mock-injected animals (CSF-Co). Likewise, IL-10 was found in the CSF of 95% of patients with bacterial meningitis.

Transforming growth factor beta 2 inhibits cerebrovascular changes and brain edema formation in the tumor necrosis factor alpha-independent early phase of experimental pneumococcal meningitis.

Macrophages and granulocytes seem to play a key role in the pathogenesis of bacterial meningitis. Transforming growth factor beta (TGF-beta) leads to macrophage deactivation, as well as to inhibition of cytokine production and of endothelial granulocyte adhesion. We have investigated the influence of TGF-beta on regional cerebral blood flow (rCBF), intracranial pressure (ICP), and brain edema formation during the early phase of experimental meningitis. Rats which were inoculated intracisternally with live pneumococci or with pneumococcal cell wall hydrolyzed by the M1 muramidase (PCW-M) developed an increase of rCBF and ICP within 4 h postintracisternal challenge. A single intraperitoneal injection of TGF-beta 2 but not of TGF-beta 2 vehicle-control prevented the changes of rCBF. Furthermore, TGF-beta 2 significantly reduced the increase of ICP in rats inoculated with PCW-M. Likewise, the elevation of brain water content after intracisternal injection of pneumococci or PCW-M was blocked by pretreatment of rats with TGF-beta 2. TGF-beta 1 exhibited similar inhibitory effects in PCW-M-injected rats. The beneficial effects of TGF-beta 2 on the initial phase after pneumococcal inoculation seem to be tumor necrosis factor alpha- (TNF-alpha) independent since (a) intracisternal or intraperitoneal injection of neutralizing anti-TNF-alpha antibodies did not significantly influence rCBF, ICP, and brain water content in PCW-M-induced meningitis; and (b) TNF-alpha was only occasionally detected at low levels in cerebrospinal fluid at 4 h after PCW-M application.

An analysis of clustering of betapapillomavirus antibodies.

Betapapillomaviruses (betaPVs) may contribute to the aetiology of cutaneous squamous cell carcinoma. However, no high-risk types have yet been identified, possibly because the high frequency of co-infection prevents a straightforward analysis of the independent effects of individual viruses. This study aimed to determine whether specific virus types were more likely to co-occur than others, thereby reducing the number of parameters needed in statistical models. Antibody data were analysed from controls who participated in case-control studies in The Netherlands, Italy and Australia and from participants in the German Nutrition Survey. Cluster analysis and two ordination techniques were used to identify patterns. Evidence of clustering was found only according to the number of viruses to which antibodies were detected. The lack of clustering of specific viral types identified suggests that if there are betaPV types that are independently related to skin carcinogenesis, they are unlikely to be identified using standard epidemiological methods.

Intrafamilial transmission and family-specific spectra of cutaneous betapapillomaviruses.

Cutaneous human betapapillomaviruses (beta-HPVs) are widespread in the general population and have been associated with skin cancer. To evaluate the impact of continuous person-to-person contact within families on an individual's beta-HPV type spectrum, we collected serial skin swab samples from parents and children from 10 families. All participants were found to be beta-HPV DNA positive, with 1 to 13 types at study entry (median, 4.0 types). Initial and cumulative (2 to 16 types) HPV type multiplicities varied widely between different families but only a little between family members. The high intrafamilial correlation of HPV multiplicity is already obvious for babies aged 10 days to 10 months. Family members typically displayed similar spectra of HPV types. More than 75% of the HPV types in babies were also detected in their parents. This indicates that HPV transmission mainly results from close contact between family members. Type-specific persistence for at least 9 months was more prevalent in parents (92%) than in children (66%). Of the types detected throughout the study, 24% turned out to persist in the parents and only 11% in the children. Interestingly, about one-half of the HPV types found to persist in one of the parents occurred less frequently or even only sporadically in the spouse. Similarly, only one-third of the persisting parental types also persisted in their children. This indicates that even regular exposure to cutaneous HPV does not necessarily lead to the establishment of a persistent infection, which may point to type-specific susceptibilities of different individuals.

Anal carcinoma in human immunodeficiency virus-positive men: results of a prospective study from Germany.

BACKGROUND: Anal intraepithelial neoplasia (AIN), a human papillomavirus (HPV)-associated potential precursor lesion of anal cancer, is frequent among human immunodeficiency virus (HIV)-positive men who have sex with men (MSM). There is a paucity of data published on the progression of high-grade AIN to invasive cancer as well as on clinical and virological characteristics comparing anal margin and anal canal carcinoma. OBJECTIVES: To search for anal carcinoma and AIN in a large series of HIV-positive MSM, to assess treatment response of anal carcinoma, and to analyse lesional HPV spectrum of anal cancers. METHODS: Detection of anal carcinoma and AIN was performed using cytology, high-resolution anoscopy, and histology in case of abnormal findings. Additionally, HPV analyses for 36 high- and low-risk α-HPV types were performed in patients with anal carcinoma. RESULTS: In total, 446 German HIV-positive MSM were examined within an observation period of 5 years and 10 months. Of these, 116 (26·0%) patients had normal findings, 163 (36·5%) had low-grade AIN, 156 (35·0%) had high-grade AIN, and 11 (2·5%) had anal carcinoma as evidenced by the highest grade of cytology/histology. Five patients with anal cancer, who had refused treatment of their precancerous lesions, had progressed from high-grade AIN to invasive cancer within a median time of 8·6 months. All anal cancers carried high-risk α-HPV types. All five squamous cell carcinomas (SCCs) of the anal canal were HPV16 positive. In contrast, only one of the four anal margin SCCs were HPV16 positive (HPV31, HPV33 and HPV33 + HPV68 were found in the other three anal margin SCCs). HPV59 was found in two adenocarcinomas, one of which additionally carried HPV33. In contrast to the cancer biopsies, a broad spectrum of surface high- and low-risk HPV types was found in anal swabs of the patients. Surgical excision resulted in long-term disease control of all anal margin carcinomas, whereas combined chemoradiotherapy in carcinomas of the anal canal was associated with high recurrence rates, high toxicity, and high mortality. CONCLUSIONS: Anal carcinoma and AIN are frequent in HIV-positive men, even in patients participating in anal cancer prevention programmes. High-grade dysplasia in these patients can progress to invasive cancer within a short period of time. Anal margin carcinoma and anal canal carcinoma differ substantially in their lesional HPV spectrum, prognosis and treatment response.