Functional host-specific adaptation of the intestinal microbiome in hominids.

Fine-scale knowledge of the changes in composition and function of the human gut microbiome compared that of our closest relatives is critical for understanding the evolutionary processes underlying its developmental trajectory. To infer taxonomic and functional changes in the gut microbiome across hominids at different timescales, we perform high-resolution metagenomic-based analyzes of the fecal microbiome from over two hundred samples including diverse human populations, as well as wild-living chimpanzees, bonobos, and gorillas. We find human-associated taxa depleted within non-human apes and patterns of host-specific gut microbiota, suggesting the widespread acquisition of novel microbial clades along the evolutionary divergence of hosts. In contrast, we reveal multiple lines of evidence for a pervasive loss of diversity in human populations in correlation with a high Human Development Index, including evolutionarily conserved clades. Similarly, patterns of co-phylogeny between microbes and hosts are found to be disrupted in humans. Together with identifying individual microbial taxa and functional adaptations that correlate to host phylogeny, these findings offer insights into specific candidates playing a role in the diverging trajectories of the gut microbiome of hominids. We find that repeated horizontal gene transfer and gene loss, as well as the adaptation to transient microaerobic conditions appear to have played a role in the evolution of the human gut microbiome.

Genome-wide mapping of gene-microbe interactions in the murine lung microbiota based on quantitative microbial profiling.

BACKGROUND: Mammalian lungs comprise a complex microbial ecosystem that interacts with host physiology. Previous research demonstrates that the environment significantly contributes to bacterial community structure in the upper and lower respiratory tract. However, the influence of host genetics on the makeup of lung microbiota remains ambiguous, largely due to technical difficulties related to sampling, as well as challenges inherent to investigating low biomass communities. Thus, innovative approaches are warranted to clarify host-microbe interactions in the mammalian lung. RESULTS: Here, we aimed to characterize host genomic regions associated with lung bacterial traits in an advanced intercross mouse line (AIL). By performing quantitative microbial profiling (QMP) using the highly precise method of droplet digital PCR (ddPCR), we refined 16S rRNA gene amplicon-based traits to identify and map candidate lung-resident taxa using a QTL mapping approach. In addition, the two abundant core taxa Lactobacillus and Pelomonas were chosen for independent microbial phenotyping using genus-specific primers. In total, this revealed seven significant loci involving eight bacterial traits. The narrow confidence intervals afforded by the AIL population allowed us to identify several promising candidate genes related to immune and inflammatory responses, cell apoptosis, DNA repair, and lung functioning and disease susceptibility. Interestingly, one genomic region associated with Lactobacillus abundance contains the well-known anti-inflammatory cytokine Il10, which we confirmed through the analysis of Il10 knockout mice. CONCLUSIONS: Our study provides the first evidence for a role of host genetic variation contributing to variation in the lung microbiota. This was in large part made possible through the careful curation of 16S rRNA gene amplicon data and the incorporation of a QMP-based methods. This approach to evaluating the low biomass lung environment opens new avenues for advancing lung microbiome research using animal models.

[Phlebology in German departments of dermatology. An analysis on behalf of the German Society of Phlebology]. / Phlebologie an deutschen Hautkliniken. Eine Bestandsaufnahme im Auftrag der Deutschen Gesellschaft für Phlebologie.

BACKGROUND: Phlebologic diseases have become extremely common and have major socio-economic impact. However, the percentage of dermatologists working in phlebology appears to be decreasing according to the data of the German Society of Phlebology (DGP). METHODS: To investigate the reasons for this development, we--on behalf of the DGP--sent a questionnaire to 120 German Departments of Dermatology in autumn 2012. RESULTS: In 76 returned questionnaires, the number of physicians with additional fellowship training in phlebology averaged 1.5; the average number of those who fulfill the criteria for training fellows in phlebology was 0.9. In 71.1 % of the departments there was a phlebologist. A special phlebologic outpatient clinic existed in 73.7 % of the departments. Sonography with Doppler (89.5 %) and duplex (86.8 %) was used as the most frequent diagnostic tool. For therapy, compression (94.7 %), sclerotherapy (liquid 78.9 %, foam 63.2 %, catheter 18.4 %), endoluminal thermic procedures (radio wave 28.9 %, laser 17.1 %) and surgery (especially crossectomy and stripping 67.1 %, phlebectomy of tributaries 75 %) were used. The average number of treatments was very heterogenous in the different departments. CONCLUSIONS: Phlebology definitely plays an important role in dermatology. Most departments fulfill the formal criteria for the license to conduct advanced training in phlebology. A wide spectrum of phlebological diagnostic and therapeutic procedures is available.

Lifestyle drugs in old age--a mini-review.

Normal aging is no disease. The individual lifestyle may be responsible for a large fraction of the so-called 'age-related' changes. An increasing number of healthy individuals make use of 'lifestyle' drugs, such as nootropics, psychopharmaca, hormones and ecodrugs. In this respect, the fact that many people try to improve their outer appearance, to solve their 'cosmetic problems', to influence their rate of hair growth and to altogether delay, halt or even reverse the natural aging process has become a relevant matter for the practising doctor. Lifestyle drugs are taken in an attempt to increase personal life quality by means of attaining a certain psychosocially defined medical or beauty ideal, rather than to manage a medically identifiable, well-defined disease. Often, patients suffering from somatoform disorders such as hypochondriac disorders, body dysmorphic disorders, somatization disorders or persistent somatoform pain disorders may spontaneously ask physicians to prescribe them lifestyle drugs. Also, when 'healthy' people demand a lifestyle drug, possible side effects and contraindications must be taken into consideration and ruled out.

[Borderline personality disorder in dermatology]. / Emotional instabile Persönlichkeitsstörung (Borderline-Störung) in der Dermatologie.

Borderline personality disorder is a syndrome of complex psychopathology which is not very common in dermatology. The emotional symptoms are broad and variable, but typically feature emotional instability, intense anger or lack of control of anger, impulsiveness, instabilities in self-perception, problems at work, chronic feelings of emptiness, unstable partnership relations and recurrent suicidal threats. Self-inflicted injuries are common and may lead patients to dermatologists. A 26-year old woman with borderline personality was hospitalized for neurosyphilis. During inpatient treatment she repeatedly cut herself with razor blades. This article highlights the diagnostic criteria and differential approach of the borderline personality disorder in order to facilitate early recognition and therapy.

[Suicidal behavior in dermatology]. / Suizidalität in der Dermatologie.

Even in dermatology one can potentially encounter suicidal patients. A risk of suicide can be preexisting, appear as complication of skin disorders or be triggered by medications such as interferons. Patients at risk must be specifically asked about suicidal ideations and tendencies. Acute suicide risk requires immediate crisis intervention. In dermatology suicide risk has been described in severe acne conglobata (especially men) and metastatic melanoma. Patients with chronic or potentially fatal disease or severe pain may be suicidal. In addition patients with depression, alcohol dependency, substance abuse, schizophrenia or borderline personality disorder are at special risk. We review psychodermatological diseases with risk of suicide and point out treatment strategies. More attention should be focused on the early recognition of a possible risk of suicide in dermatology patients.

New lifestyle drugs and somatoform disorders in dermatology.

An increasing number of healthy individuals make use of 'lifestyle' drugs, such as nootropics, psychopharmaca, hormones and eco-drugs. In this respect, the fact that many people try to improve their outer appearance, solve their 'cosmetic problems', influence their rate of hair growth and altogether delay, halt or even reverse the natural ageing process has become a relevant matter for the practising dermatologist. Lifestyle drugs in dermatology are taken in an attempt to increase personal life quality by means of attaining a certain, psychosocially defined beauty ideal. They are not taken to manage a medically identifiable, well-defined disease. Often, patients suffering from somatoform disorders, such as hypochondriac disorders, body dysmorphic disorders, somatization disorders or persistent somatoform pain disorders, may spontaneously ask physicians, in particular dermatologists and plastic surgeons, to prescribe them lifestyle drugs. Typically, patients repeatedly present with alleged 'physical symptoms' that turn out to be subjective complaints without any underlying identifiable medical disease. The use of lifestyle drugs without any proper medical indication may lead to a chronification of the emotional disorders that had ultimately been the cause of the patients' request for such drugs. Such disorders may need to be treated promptly with psychotherapy and/or appropriate psychopharmacotherapy, and the choice of the treatment requires an accurate differential diagnostic approach.

[Nihilodermia in psychodermatology]. / Nihilodermie in der Psychodermatologie.

"Nihilodermia" refers to a group of difficult "problem" patients in dermatology without objective findings but with recurrent symptoms and stubborn demand for medical examination. These primary emotional disorders are somatoform disorders, but the patients usually strictly deny a psychosocial aspect and expect purely somatic treatment. Clinical patterns include pruritus, pain, paresthesias, feelings of disfiguration, eco-syndromes, erythrophobia and psychogenic pseudoeffluvium. The relevant somatoform disorders in dermatology can be differentiated as somatization disorders, hypochondriacal disorders, somatoform autonomous disorders, persistent somatoform pain disorders and "other somatoform disorders". A precise differential diagnostic division is necessary in order to initiate adequate therapy strategies.

Assessment of psychological aspects during systemic provocation tests in patients with pseudoallergic drug reactions.

BACKGROUND: Basic mechanisms of pseudoallergic drug reactions as well as a possible role of the psyche are currently unknown. OBJECTIVE: Examination of psychological status and reactions during diagnostic provocation tests in patients with previous pseudoallergic reactions to drugs. SUBJECTS AND METHODS: Ten inpatients, admitted for provocation tests, were studied in a double-blind, placebo-controlled setting, with inventories of anxiety and depression being measured at baseline and psychological reactions and symptoms being recorded daily by patients and the attending physician. RESULTS: Patients reported more than twice as many symptoms as the physician, independent of the type of exposure. While the basic psychological profile of the patients was normal, anxiety trait and state values were high during testing, with a significant increase depending on whether the patients thought they had received a drug or a placebo. Similarly, frequency of symptoms was dependent on the patients' perception of the type of exposure. CONCLUSION: These findings demonstrate a high level of anxiety during systemic provocation tests in patients with previous pseudoallergic drug reactions, raising serious questions as to the diagnostic validity of the routine application of this testing.

Clinical pictures and classification of somatoform disorders in dermatology.

Somatoform disorders in dermatology are a heterogeneous group from a biopsychosocial point of view. Among the clinical patterns we find, for example, pruritus, pain, paresthesia as well as feelings of disfiguration, eco-syndromes, erythrophobia or psychogenic pseudoeffluvium. The multiple clinical symptoms are usually accompanied by psychosocial disorders, these are subjective complaints by the patient which cannot be medically objectified. The relevant somatoform disorders in dermatology can be differentiated as somatisation disorders, hypochondriacal disorders, somatoform autonomous disorders, persistent somatoform pain disorders and "other somatoform disorders". A precise differential-diagnostic division is necessary in order to initiate adequate therapy strategies. With this overview article, we would like to make an updated classification recommendation for dermatology and present experiences in therapy.

Crossreacting IgG antibodies against fox mite antigens in human scabies.

Scabies continues to be an important parasitic disease of mammals. There remain, however, major gaps in the understanding of the human host immune response, and a simple diagnostic test is lacking. In contrast to human mites, red fox mites (Sarcoptes scabiei var. vulpis) can be collected easily and have been used, due to crossreactivity, for enzyme-linked immunosorbent assay (ELISA) studies in dogs and pigs. We wanted to investigate the possibility that crossreactivity might also exist for the human mite, and determined titers against fox mite antigens by ELISA in 41 patients with scabies. Specific IgG was significantly higher in patients with scabies than in healthy controls (P=0.01). The sensitivity was, however, only 48%, although it increased slightly during treatment (P=0.86). A positive correlation was also noted between disease duration and severity of infestation (r=0.5), with specific IgG titers increasing in parallel with severity of symptoms (P=0.01). Patients with symptomatic scabies for more than 4 weeks had furthermore significantly higher IgG titers than patients with a shorter duration of disease (P=0.007). In conclusion, these findings demonstrate IgG antibodies in human scabies that crossreact with fox mite antigens, thus encouraging the search for improved ELISAs with more specific mite antigens to produce a more sensitive detection system for scabies in humans.

Evidence for altered mast cell proliferation and apoptosis in cutaneous mastocytosis.

BACKGROUND: Mastocytosis presents as a focal or generalized increase of mast cells, particularly in the skin, but also in other organs. Activating mutations of KIT (formerly c-kit), the receptor of the mast cell growth factor stem cell factor (SCF), appear to play a key role in the pathogenesis of sporadic adult onset mastocytosis. However, these mutations are not present in childhood-onset and familial mastocytosis and also fail to explain the heterogeneity of adult-onset disease. Other factors such as prolonged survival of mast cells may therefore participate in causing and modulating the pathological increase of mast cells in mastocytosis. OBJECTIVES: To examine the expression of proliferation and apoptosis markers in the mast cells of cutaneous mastocytosis lesions in order to gain further insight into the pathogenesis of mastocytosis. METHODS: Lesional cutaneous biopsies from eight infants with solitary mastocytomas, five children with multiple mastocytomas, 11 children with generalized urticaria pigmentosa, 12 adults with urticaria pigmentosa, and skin from seven normal controls were used in this study. Serial sections were stained with toluidine blue to quantify mast cell numbers and with antibodies against the proliferation marker Ki67 protein, the tumour suppressor protein p53, and the inhibitor of cyclins and cyclin-dependent kinases p21WAF1/CIP1, using the alkaline phosphatase antialkaline phosphatase technique. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labelling (TUNEL) method was used to assess apoptosis. RESULTS: Cutaneous mast cell counts were significantly increased in all patient sections, particularly in childhood lesions, and similarly, a small but significant increase of proliferation was found in the lesional mast cells of all patients. Enhanced mast cell numbers and proliferation was associated with a significant decrease of TUNEL staining, particularly in mastocytomas. p53 expression was highly variable, with an overall significant increase in all patient skin mast cells, whereas p21 expression was barely observed at all. CONCLUSIONS: These findings further support the concept that an imbalance of mast cell proliferation and apoptosis is prevalent in mastocytosis lesions that may account in part for the increased focal mast cell accumulation in this condition.

Decreased cutaneous expression of stem cell factor and of the p75NGF receptor in urticaria.

BACKGROUND: Mast cells, the main effector cells in urticaria, have been reported to be increased in number in lesional and nonlesional skin of urticaria patients, but the underlying mechanisms have so far not been studied. Serum NGF has however, been reported to be increased in urticaria. OBJECTIVES: We have therefore explored the potential involvement of known mast cell growth modulating factors in urticaria. METHODS: Tissue sections from patients with different types of urticaria and healthy controls were studied for the immunohistochemical expression of known mast cell growth factors (stem cell factor, SCF; nerve growth factor, NGF), of the inhibitory granulocyte-macrophage colony-stimulating factor (GM-CSF), and of the corresponding receptors, using the alkaline phosphatase-antialkaline phosphatase technique. RESULTS: Compared to skin of normal controls, staining for SCF, but not for NGF and GM-CSF, was significantly decreased in epidermis, endothelium and perivascular cells in lesional and nonlesional skin of all urticarias. On separate analysis of urticaria subtypes, decreased expression reached significance only in delayed pressure urticaria. Expression of the p75NGF receptor (p75NGFR) was also significantly decreased on endothelium and on perivascular cells of lesional and nonlesional skin in all urticarias. On evaluation of serial sections, p75NGFR expression was also decreased on c-Kit positive dermal mast cells. In contrast, expression of the NGF receptor tyrosine kinase and of the SCF and GM-CSF receptors was unchanged. CONCLUSIONS: These findings show that SCF and p75NGFR are selectively and systemically down-regulated in the skin of urticaria patients and may represent a negative feedback to increased mast cell reactivity and proliferation.

Laser-induced weal and flare reactions: clinical aspects and pharmacological modulation.

BACKGROUND: Among the adverse effects of cutaneous laser therapy, weal and flare reactions immediately after treatment have received little attention, and the pathomechanisms are unclear. OBJECTIVES: To study clinical features and possible mechanisms of laser-induced weal and flare reactions in order to identify means of possible therapeutic intervention. METHODS: Normal skin from the inner arm of 20 volunteers was treated with an argon laser, and the size of weal and flare reactions was measured over a 60-min period. Skin biopsies were taken from four volunteers before and up to 24 h after laser treatment and examined histologically and immunohistologically. Possible underlying mechanisms were also explored using various topical or systemic pharmacological agents. RESULTS: Wealing was noted in 19 of 20, and flare reactions in all volunteers, with peak values at 15 min. Skin biopsies showed central coagulation of the tissue, cleft formation between epidermis and dermis, normal numbers of morphologically intact mast cells on toluidine blue staining close to the lesion, and only minor upregulation of endothelial and leucocyte adhesion molecules. In agreement with these findings, pretreatment with acetylsalicylic acid, the H1-blocker loratadine and triamcinolone cream was ineffective or resulted in a non-significant reduction of weal and flare reactions. In contrast, local anaesthetics as well as neuropeptide depletion of skin with capsaicin abolished the reactions almost completely. CONCLUSIONS: Transient weal and flare reactions in response to laser treatment occur in almost all persons and are based primarily on a neurogenic rather than a histamine- or mast cell-dependent mechanism.

[CD8-positive, CD30-negative cutaneous T-cell lymphoma simulating pyoderma gangrenosum]. / CD8-positives, CD30-negatives kutanes T-Zell-Lymphom unter dem klinischen Bild eines Pyoderma gangraenosum.

Ulcerated primary cutaneous lymphomas are not rare, but the clinical manifestation as a pyoderma gangrenosum look-alike is extraordinary. CD8-positive lymphomas are rare, unclassifiable tumours with variable prognosis. We report on a 49-year-old patient with a large ulcerated primary cutaneous lymphoma on the left chest wall presenting as pyoderma gangrenosum. With immunohistochemical staining, most lymphocytes were shown to be CD8-positive. The CD30 antigen was not expressed. After radiotherapy with complete skin irradiation, the lymphoma regressed completely. The patient has been free of relapse for 28 months so far.

Acute herpes zoster neuralgia: retrospective analysis of clinical aspects and therapeutic responsiveness.

BACKGROUND: Although the efficacy of modern antiviral agents for the treatment of herpes zoster is unquestioned, their ability to affect the associated pain remains controversial. OBJECTIVE: We have therefore evaluated the inpatient hospital records of 550 patients with herpes zoster with regard to pain-related clinical aspects and therapeutic responsiveness. METHODS: Intensity of pain was quantified by calculating a daily pain equivalence index (PEI) on the basis of different classes of pain medication and the number of tablets used in each category. RESULTS: The mean age of patients was 66.7 years, cranial segments were predominantly involved (55%), 64% of patients suffered from associated diseases and 77% experienced herpes-related pain. The PEI was 0.90 in the entire patient population, with significantly higher values in women and in patients with 3 or more associated diseases. It was lower in sacral and cranial nerve involvement, and it decreased rapidly in patients prior to discharge from hospital. Although there were significant differences in hospital stay between patients who received aciclovir and those who did not (mean 20.3 vs. 23.8 days), and for high- versus low-dose oral or intravenous administration, no significant differences were noted between the two groups for initial PEI values and during the course of observation, irrespective of the route of administration or the dose of aciclovir and the individual patient's PEI value. The groups were otherwise closely similar with regard to basic demographic and clinical data. 23.3% predominantly aged female patients with more associated diseases than the total patient population had a persistently elevated PEI and stayed in hospital beyond 21 days (mean 35.1 days), representing patients who went on to postherpetic neuralgia. CONCLUSION: These data further delineate clinical aspects of acute herpes zoster neuralgia, underline the unsolved therapeutic problems associated with this condition despite otherwise effective antiviral treatment, and characterise a subgroup of patients at risk to develop postherpetic neuralgia.

Expression of mast cell growth modulating and chemotactic factors and their receptors in human cutaneous scars.

In order to explore possible mechanisms involved in the previously documented turnover of mast cell subpopulations in human cutaneous scars, we have examined selected factors known to stimulate and/or modulate mast cell hyperplasia (SCF, NGF, TGFbeta1, GM-CSF) and their receptors in human cutaneous scar tissue. On immunohistochemistry, numbers of SCF- and TGFbeta1-positive cells were significantly increased in the epidermis and throughout the dermis in scars (n = 27) of varying ages (4-369 d old), compared with normal skin (n = 12). Furthermore, TRbetaRI, II, and the NGF-p75 receptors were significantly increased in the epidermis, TRbetaRI and NGF-TrkA throughout the dermis, and TRbetaRII, NGF-p75, and GM-CSFR only in the mid- and lower dermis of scars. NGF and GM-CSF expression was in contrast scarce and weak, with no differences between normal skin and scars. In tissue extracts, mRNA levels of SCF, TGFbeta1, TRbetaI and II, and both NGF-receptors, but not GM-CSFR, were significantly increased as well. TRbetaI and II were identified in up to 90% and 83%, respectively, of isolated normal skin mast cells on flow cytometry, and GM-CSFR and NGFR-p75 were identified on 70% and 73%, respectively, of avidin-positive normal mast cells on double immunofluorescence microscopy. As described before for the SCF receptor KIT, GM-CSFR and NGFR-p75 were partly or entirely downregulated on avidin-positive mast cells in scars. The marked upregulation of TGFbeta1, its type I and II receptors, and SCF suggest that these factors play a major role in the orchestration of mast cell increase in human cutaneous scars whereas the role of NGF and GM-CSF is less clear, despite the significant upregulation of their receptors.