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.

[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.

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.

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.

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.

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.

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.

Altered expression of mast cell chymase and tryptase and of c-Kit in human cutaneous scar tissue.

In order to explore a possible involvement of mast cells during human wound healing, we studied sections from scars (4-369-d-old) (N = 20) and normal skin (N = 10) for mast-cell-specific tryptase and chymase by enzyme histochemistry, for the stem cell factor receptor c-Kit and the melanosomal marker TA99 by immunohistochemistry, and for simultaneous c-Kit expression and avidin fluorescence by double staining. Enzyme activities and mRNA expression were also studied in tissue extracts. Chymase-reactive mast cell numbers as well as chymase activity and mRNA expression were reduced in all scars, whereas overall numbers of tryptase-reactive cells did not differ from normal skin, although tryptase activity and mRNA expression were increased in scar extracts. In contrast, numbers of c-Kit positive cells were significantly increased in old scars, and in the mid and lower dermis of all scars. A marked reduction of c-Kit reactivity was noted, however, in avidin-positive dermal mast cells and in epidermal basal cells, despite unchanged numbers of melanosome-positive cells, with an associated overall decrease of c-Kit mRNA in scar extracts. These data thus show that numbers of resident mast cells are very low in human cutaneous scars, suggesting massive mediator release from these cells into fresh wounds. Downregulation of stem cell factor receptors may also prevent these cells from increasing in number even in old scars. Instead, scar tissue is populated by a mast cell subpopulation that is chymase-, avidin-, tryptase +, c-Kit +, reflecting most probably an increased immigration and/or proliferation of immature mast cells and their precursors.

Clusters of perifollicular macrophages in normal murine skin: physiological degeneration of selected hair follicles by programmed organ deletion.

In back skin sections from adolescent C57BL/6 mice, regularly distributed, perifollicular inflammatory cell clusters (PICC) were found located around the distal noncycling portion of about 2% of all hair follicles examined. The PICC and the affected hair follicles were characterized during spontaneously developed or induced hair cycle stages, using antibodies against MHC Class II, F4/80, ER-MP23, NLDC 145, CD4, CD8, gammadeltaTCR, IL-1 receptor, and ICAM-1. PICC consisted predominantly of macrophages (MAC), accompanied by a few CD4+ cells, whereas gammadeltaTCR+ and CD8+ cells were absent. During anagen and catagen, some of the PICC+ hair follicles showed variable degenerative phenomena reminiscent of scarring alopecia: thickened basement membrane, ectopic MHC II expression, MAC infiltration into the follicle epithelium, and signs of keratinocyte apoptosis. Loss of distal outer root sheath keratinocytes was detected in 10% of PICC+ hair follicles (0.2% of all hair follicles). Because PICC were located in the vicinity of the bulge region, MAC-dependent damage to follicle stem cells might eventually lead to follicle degeneration. These perifollicular MAC clusters around selected hair follicles may indicate the existence of a physiological program of MAC-dependent controlled follicle degeneration by which damaged or malfunctioning follicles are removed by programmed organ deletion (POD).

Synaptic ribbons, spheres and intermediate structures in the developing rat retina.

The present study was conducted to investigate the qualitative and quantitative development of synaptic bodies in retinae of Wistar rats during postnatal days 4-28. In addition, the effects of different light regimens and of eye pigmentation on SB numbers were studied. Synaptic bodies were counted and measured in the outer plexiform layer of retinal tissue fixed and processed by routine electron microscopical techniques. At postnatal days 4 and 5, retinae showed only few synaptic bodies. The main numerical development of synaptic bodies occurred between postnatal days 4 and 9, numbers remaining more or less constant thereafter. The intracellular location of synaptic ribbons changed from predominantly cytoplasmic sites to positions at the membrane. In Wistar rats of postnatal day 15 held under a light/dark regimen, synaptic ribbon numbers and lengths were found to be significantly larger at night than at daytime. This was not observed in animals kept under constant darkness. In retinae of a pigmented rat strain, Brown Norway, total numbers of synaptic bodies were similar to those of Wistar rats, whereas the relative proportions of synaptic ribbons and spheres or sphere-like structures, respectively, differed between strains. These results are discussed with regard to synaptic body formation and regulation under the influence of light and eye pigmentation.

Day- and nighttime content of monoamines and their metabolites in the pineal gland of rat and hamster.

Day- and nighttime content of catecholamines, serotonin and their metabolites were measured in the pineal gland of Sprague-Dawley rats and Djungarian hamsters. In addition, monoamine turnover rates were determined in the hamster pineal gland following administration of alpha-methyl-p-tyrosine. Animals were decapitated in the middle of the light or dark period, respectively, and pineal tissue was analysed by high performance liquid chromatography with electrochemical detection. Pineals of both species exhibited day/night-differences in serotonin, 5-hydroxyindole-3-acetic acid and dopamine content. The hamster pineal gland further showed day/night differences in its content of epinephrine and 3-methoxy-4-hydroxyphenylethyleneglycol. The dopamine turnover rate was augmented at night, while norepinephrine turnover was constant. Immunohistochemical incubations of pineal paraffine sections showed fibers and terminals stained by antisera to tyrosine-hydroxylase (TH) and dopamine-beta-hydroxylase, and a few perikarya-like structures exhibiting TH immunoreactivity. The results support the view that dopamine, rather than only functioning as a norepinephrine precursor, is actively involved in the control of melatonin synthesis.

Day- and night-time contents of monoamines and their metabolites in the medial preoptic area of the rat hypothalamus.

The present study was conducted to investigate whether monoamines and their metabolites in the medial preoptic area (mPOA) of the rat hypothalamus exhibit differences in their contents between day and night. We therefore sampled the mPOA from adult animals of either sex at the middle of the light or dark period, respectively, and analyzed the tissue by means of high performance liquid chromatography with electrochemical detection. We found that, in female animals at mid-night, dopamine and 3,4-dihydroxyphenyl acetic acid (DOPAC) was reduced to 43 and 30%, respectively, of daytime levels, while the norepinephrine content was doubled. No significant differences were observed in male animals. We also conducted immunohistochemistry of the catecholamine synthesizing enzymes, tyrosine hydroxylase (TH) and dopamine-beta-hydroxylase (DBH), in sections from perfusion-fixed male rats and showed that TH is present in neuronal perikarya and processes in the anteroventral periventricular region of the mPOA, while DBH was only seen in fibers and terminals. Our results of sex-specific and day time-dependent variations in dopamine and norepinephrine concentrations indicate that the two monoamines are candidate neurotransmitters that may transmit diurnal information to the mPOA.

Strain differences in the ratio of synaptic body types in photoreceptors of the rat retina.

In the retinal outer plexiform layer of seven different rat strains, synaptic bodies (SB) were counted and, according to their morphology, characterized as synaptic ribbons (SR), synaptic spheres (SS) or intermediate structures. It was found that absolute SB numbers showed relatively small variations while SR/SS ratios differed considerably between the strains investigated. These results are discussed with respect to retinal pigmentation and to formation and degradation, respectively, of synaptic ribbons.

Psychosocial stress in tree shrews: clomipramine counteracts behavioral and endocrine changes.

Male tree shrews (Tupaia belangeri) provide an animal model to study the neurobehavioral consequences of chronic psychosocial stress. When living in visual and olfactory contact with a male conspecific by which it has been defeated, the subordinante tree shrew shows dramatic behavioral, physiological, and neuroendocrine changes. Because the over all pattern of these changes resemble a depression-like symptomatology, we investigated to what extent the behavioral and endocrine changes in subordinate animals can be reversed by treatment with the tricyclic antidepressant clomipramine. In the present study, animals were subjected to a 10-day period of psychosocial conflict to elicit stress-induced behavioral and endocrine alterations before the onset of drug treatment, and psychosocial stress continued throughout the treatment period of 30 days. Clomipramine was administered orally once daily at a dose of 50 mg/kg. The drug had a time-dependent restorative influence on marking and grooming behavior, locomotor activity, risk assessment, as well as on urinary cortisol and norepinephrine excretion. It, thus, appears that the clomipramine treatment counteracts the behavioral and endocrine effects of chronic psychosocial stress in tree shrews, and the time course of recovery corresponds closely to that observed when treating depressed patients in the clinic.

Preclinical diagnosis of pseudoxanthoma elasticum - methodological restrictions and ethical problems.

Pseudoxanthoma elasticum (PXE) is an inherited connective tissue disease. Only recently, mutations in the MRP6 gene on chromosome 16p13.1 have been identified in PXE families. Up to now, predictive testing has not been available. Since ultrastructural connective tissue alterations in overtly normal skin of predilection sites have supported preclinical diagnosis in children of affected individuals, we have screened the daughters of a PXE patient for these alterations. The patient's biopsy from lesional skin revealed elastin and collagen fibril abnormalities, but biopsies from the clinically inconspicuous daughters showed only ultrastructural alterations of collagen fibrils. These findings are inconclusive regarding the diagnosis of PXE in the daughters. Predictive or preclinical diagnosis of incurable, late-onset disorders creates complex social, ethical, and legal problems which call for special management strategies.

[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.