A disease-associated gene desert directs macrophage inflammation through ETS2.

Increasing rates of autoimmune and inflammatory disease present a burgeoning threat to human health1. This is compounded by the limited efficacy of available treatments1 and high failure rates during drug development2, highlighting an urgent need to better understand disease mechanisms. Here we show how functional genomics could address this challenge. By investigating an intergenic haplotype on chr21q22-which has been independently linked to inflammatory bowel disease, ankylosing spondylitis, primary sclerosing cholangitis and Takayasu's arteritis3-6-we identify that the causal gene, ETS2, is a central regulator of human inflammatory macrophages and delineate the shared disease mechanism that amplifies ETS2 expression. Genes regulated by ETS2 were prominently expressed in diseased tissues and more enriched for inflammatory bowel disease GWAS hits than most previously described pathways. Overexpressing ETS2 in resting macrophages reproduced the inflammatory state observed in chr21q22-associated diseases, with upregulation of multiple drug targets, including TNF and IL-23. Using a database of cellular signatures7, we identified drugs that might modulate this pathway and validated the potent anti-inflammatory activity of one class of small molecules in vitro and ex vivo. Together, this illustrates the power of functional genomics, applied directly in primary human cells, to identify immune-mediated disease mechanisms and potential therapeutic opportunities.

Noradrenergic neuromodulation in ageing and disease.

The locus coeruleus (LC) is a small brainstem structure located in the lower pons and is the main source of noradrenaline (NA) in the brain. Via its phasic and tonic firing, it modulates cognition and autonomic functions and is involved in the brain's immune response. The extent of degeneration to the LC in healthy ageing remains unclear, however, noradrenergic dysfunction may contribute to the pathogenesis of Alzheimer's (AD) and Parkinson's disease (PD). Despite their differences in progression at later disease stages, the early involvement of the LC may lead to comparable behavioural symptoms such as preclinical sleep problems and neuropsychiatric symptoms as a result of AD and PD pathology. In this review, we draw attention to the mechanisms that underlie LC degeneration in ageing, AD and PD. We aim to motivate future research to investigate how early degeneration of the noradrenergic system may play a pivotal role in the pathogenesis of AD and PD which may also be relevant to other neurodegenerative diseases.

Transcutaneous spinal DC stimulation reduces pain sensitivity in humans.

Non-invasive approaches to pain management are needed to manage patient pain escalation and to providing sufficient pain relief. Here, we evaluate the potential of transcutaneous spinal direct current stimulation (tsDCS) to modulate pain sensitivity to electrical stimuli and mechanical pinpricks in 24 healthy subjects in a sham-controlled, single-blind study. Pain ratings to mechanical pinpricks and electrical stimuli were recorded prior to and at three time points (0, 30, and 60min) following 15min of anodal tsDCS (2.5mA, "active" electrode centered over the T11 spinous process, return electrode on the left posterior shoulder). Pain ratings to the pinpricks of the highest forces tested (128, 256, 512mN) were reduced at 30min and 60min following anodal tsDCS. These findings demonstrate that pain sensitivity in healthy subjects can be suppressed by anodal tsDCS and suggest that tsDCS may provide a non-invasive tool to manage mechanically-induced pain.

Campylobacter jejuni infection of infant mice: acute enterocolitis is followed by asymptomatic intestinal and extra-intestinal immune responses.

Campylobacter (C.) jejuni is among the leading bacterial agents causing enterocolitis worldwide. Despite the high prevalence of C. jejuni infections and its significant medical and economical consequences, intestinal pathogenesis is poorly understood. This is mainly due to the lack of appropriate animal models. In the age of 3 months, adult mice display strong colonization resistance (CR) against C. jejuni. Previous studies underlined the substantial role of the murine intestinal microbiota in maintaining CR. Due to the fact that the host-specific gut flora establishes after weaning, we investigated CR against C. jejuni in 3-week-old mice and studied intestinal and extra-intestinal immunopathogenesis as well as age dependent differences of the murine colon microbiota. In infant animals infected orally immediately after weaning C. jejuni strain B2 could stably colonize the gastrointestinal tract for more than 100 days. Within six days following infection, infant mice developed acute enterocolitis as indicated by bloody diarrhea, colonic shortening, and increased apoptotic cell numbers in the colon mucosa. Similar to human campylobacteriosis clinical disease manifestations were self-limited and disappeared within two weeks. Interestingly, long-term C. jejuni infection was accompanied by distinct intestinal immune and inflammatory responses as indicated by increased numbers of T- and B-lymphocytes, regulatory T-cells, neutrophils, as well as apoptotic cells in the colon mucosa. Strikingly, C. jejuni infection also induced a pronounced influx of immune cells into extra-intestinal sites such as liver, lung, and kidney. Furthermore, C. jejuni susceptible weaned mice harbored a different microbiota as compared to resistant adult animals. These results support the essential role of the microflora composition in CR against C. jejuni and demonstrate that infant mouse models resemble C. jejuni mediated immunopathogenesis including the characteristic self-limited enterocolitis in human campylobacteriosis. Furthermore, potential clinical and immunological sequelae of chronic C. jejuni carriers in humans can be further elucidated by investigation of long-term infected infant mice. The observed extraintestinal disease manifestations might help to unravel the mechanisms causing complications such as reactive arthritis or Guillain-Barré syndrome.

Campylobacter jejuni induces extra-intestinal immune responses via Toll-like-receptor-4 signaling in conventional IL-10 deficient mice with chronic colitis.

Campylobacter jejuni is one of the predominant causes for foodborne bacterial infections worldwide. We investigated whether signaling of C. jejuni-lipoproteins and -lipooligosaccharide via Toll-like-receptor (TLR) -2 and -4, respectively, is inducing intestinal and extra-intestinal immune responses following infection of conventional IL-10(-/-) mice with chronic colitis. At day 3 following oral infection, IL-10(-/-) mice lacking TLR-2 or TLR-4 harbored comparable C. jejuni strain ATCC 43431 loads in their colon. Interestingly, infected TLR-4(-/-) IL-10(-/-) mice displayed less compromized epithelial barrier function as indicated by lower translocation rates of live gut commensals into mesenteric lymphnodes (MLNs), and exhibited less distinct B lymphocyte responses in their colonic mucosa as compared to naїve IL-10(-/-) controls. Furthermore, in extra-intestinal compartments such as MLNs and spleens, abundance of myeloid cells was less distinct whereas relative percentages of activated T helper cells and cytotoxic T cells were higher in spleens and dendritic cells more abundant in MLNs of infected IL-10(-/-) animals lacking TLR-4 as compared to IL-10(-/-) controls. Taken together, in conventionally colonized IL-10(-/-) mice, TLR-4, but not TLR-2, is involved in mediating extra-intestinal pro-inflammatory immune responses following C. jejuni infection. Thus, conventional IL-10(-/-) mice are well suited to further dissect mechanisms underlying Campylobacter infections in vivo.

[Campylobacteriosis of man : livestock as reservoir for Campylobacter species]. / Die Campylobacteriose des Menschen : Nutztiere als Reservoir für Campylobacter-Arten.

Over the last few years, infections with Campylobacter have significantly increased in Europe and Germany and these bacteria have even surpassed Salmonella as the most prevalent bacteria, causing gastroenteritis. Especially contamination during the handling and consumption of meat products seems to be the most important risk factor which plays a prominent role for transmission to man. In addition, contact with pets and other animals, drinking raw or improperly pasteurized milk, and the tenacity of Campylobacter in different environments, especially water, have also to be considered for an adequate risk assessment. Besides gastroenteritis, arthralgia, and Guillain-Barré syndrome are important clinical complications of Campylobacter infections in man. At the same time, it is mostly unclear why the course of infection in man and in reservoir animals differs significantly, especially as only a few classical bacterial virulence factors have been identified so far. For these reasons, the development of efficient prevention strategies is of utmost importance in order to control campylobacteriosis.

Control of ionization processes in high band gap materials via tailored femtosecond pulses.

Control of two basic ionization processes in dielectrics i.e. photo ionization and electron-electron impact ionization on intrinsic time and intensity scales is investigated experimentally and theoretically. Temporally asymmetric femtosecond pulses of identical fluence, spectrum and pulse duration result in different final free electron densities. We found that an asymmetric pulse and its time reversed counterpart address two ionization processes in a different fashion. This results in the observation of different thresholds for surface material modification in sapphire and fused silica. We conclude that control of ionization processes with tailored femtosecond pulses is suitable for robust manipulation of breakdown and thus control of the initial steps of laser processing of high band gap materials.

Relationship between drug use and sexual behaviors and the occurrence of sexually transmitted diseases among high-risk male youth.

BACKGROUND AND OBJECTIVES: Sexually active adolescents, especially those in detention, are at high risk for acquisition of sexually transmitted diseases (STDs), including HIV infection. Yet little information is available that describes their risk behaviors associated with STDs. The overall objective was to define the relationship between risk behaviors and STD acquisition among adolescents. GOALS OF THIS STUDY: The first goal was to characterize drug use and sexual behaviors that place a population of adolescent male detainees at STD/HIV risk. The second goal was to define possible interrelationships between drug use, especially alcohol use, and risky sexual behaviors with STD acquisition. STUDY DESIGN: The study group consisted of 414 adolescent male detainees 12 to 18 years of age who participated in an interview and a clinical assessment. Two hundred sixty-nine of the 414 subjects agreed to STD laboratory tests, including serologic testing for hepatitis B and syphilis, and urethral cultures to screen for chlamydial and gonorrheal urethritis. RESULTS: Results showed that 15% had current evidence of at least one STD, and 34% had a history or current evidence of at least one STD (STD occurrence). The subjects were frequently engaging in risky sexual and drug use behaviors. Two multivariate models described three factors that significantly place the male adolescent in detention at risk for STDs: multiple sexual partners, inconsistent condom use, and the quantity of alcohol consumed per week. CONCLUSION: Youth in detention place themselves at risk for STDs including HIV because of their risky sexual behavior and drug use. Addressing alcohol use and barriers to condom use appear to be essential components of any STD prevention program targeting this largely minority youth population.