Synthetic double-stranded RNAs are adjuvants for the induction of t helper 1 and humoral immune responses to human papillomavirus in rhesus macaques

Toll-like receptor (TLR) ligands are being considered as adjuvants for the induction of antigen-specific immune responses, as in the design of vaccines. Polyriboinosinic-polyribocytoidylic acid (poly I:C), a synthetic double-stranded RNA (dsRNA), is recognized by TLR3 and other intracellular receptors. Poly ICLC is a poly I:C analogue, which has been stabilized against the serum nucleases that are present in the plasma of primates. Poly I:C12U, another analogue, is less toxic but also less stable in vivo than poly I:C, and TLR3 is essential for its recognition. To study the effects of these compounds on the induction of protein-specific immune responses in an animal model relevant to humans, rhesus macaques were immunized subcutaneously (s.c.) with keyhole limpet hemocyanin (KLH) or human papillomavirus (HPV)16 capsomeres with or ithout dsRNA or a control adjuvant, the TLR9 ligand CpG-C. All dsRNA compounds served as adjuvants for KLH-specific cellular immune responses, with the highest proliferative responses being observed with 2 mg/animal poly ICLC (p = 0.002) or 6 mg/animal poly I:C12U (p = 0.001) when compared with immunization with KLH alone. Notably, poly ICLC-but not CpG-C given at the same dose-also helped to induce HPV16-specific Th1 immune responses while both adjuvants supported the induction of strong anti-HPV16 L1 antibody responses as determined by ELISA and neutralization assay. In contrast, control animals injected with HPV16 capsomeres alone did not develop substantial HPV16-specific immune responses. Injection of dsRNA led to increased numbers of cells producing the T cell-activating chemokines CXCL9 and CXCL10 as detected by in situ hybridization in draining lymph nodes 18 hours after injections, and to increased serum levels of CXCL10 (p = 0.01). This was paralleled by the reduced production of the homeostatic T cell-attracting chemokine CCL21. Thus, synthetic dsRNAs induce an innate chemokine response and act as adjuvants for virus-specific Th1 and humoral immune responses in nonhuman primates

Prevalence and antimicrobial susceptibility of Arcobacter species in human stool samples derived from out- and inpatients: the prospective German Arcobacter prevalence study Arcopath

Background: Arcobacter species, particularly A. butzleri, but also A. cryaerophilus constitute emerging pathogens causing gastroenteritis in humans. However, isolation of Arcobacter may often fail during routine diagnostic procedures due to the lack of standard protocols. Furthermore, defined breakpoints for the interpretation of antimicrobial susceptibilities of Arcobacter are missing. Hence, reliable epidemiological data of human Arcobacter infections are scarce and lacking for Germany. We therefore performed a 13-month prospective Arcobacter prevalence study in German patients. Results: A total of 4636 human stool samples was included and Arcobacter spp. were identified from 0.85% of specimens in 3884 outpatients and from 0.40% of specimens in 752 hospitalized patients. Overall, A. butzleri was the most prevalent species (n = 24; 67%), followed by A. cryaerophilus (n = 10; 28%) and A. lanthieri (n = 2; 6%). Whereas A. butzleri, A. cryaerophilus and A. lanthieri were identified in outpatients, only A. butzleri could be isolated from samples of hospitalized patients. Antimicrobial susceptibility testing of Arcobacter isolates revealed high susceptibilities to ciprofloxacin, whereas bimodal distributions of MICs were observed for azithromycin and ampicillin. Conclusions: In summary, Arcobacter including A. butzleri, A. cryaerophilus and A. lanthieri could be isolated in 0.85% of German outpatients and ciprofloxacin rather than other antibiotics might be appropriate for antibiotic treatment of infections. Further epidemiological studies are needed, however, to provide a sufficient risk assessment of Arcobacter infections in humans

Wahrscheinlicher Fall einer Reinfektion durch Legionella pneumophila

In Deutschland wird die Legionärskrankheit in der Regel durch die Spezies Legionella (L.) pneumophila verursacht. Von rezidivierenden Fällen der Legionärskrankheit wird selten berichtet, sie sind entweder auf eine zweite Infektion (Reinfektion) oder auf einen Rückfall (Wiederaufflammen; engl. relapse) einer zwischenzeitlich ruhenden/gebesserten, aber nicht völlig ausgeheilten Erkrankung zurückzuführen. Wir berichten über einen Fall einer rezidivierenden Legionärskrankheit bei einer 86-jährigen Patientin mit einer Erkrankung durch L. pneumophila Serogruppe 1, monoklonaler Antikörpersubtyp Knoxville, Sequenztyp unbekannt. Zwischen den beiden, mehrere Monate auseinander liegenden, Krankheitsepisoden hatte sich die Patientin vollständig erholt. Im Trinkwasser der Wohnung der Patientin konnten wir L. pneumophila Serogruppe 1, monoklonaler Antikörpersubtyp Knoxville, Sequenztyp 182, nachweisen. Nach der ersten Krankheitsepisode wurde die Exposition gegenüber kontaminiertem Trinkwasser durch Einsatz von Wasserfiltern unterbrochen. Die Filter wurden später wegen des geringen Wasserdrucks entfernt, nur wenige Wochen später trat die zweite Krankheitsepisode auf. Es ist unklar, ob eine immunologische Veranlagung zu diesem Fall einer wahrscheinlichen Reinfektion der Legionärskrankheit beigetragen hat. Klinische, mikrobiologische und epidemiologische Informationen lassen darauf schließen, dass es sich bei der zweiten Episode um eine erneute Infektion handelte. Im Falle einer rezidivierenden Legionärskrankheit ist eine möglichst vollständige Sammlung von Patienten- und Wasserproben erforderlich, um zu entscheiden, ob es sich um einen Rückfall oder eine Reinfektion handelt, um die Infektionsquelle zu identifizieren und weitere Hinweise für die Rolle einer immunologischen Prädisposition zu erhalten

Synthetic Double-Stranded RNAs Are Adjuvants for the Induction of T Helper 1 and Humoral Immune Responses to Human Papillomavirus in Rhesus Macaques

Toll-like receptor (TLR) ligands are being considered as adjuvants for the induction of antigen-specific immune responses, as in the design of vaccines. Polyriboinosinic-polyribocytoidylic acid (poly I:C), a synthetic double-stranded RNA (dsRNA), is recognized by TLR3 and other intracellular receptors. Poly ICLC is a poly I:C analogue, which has been stabilized against the serum nucleases that are present in the plasma of primates. Poly I:C12U, another analogue, is less toxic but also less stable in vivo than poly I:C, and TLR3 is essential for its recognition. To study the effects of these compounds on the induction of protein-specific immune responses in an animal model relevant to humans, rhesus macaques were immunized subcutaneously (s.c.) with keyhole limpet hemocyanin (KLH) or human papillomavirus (HPV)16 capsomeres with or without dsRNA or a control adjuvant, the TLR9 ligand CpG-C. All dsRNA compounds served as adjuvants for KLH-specific cellular immune responses, with the highest proliferative responses being observed with 2 mg/animal poly ICLC (p = 0.002) or 6 mg/animal poly I:C12U (p = 0.001) when compared with immunization with KLH alone. Notably, poly ICLC—but not CpG-C given at the same dose—also helped to induce HPV16-specific Th1 immune responses while both adjuvants supported the induction of strong anti-HPV16 L1 antibody responses as determined by ELISA and neutralization assay. In contrast, control animals injected with HPV16 capsomeres alone did not develop substantial HPV16-specific immune responses. Injection of dsRNA led to increased numbers of cells producing the T cell–activating chemokines CXCL9 and CXCL10 as detected by in situ hybridization in draining lymph nodes 18 hours after injections, and to increased serum levels of CXCL10 (p = 0.01). This was paralleled by the reduced production of the homeostatic T cell–attracting chemokine CCL21. Thus, synthetic dsRNAs induce an innate chemokine response and act as adjuvants for virus-specific Th1 and humoral immune responses in nonhuman primates

Concise review:workshop review: understanding and assessing the risks of stem cell-based therapies

The field of stem cell therapeutics is moving ever closer to widespread application in the clinic. However, despite the undoubted potential held by these therapies, the balance between risk and benefit remains difficult to predict. As in any new field, a lack of previous application in man and gaps in the underlying science mean that regulators and investigators continue to look for a balance between minimizing potential risk and ensuring therapies are not needlessly kept from patients. Here, we attempt to identify the important safety issues, assessing the current advances in scientific knowledge and how they may translate to clinical therapeutic strategies in the identification and management of these risks. We also investigate the tools and techniques currently available to researchers during preclinical and clinical development of stem cell products, their utility and limitations, and how these tools may be strategically used in the development of these therapies. We conclude that ensuring safety through cutting-edge science and robust assays, coupled with regular and open discussions between regulators and academic/industrial investigators, is likely to prove the most fruitful route to ensuring the safest possible development of new product

Improved Upper Limit on the Neutrino Mass from a Direct Kinematic Method by KATRIN

We report on the neutrino mass measurement result from the first four-week science run of the Karlsruhe Tritium Neutrino experiment KATRIN in spring 2019. Beta-decay electrons from a high-purity gaseous molecular tritium source are energy analyzed by a high-resolution MAC-E filter. A fit of the integrated electron spectrum over a narrow interval around the kinematic end point at 18.57 keV gives an effective neutrino mass square value of $(−1.0^{+0.9}_{−1.1}) eV^2$. From this, we derive an upper limit of 1.1 eV (90% confidence level) on the absolute mass scale of neutrinos. This value coincides with the KATRIN sensitivity. It improves upon previous mass limits from kinematic measurements by almost a factor of 2 and provides model-independent input to cosmological studies of structure formation

Frequency planning and ramifications of coloring

This paper surveys frequency assignment problems coming up in planning wireless communication services. It particularly focuses on cellular mobile phone systems such as GSM, a technology that revolutionizes communication. Traditional vertex coloring provides a conceptual framework for the mathematical modeling of many frequency planning problems. This basic form, however, needs various extensions to cover technical and organizational side constraints. Among these ramifications are T-coloring and list coloring. To model all the subtleties, the techniques of integer programming have proven to be very useful.The ability to produce good frequency plans in practice is essential for the quality of mobile phone networks. The present algorithmic solution methods employ variants of some of the traditional coloring heuristics as well as more sophisticated machinery from mathematical programming. This paper will also address this issue.Finally, this paper discusses several practical frequency assignment problems in detail, states the associated mathematical models, and also points to public electronic libraries of frequency assignment problems from practice. The associated graphs have up to several thousand vertices and range form rather sparse to almost complete

Frequency assignment in cellular phone networks

We present a graph-theoretic model for the frequency assignment problem in Cellular Phone Networks: Obeying several technical and legal restrictions, frequencies have to be assigned to transceivers so that interference is as small as possible. This optimization problem is NP-hard. Good approximation cannot be guaranteed, unless P = NP. We describe several assignment heuristics. These heuristics are simple and not too hard to implement. We give an assessment of the heuristics ' efficiency and practical usefulness. For this purpose, typical instances of frequency assignment problems with up to 4240 transceivers and 75 frequencies of a German cellular phone network operator are used. The results are satisfying from a practitioner's point of view. The best performing heuristics were integrated into a network planning system used in practice

Ciguatera fish poisoning: A first epidemic in Germany highlights an increasing risk for European countries

Toxin-producing microalgae are thriving worldwide due to coral reef destruction and global warming with major consequences on ecosystems, international trade and human health. Microalgae belonging to the family of flagellate protists, in particular dinoflagellates, secrete a variety of high-molecular-weight polyether toxins that accumulate through the marine food chain to cause disease in humans by acting as sodium channel activator toxins; ciguatera is the most frequent seafood-borne illness worldwide with 50,000 to 500,000 global incidences per annum and is usually limited to endemic areas located between 35° northern and 35° southern latitude. The rising global incidence frequency renders it a major human health problem, because no curative treatment is available yet and reliable detection assays are lacking. During the last decade ciguatera has increasingly become endemic in previously unaffected areas for two reasons: first global warming has contributed to the emergence of dinoflagellate species in subtropical and even temperate regions that previously had been constrained to tropical areas and second: in Europe globalization of fishing industry and tourism has led to a progressive increase in the number of ciguatera cases and a lack of awareness among medical personnel contributes to under-reporting. We review, through a recent ciguatera outbreak in Germany, the risk for ciguatera poisoning in Europe and highlight characteristic symptoms, current knowledge about disease pathomechanisms and treatment options