HIV-1 coreceptor usage and CXCR4-specific viral load predict clinical disease progression during combination antiretroviral therapy

BACKGROUND: Although combination antiretroviral therapy (cART) dramatically reduces rates of AIDS and death, a minority of patients experience clinical disease progression during treatment. OBJECTIVE: To investigate whether detection of CXCR4(X4)-specific strains or quantification of X4-specific HIV-1 load predict clinical outcome. METHODS: From the Swiss HIV Cohort Study, 96 participants who initiated cART yet subsequently progressed to AIDS or death were compared with 84 contemporaneous, treated nonprogressors. A sensitive heteroduplex tracking assay was developed to quantify plasma X4 and CCR5 variants and resolve HIV-1 load into coreceptor-specific components. Measurements were analyzed as cofactors of progression in multivariable Cox models adjusted for concurrent CD4 cell count and total viral load, applying inverse probability weights to adjust for sampling bias. RESULTS: Patients with X4 variants at baseline displayed reduced CD4 cell responses compared with those without X4 strains (40 versus 82 cells/microl; P = 0.012). The adjusted multivariable hazard ratio (HR) for clinical progression was 4.8 [95% confidence interval (CI) 2.3-10.0] for those demonstrating X4 strains at baseline. The X4-specific HIV-1 load was a similarly independent predictor, with HR values of 3.7 (95% CI, 1.2-11.3) and 5.9 (95% CI, 2.2-15.0) for baseline loads of 2.2-4.3 and > 4.3 log10 copies/ml, respectively, compared with < 2.2 log10 copies/ml. CONCLUSIONS: HIV-1 coreceptor usage and X4-specific viral loads strongly predicted disease progression during cART, independent of and in addition to CD4 cell count or total viral load. Detection and quantification of X4 strains promise to be clinically useful biomarkers to guide patient management and study HIV-1 pathogenesis.

Should the standard dimethyl sulfoxide concentration be reduced? Results of a European Group for Blood and Marrow Transplantation prospective noninterventional study on usage and side effects of dimethyl sulfoxide.

BACKGROUND Dimethyl sulfoxide (DMSO) is essential for the preservation of liquid nitrogen-frozen stem cells, but is associated with toxicity in the transplant recipient. STUDY DESIGN AND METHODS In this prospective noninterventional study, we describe the use of DMSO in 64 European Blood and Marrow Transplant Group centers undertaking autologous transplantation on patients with myeloma and lymphoma and analyze side effects after return of DMSO-preserved stem cells. RESULTS While the majority of centers continue to use 10% DMSO, a significant proportion either use lower concentrations, mostly 5 or 7.5%, or wash cells before infusion (some for selected patients only). In contrast, the median dose of DMSO given (20 mL) was much less than the upper limit set by the same institutions (70 mL). In an accompanying statistical analysis of side effects noted after return of DMSO-preserved stem cells, we show that patients in the highest quartile receiving DMSO (mL and mL/kg body weight) had significantly more side effects attributed to DMSO, although this effect was not observed if DMSO was calculated as mL/min. Dividing the myeloma and lymphoma patients each into two equal groups by age we were able to confirm this result in all but young myeloma patients in whom an inversion of the odds ratio was seen, possibly related to the higher dose of melphalan received by young myeloma patients. CONCLUSION We suggest better standardization of preservation method with reduced DMSO concentration and attention to the dose of DMSO received by patients could help reduce the toxicity and morbidity of the transplant procedure.

Abies – Circum-Mediterranean firs in Europe: distribution, habitat, usage and threats

Most European firs occur predominantly in small to medium-sized populations in the Mediterranean region, sometimes with fragmented and limited distributions, except for silver fir (Abies alba). They all are genetically closely related and can easily hybridise, perhaps as a consequence of late speciation during the late Quaternary. Circum-Mediterranean firs occur principally in mountain areas with medium to high precipitations rates which are mostly concentrated during the winter period. The species are able to tolerate long droughts in summer and tend to form pure stands when in optimal habitats. In the past firs have been extensively logged for construction and fire wood and their stands were replaced by other more disturbance adapted species or converted into rural areas. Nowadays with the exception of silver fir and Caucasian fir (Abies nordmanniana), circum-Mediterranean firs do not have a wide commercial interest. In Turkey they are still exploited for timber wood, while other firs have an ornamental use in gardening. Great importance is given to their preservation, especially to those populations which have very limited areas and specimens, with the creation of protected reserves and conservation programmes. Wild fires, livestock grazing and genetic drift represent actually their main threats.

Betula pendula, Betula pubescens and other birches in Europe: distribution, habitat, usage and threats

Silver birch (Betula pendula Roth) and downy birch (Betula pubescens Ehrh.) are short-lived, relatively small broadleaved trees that occur throughout most of Europe, particularly in northern regions. In southern Europe, birch trees are confined to mountainous areas, as they do not tolerate prolonged summer drought. Birch has a light canopy of small serrated leaves, and characteristic smooth, white to grey bark. In northern regions, birch trees can dominate the landscape up to the tree-line, whereas in the centre of their range they often occur early in secondary succession because of their abundant seed production, low demands on soil quality, and intolerance of shade. Birch trees provide the predominant hard wood source in northern Europe, and some varieties of Betula pendula produce highly priced veneers, while Betula pubescens is mostly used for pulp and fire wood. Other rarer species of birch are endemic to Europe contributing to the continental biodiversity even at high elevations and latitudes.

Castanea sativa in Europe: distribution, habitat, usage and threats

The sweet chestnut (Castanea sativa Mill.) is the only native species of the genus in Europe. The broad diffusion and active management by man resulted in the establishment of the species at the limits of its potential ecological range, which makes it difficult to trace its original natural area. The present distribution ranges from North-Western Africa (e.g. Morocco) to North-Western Europe (southern England, Belgium) and from south-western Asia (e.g. Turkey) to Eastern Europe (e.g. Romania), the Caucasus (Georgia, Armenia) and the Caspian Sea. In Europe the main chestnut forests are concentrated in a few countries such as Italy, France and the Iberian Peninsula. The sweet chestnut has a remarkable multipurpose character, and may be managed for timber production (coppice and high forest) as well as for fruit production (traditional orchards), including a broad range of secondary products and ecosystem services.

Fraxinus excelsior in Europe: distribution, habitat, usage and threats

Common ash (Fraxinus excelsior L.) is a medium-sized deciduous tree with large compound leaves that develop relatively late in spring. It flowers before leaf-buds burst and trees can carry male, female, or hermaphrodite flowers, or different combinations of the flower types. It grows throughout the European temperate zone, but is absent from the driest Mediterranean areas because it does not tolerate extended summer drought, and from the northern boreal regions, with its seedlings in particular being vulnerable to late spring frost. Soils exert a strong control on common ash distribution locally. The species grows best on fertile soils where soil pH exceeds 5.5. It rarely forms pure stands, more often it is found in small groups in mixed stands. Ash trees produce high quality timber that combines light weight, strength, and flexibility. Before the mass use of steel, it was used for a wide range of purposes, from agricultural implements to construction of boat and car frames. Today

Larix decidua and other larches in Europe: distribution, habitat, usage and threats

The European larch (Larix decidua Mill.) is a pioneer, very long-lived, fast-growing coniferous tree, which occurs in the central and eastern mountains of Europe, forming open forests or pasture woods at the upper tree limits. Larch is the only deciduous conifer in Europe as an adaptation to continental alpine climates. In fact, it is able to tolerate very cold temperatures during winter and, by losing its needles, avoids foliage desiccation. It is a transitional species, colonising open terrain after natural disturbances. It forms pure stands but more often it is found with other alpine tree species, which tend to replace it if no other disturbances occur. Thanks to its adaptability and the durability of its wood, the European larch represents an important silvicultural tree species in the alpine regions, planted even outside its natural ranges. Its wood is largely used for carpentry, furniture and pulp for paper. In lower altitudes or with high precipitation rates, larch is more susceptible to fungal diseases. Outbreaks of insect defoliators, principally caused by the larch bud moth (Zeiraphera diniana), can limit tree development, with economic losses in plantations, but they rarely lead to the death of the trees.

Picea abies in Europe: distribution, habitat, usage and threats

Among the coniferous species, Norway spruce (Picea abies (L.) Karst.) is one of the most important trees in Europe both for economic and ecological aspects, with a long tradition of cultivation. It can be a big tree, reaching 50-60 m in height with a straight and regular trunk, particularly used for timber constructions, pulpwood for paper and furniture. This widespread species dominates the Boreal forests in Northern Europe and the subalpine areas of the Alps and Carpathian Mountains. Thanks to its high performances in different site conditions, it can also be found outside its natural distribution on lower elevations in more temperate forests. Norway spruce has been massively planted up to its niche limits, where it is particularly susceptible to heat and drought, due to its shallow root system. For this reason it is expected to be severely affected under global warming conditions. Disturbed and weakened plants can be easily attacked by rot fungi such as Heterobasidion annosum and Armillaria, or by the bark beetles Ips typographus, one of the most destructive spruce forest pests.

Juglans regia in Europe: distribution, habitat, usage and threats

Juglans regia L., commonly known as common, English or Persian walnut, is an economically very important tree species, prized both for its nuts and for its attractive high-quality timber. It is the most widespread nut tree worldwide.

Usage of Complementary Medicine in Switzerland: Results of the Swiss Health Survey 2012 and Development Since 2007

Background Complementary medicine (CM) is popular in Switzerland. Several CM methods (traditional Chinese medicine/acupuncture, homeopathy, anthroposophic medicine, neural therapy, and herbal medicine) are currently covered by the mandatory basic health insurance when performed by a certified physician. Treatments by non-medical therapists are partially covered by a supplemental and optional health insurance. In this study, we investigated the frequency of CM use including the evolvement over time, the most popular methods, and the user profile. Methods Data of the Swiss Health Surveys 2007 and 2012 were used. In 2007 and 2012, a population of 14,432 and 18,357, respectively, aged 15 years or older answered the written questionnaire. A set of questions queried about the frequency of use of various CM methods within the last 12 months before the survey. Proportions of usage and 95% confidence intervals were calculated for these methods and CM in general. Users and non-users of CM were compared using logistic regression models. Results The most popular methods in 2012 were homeopathy, naturopathy, osteopathy, herbal medicine, and acupuncture. The average number of treatments within the 12 months preceding the survey ranged from 3 for homeopathy to 6 for acupuncture. 25.0% of the population at the age of 15 and older had used at least one CM method in the previous 12 months. People with a chronic illness or a poor self-perceived health status were more likely to use CM. Similar to other countries, women, people of middle age, and those with higher education were more likely to use CM. 59.9% of the adult population had a supplemental health insurance that partly covered CM treatments. Conclusions Usage of CM in Switzerland remained unchanged between 2007 and 2012. The user profile in Switzerland was similar to other countries, such as Germany, United Kingdom, United States or Australia.

Avoidance of Long Mononucleotide Repeats in Codon Pair Usage

Protein is an essential component for life, and its synthesis is mediated by codons in any organisms on earth. While some codons encode the same amino acid, their usage is often highly biased. There are many factors that can cause the bias, but a potential effect of mononucleotide repeats, which are known to be highly mutable, on codon usage and codon pair preference is largely unknown. In this study we performed a genomic survey on the relationship between mononucleotide repeats and codon pair bias in 53 bacteria, 68 archaea, and 13 eukaryotes. By distinguishing the codon pair bias from the codon usage bias, four general patterns were revealed: strong avoidance of five or six mononucleotide repeats in codon pairs; lower observed/expected (o/e) ratio for codon pairs with C or G repeats (C/G pairs) than that with A or T repeats (A/T pairs); a negative correlation between genomic GC contents and the o/e ratios, particularly for C/G pairs; and avoidance of C/G pairs in highly conserved genes. These results support natural selection against long mononucleotide repeats, which could induce frameshift mutations in coding sequences. The fact that these patterns are found in all kingdoms of life suggests that this is a general phenomenon in living organisms. Thus, long mononucleotide repeats may play an important role in base composition and genetic stability of a gene and gene functions.

Tissue-transplant fusion and vascularization of myocardial microtissues and macrotissues implanted into chicken embryos and rats

Cell-based therapies and tissue engineering initiatives are gathering clinical momentum for next-generation treatment of tissue deficiencies. By using gravity-enforced self-assembly of monodispersed primary cells, we have produced adult and neonatal rat cardiomyocyte-based myocardial microtissues that could optionally be vascularized following coating with human umbilical vein endothelial cells (HUVECs). Within myocardial microtissues, individual cardiomyocytes showed native-like cell shape and structure, and established electrochemical coupling via intercalated disks. This resulted in the coordinated beating of microtissues, which was recorded by means of a multi-electrode complementary metal-oxide-semiconductor microchip. Myocardial microtissues (microm3 scale), coated with HUVECs and cast in a custom-shaped agarose mold, assembled to coherent macrotissues (mm3 scale), characterized by an extensive capillary network with typical vessel ultrastructures. Following implantation into chicken embryos, myocardial microtissues recruited the embryo's capillaries to functionally vascularize the rat-derived tissue implant. Similarly, transplantation of rat myocardial microtissues into the pericardium of adult rats resulted in time-dependent integration of myocardial microtissues and co-alignment of implanted and host cardiomyocytes within 7 days. Myocardial microtissues and custom-shaped macrotissues produced by cellular self-assembly exemplify the potential of artificial tissue implants for regenerative medicine.

Highly pathogenic adapted HIV-1 strains limit host immunity and dictate rapid disease progression.

OBJECTIVE: The study of HIV-1 rapid progressors has been limited to specific case reports. Nevertheless, identification and characterization of the viral and host factors involved in rapid progression are crucial when attempting to uncover the correlates of rapid disease outcome. DESIGN: We carried out comparative functional analyses in rapid progressors (n = 46) and standard progressors (n = 46) early after HIV-1 seroconversion (≤1 year). The viral traits tested were viral replicative capacity, co-receptor usage, and genomic variation. Host CD8 T-cell responses, humoral activity, and HLA immunogenetic markers were also determined. RESULTS: Our data demonstrate an unusual convergence of highly pathogenic HIV-1 strains in rapid progressors. Compared with standard progressors, rapid progressor viral strains show higher in-vitro replicative capacity (81.5 vs. 67.9%; P = 0.025) and greater X4/DM co-receptor usage (26.3 vs. 2.8%; P = 0.006) in early infection. Limited or absent functional HIV-1 CD8 T-cell responses and neutralizing activity were measured in rapid progressors. Moreover, the increase in common HLA allele-restricted CD8 T-cell escape mutations in rapid progressors acts as a signature of uncontrolled HIV-1 replication and early impairment of adaptive cellular responses. CONCLUSION: Our data support a dominant role for viral factors in rapid progressors. Robust HIV-1 replication and intrinsic viral properties limit host adaptive immune responses, thus driving rapid disease progression.

Germanic Mythology in Music: Cultural Memory and Conflict within the Framework of Modern Globalization

The multi-layered enactment of a national past in music has been strongly intertwined with the usage of mythological elements. Having often been compiled as a coherent narrative during the emergence of the European nation-states (like the Finnish Kalevala), the mythological material has often been perceived as a form of historical truth and national justification. This focal role is also apparent in various music genres ranging from folk revival to metal in post-1989 Europe. Within the globalized context, however, local-national interpretations can collide with earlier nationalist appropriations. This complex and sometimes politically conflicting situation becomes particularly evident with groups falling back on symbols and narrations that had previously been employed by Nazi-Germany. While Nazi-Germany had, among others, tried replace the Christmas tradition with elements and songs from Germanic (and other) mythological sources, modern Neo-Nazi music groups often employ central mythological names (like Odin or Tyr) and iconic elements (like Vikings and warriors) in song lyrics and CD cover designs. However, while many covers and lyrics are legally forbidden in Germany, Scandinavian and Baltic groups (like the Faroese Viking metal group Tyr and the Latvian pagan metal band Skyforger) employ similar elements of Norse mythology, which are often combined with traditional material. Discussing selected case studies, this paper highlights central discursive points of colliding historical-national associations and individual interpretations of the mythological elements in musical contexts. How far can the material be disassociated from the earlier historical political usage and instrumentalization? Is this necessary ? And how can the specific global-local conflict points be approached by a theoretical framework ?

Temporary anchorage device usage: a survey among Swiss orthodontists.

BACKGROUND The aim of the survey was to obtain information on the treatment plan preferences, mechanics and characteristics of temporary anchorage device (TAD) application using a single case presented to orthodontists in Switzerland. METHODS A structured questionnaire to be completed by all study participants with case-specific (treatment plan including mechanics and TAD usage) and general questions (general fixed appliance and TAD usage as well as professional, educational and demographic questions) together with an orthodontic borderline case was utilised. The case was a female adult with dental Class II/2, deep bite and maxillary anterior crowing, who had been treated in childhood with extraction of four premolars and fixed appliance followed by wisdom tooth extraction. RESULTS The response rate was 24.4% (108 out of 443). The majority (96.3%, 104) proposed comprehensive treatment, while 3.7% (4) planned only alignment of maxillary teeth. 8.3% (9) included a surgical approach in their treatment plan. An additional 0.9% (1) combined the surgical approach with Class II mechanics. 75.1% (81) decided on distalization on the maxilla using TADs, 7.4% (8) planned various types of Class II appliances and 3.7% (4) combined distalization using TADs or headgear with Class II appliances and surgery. Palatal implants were the most popular choice (70.6%, 60), followed by mini-screws (22.4%, 19) and mini-plates on the infrazygomatic crests (7.0%, 6). The preferred site of TAD insertion showed more variation in sagittal than in transversal dimension, and the median size of mini-screws used was 10.0-mm long (interquartile range (IQR) 2.3 mm) and 2.0-mm wide (IQR 0.3 mm). CONCLUSIONS Distalization against palatal implants and then distalization against mini-screws were the most popular treatment plans. Preferred site for TAD insertion varied depending on type and size but varied more widely in the sagittal than in the transversal dimension.