The long pentraxin PTX3 at the crossroads between innate immunity and tissue remodelling

Innate immunity represents the first line of defence against pathogens and plays key roles in the activation and orientation of the adaptive immune response. The innate immune system comprises both a cellular and a humoral arm. Components of the humoral arm include soluble pattern recognition molecules that recognize pathogen-associated molecular patterns and initiate the immune response in coordination with the cellular arm, therefore acting as functional ancestors of antibodies. Pentraxins are essential constituents of the humoral arm of innate immunity and represent a superfamily of highly conserved acute phase proteins, traditionally classified into short and long pentraxins. Pentraxin 3 (PTX3) is the prototypic member of the long pentraxins subfamily. As opposed to C-reactive protein, whose sequence and regulation have not been conserved during evolution from mouse to man, the evolutionary conservation of sequence, gene organization and regulation of PTX3 has allowed addressing its pathophysiological roles in genetically modified mice, in diverse conditions, ranging from infections to sterile inflammation, angiogenesis and female fertility. Despite this conservation, a number of predominantly non-coding polymorphisms have been identified in the PTX3 gene which, when associated in particular haplotypes, have been shown to be relevant in clinical conditions including infection and fertility. Here we review the studies on PTX3, with emphasis on pathogen recognition, tissue remodelling and crosstalk with other components of the innate immune system.

Alternative DNA base-pairs: from efforts to expand the genetic code to potential material applications

The complementary Watson-Crick base-pairs, A:T and G:C, have long been recognized as pivotal to both the stability of the DNA double helix and replication/transcription. Recently, the replacement of the Watson-Crick base-pairs with other molecular entities has received considerable attention. In this tutorial review we highlight different approaches used to replace natural base-pairs and equip them with novel function. We also discuss the advantages that non-natural base-pairs convey with respect to practical applications.

Line focusing for soft x-ray laser-plasma lasing

A computational study of line-focus generation was done using a self-written ray-tracing code and compared to experimental data. Two line-focusing geometries were compared, i.e., either exploiting the sagittal astigmatism of a tilted spherical mirror or using the spherical aberration of an off-axis- illuminated spherical mirror. Line focusing by means of astigmatism or spherical aberration showed identical results as expected for the equivalence of the two frames of reference. The variation of the incidence angle on the target affects the line-focus length, which affects the amplification length such that as long as the irradiance is above the amplification threshold, it is advantageous to have a longer line focus. The amplification threshold is physically dependent on operating parameters and plasma-column conditions and in the present study addresses four possible cases.

Early molecular and cytogenetic response is predictive for long-term progression-free and overall survival in chronic myeloid leukemia (CML)

In the face of competing first-line treatment options for CML, early prediction of prognosis on imatinib is desirable to assure favorable survival or otherwise consider the use of a second-generation tyrosine kinase inhibitor (TKI). A total of 1303 newly diagnosed imatinib-treated patients (pts) were investigated to correlate molecular and cytogenetic response at 3 and 6 months with progression-free and overall survival (PFS, OS). The persistence of BCR-ABL transcript levels >10% according to the international scale (BCR-ABL(IS)) at 3 months separated a high-risk group (28% of pts; 5-year OS: 87%) from a group with >1-10% BCR-ABL(IS) (41% of pts; 5-year OS: 94%; P=0.012) and from a group with 1% BCR-ABL(IS) (31% of pts; 5-year OS: 97%; P=0.004). Cytogenetics identified high-risk pts by >35% Philadelphia chromosome-positive metaphases (Ph+, 27% of pts; 5-year OS: 87%) compared with 35% Ph+ (73% of pts; 5-year OS: 95%; P=0.036). At 6 months, >1% BCR-ABL(IS) (37% of pts; 5-year OS: 89%) was associated with inferior survival compared with 1% (63% of pts; 5-year OS: 97%; P<0.001) and correspondingly >0% Ph+ (34% of pts; 5-year OS: 91%) compared with 0% Ph+ (66% of pts; 5-year OS: 97%; P=0.015). Treatment optimization is recommended for pts missing these landmarks.

Long-lasting protection of activity of nucleoside reverse transcriptase inhibitors and protease inhibitors (PIs) by boosted PI containing regimens

Background The accumulation of mutations after long-lasting exposure to a failing combination antiretroviral therapy (cART) is problematic and severely reduces the options for further successful treatments. Methods We studied patients from the Swiss HIV Cohort Study who failed cART with nucleoside reverse transcriptase inhibitors (NRTIs) and either a ritonavir-boosted PI (PI/r) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). The loss of genotypic activity <3, 3–6, >6 months after virological failure was analyzed with Stanford algorithm. Risk factors associated with early emergence of drug resistance mutations (<6 months after failure) were identified with multivariable logistic regression. Results Ninety-nine genotypic resistance tests from PI/r-treated and 129 from NNRTI-treated patients were analyzed. The risk of losing the activity of ≥1 NRTIs was lower among PI/r- compared to NNRTI-treated individuals <3, 3–6, and >6 months after failure: 8.8% vs. 38.2% (p = 0.009), 7.1% vs. 46.9% (p<0.001) and 18.9% vs. 60.9% (p<0.001). The percentages of patients who have lost PI/r activity were 2.9%, 3.6% and 5.4% <3, 3–6, >6 months after failure compared to 41.2%, 49.0% and 63.0% of those who have lost NNRTI activity (all p<0.001). The risk to accumulate an early NRTI mutation was strongly associated with NNRTI-containing cART (adjusted odds ratio: 13.3 (95% CI: 4.1–42.8), p<0.001). Conclusions The loss of activity of PIs and NRTIs was low among patients treated with PI/r, even after long-lasting exposure to a failing cART. Thus, more options remain for second-line therapy. This finding is potentially of high relevance, in particular for settings with poor or lacking virological monitoring.

Functional flexibility of intestinal IgA - broadening the fine line

Intestinal bacteria outnumber our own human cells in conditions of both health and disease. It has long been recognized that secretory antibody, particularly IgA, is produced in response to these microbes and hypothesized that this must play an important role in defining the relationship between a host and its intestinal microbes. However, the exact role of IgA and the mechanisms by which IgA can act are only beginning to be understood. In this review we attempt to unravel the complex interaction between so-called "natural," "primitive" (T-cell-independent), and "classical" IgA responses, the nature of the intestinal microbiota/intestinal pathogens and the highly flexible dynamic homeostasis of the mucosal immune system. Such an analysis reveals that low-affinity IgA is sufficient to protect the host from excess mucosal immune activation induced by harmless commensal microbes. However, affinity-maturation of "classical" IgA is essential to provide protection from more invasive commensal species such as segmented filamentous bacteria and from true pathogens such as Salmonellatyphimurium. Thus a correlation is revealed between "sophistication" of the IgA response and aggressiveness of the challenge. A second emerging theme is that more-invasive species take advantage of host inflammatory mechanisms to more successfully compete with the resident microbiota. In many cases, the function of IgA may be to limit such inflammatory responses, either directly by coagulating or inhibiting virulence of bacteria before they can interact with the host or by modulating immune signaling induced by host recognition. Therefore IgA appears to provide an added layer of robustness in the intestinal ecosystem, promoting "commensal-like" behavior of its residents.

UMTS base station-like exposure, well-being, and cognitive performance

BACKGROUND: Radio-frequency electromagnetic fields (RF EMF) of mobile communication systems are widespread in the living environment, yet their effects on humans are uncertain despite a growing body of literature. OBJECTIVES: We investigated the influence of a Universal Mobile Telecommunications System (UMTS) base station-like signal on well-being and cognitive performance in subjects with and without self-reported sensitivity to RF EMF. METHODS: We performed a controlled exposure experiment (45 min at an electric field strength of 0, 1, or 10 V/m, incident with a polarization of 45 degrees from the left back side of the subject, weekly intervals) in a randomized, double-blind crossover design. A total of 117 healthy subjects (33 self-reported sensitive, 84 nonsensitive subjects) participated in the study. We assessed well-being, perceived field strength, and cognitive performance with questionnaires and cognitive tasks and conducted statistical analyses using linear mixed models. Organ-specific and brain tissue-specific dosimetry including uncertainty and variation analysis was performed. RESULTS: In both groups, well-being and perceived field strength were not associated with actual exposure levels. We observed no consistent condition-induced changes in cognitive performance except for two marginal effects. At 10 V/m we observed a slight effect on speed in one of six tasks in the sensitive subjects and an effect on accuracy in another task in nonsensitive subjects. Both effects disappeared after multiple end point adjustment. CONCLUSIONS: In contrast to a recent Dutch study, we could not confirm a short-term effect of UMTS base station-like exposure on well-being. The reported effects on brain functioning were marginal and may have occurred by chance. Peak spatial absorption in brain tissue was considerably smaller than during use of a mobile phone. No conclusions can be drawn regarding short-term effects of cell phone exposure or the effects of long-term base station-like exposure on human health.

The platelet collagen receptor glycoprotein VI is a member of the immunoglobulin superfamily closely related to FcalphaR and the natural killer receptors

We have cloned the platelet collagen receptor glycoprotein (GP) VI from a human bone marrow cDNA library using rapid amplification of cDNA ends with platelet mRNA to complete the 5' end sequence. GPVI was isolated from platelets using affinity chromatography on the snake C-type lectin, convulxin, as a critical step. Internal peptide sequences were obtained, and degenerate primers were designed to amplify a fragment of the GPVI cDNA, which was then used as a probe to screen the library. Purified GPVI, as well as Fab fragments of polyclonal antibodies made against the receptor, inhibited collagen-induced platelet aggregation. The GPVI receptor cDNA has an open reading frame of 1017 base pairs coding for a protein of 339 amino acids including a putative 23-amino acid signal sequence and a 19-amino acid transmembrane domain between residues 247 and 265. GPVI belongs to the immunoglobulin superfamily, and its sequence is closely related to FcalphaR and to the natural killer receptors. Its extracellular chain has two Ig-C2-like domains formed by disulfide bridges. An arginine residue is found in position 3 of the transmembrane portion, which should permit association with Fcgamma and its immunoreceptor tyrosine-based activation motif via a salt bridge. With 51 amino acids, the cytoplasmic tail is relatively long and shows little homology to the C-terminal part of the other family members. The ability of the cloned GPVI cDNA to code for a functional platelet collagen receptor was demonstrated in the megakaryocytic cell line Dami. Dami cells transfected with GPVI cDNA mobilized intracellular Ca(2+) in response to collagen, unlike the nontransfected or mock transfected Dami cells, which do not respond to collagen.

Feasibility of future epidemiological studies on possible health effects of mobile phone base stations

The increasing deployment of mobile communication base stations led to an increasing demand for epidemiological studies on possible health effects of radio frequency emissions. The methodological challenges of such studies have been critically evaluated by a panel of scientists in the fields of radiofrequency engineering/dosimetry and epidemiology. Strengths and weaknesses of previous studies have been identified. Dosimetric concepts and crucial aspects in exposure assessment were evaluated in terms of epidemiological studies on different types of outcomes. We conclude that in principle base station epidemiological studies are feasible. However, the exposure contributions from all relevant radio frequency sources have to be taken into account. The applied exposure assessment method should be piloted and validated. Short to medium term effects on physiology or health related quality of life are best investigated by cohort studies. For long term effects, groups with a potential for high exposure need to first be identified; for immediate effect, human laboratory studies are the preferred approach.

Prolactin upregulates sphingosine kinase-1 expression and activity in the human breast cancer cell line MCF7 and triggers enhanced proliferation and migration

Sphingosine kinases (SK) catalyze the formation of sphingosine-1-phosphate (S1P) which plays a crucial role in cell growth and survival. Here, we show that prolactin (PRL) biphasically activates the SK-1, but not the SK-2 subtype, in the breast adenocarcinoma cell-line MCF7. A first peak occurs after minutes of stimulation and is followed by a second delayed activation after hours of stimulation. A similar biphasic effect on SK-1 activity is seen for 17beta-estradiol (E(2)). The delayed activation of SK-1 derives from an upregulated mRNA and protein expression and is due to increased SK-1 promoter activity and mechanistically involves STAT5 activation as well as protein kinase C and the classical mitogen-activated protein kinases. Furthermore, glucocorticoids also block both hormone-induced SK-1 expression and activity. Functionally, long-term stimulation of MCF7 cells with PRL or E(2) is well known to trigger increased cell proliferation and migration. Both hormone-induced cell responses critically involve SK-1 activation since the depletion of SK-1, but not SK-2, by siRNA transfection abolishes the hormone-induced cell proliferation and migration. In summary, our data show that PRL and E(2) cause a pronounced delayed SK-1 activation which is due to increased gene transcription, and critically determines the capability of cells to grow and move. Thus, the SK-1 may represent a novel attractive target for anti-tumor therapy.

Stability of soft tissue profile after mandibular setback in sagittal split osteotomies: a longitudinal and long-term follow-up study

PURPOSE: The aim of the study was to conduct a long-term prospective follow-up on the stability of soft tissues after bilateral sagittal split osteotomy (BSSO) with rigid internal fixation to set back the mandible. PATIENTS AND METHODS: Seventeen consecutive patients (6 females, 11 males) were re-examined 12.7 years (T5) after surgery. The precedent follow-ups included: before surgery (T1), 5 days (T2) after surgery, 6.6 months (T3) after surgery, and 14.4 months after (T4) surgery. Lateral cephalograms were traced by hand, digitized, and evaluated with the Dentofacial Planner program (Dentofacial Software, Toronto, Canada). The x-axis for the system of coordinates ran through Sella (point 0) and the line NSL -7 degrees. RESULTS: The net effect of the soft tissue chin (soft tissue pogonion) was 79% of the setback at pogonion. At the lower lip (labrale inferior) it was 100% of the setback at lower incisor position. Point B' followed point B to 99%. Labrale inferior and menton' also showed a significant backward, as well as a downward, movement (T5 to T2). Gender correlated significantly (P = .004) with the anterior displacement of point B' and pogonion' (P = .012). The soft tissue relapse 12.7 years after BSSO setback surgery at point B' was 3% and 13% at pogonion'. CONCLUSION: Among the reasons for 3-dimensional long-term soft tissue changes of shape, the surgical technique, the normal process of human aging, the initial growth direction, and remodeling processes must be considered. Growth direction positively influenced the long-term outcome of setback surgery in female compared with male patients because further posterior movement of the mandibular soft tissue occurred.

Stability of the hard and soft tissue profile after mandibular advancement in sagittal split osteotomies: a longitudinal and long-term follow-up study

The aim of the study was to conduct a long-term follow-up investigation of the stability of hard and soft tissues after bilateral sagittal split osteotomy (BSSO) with rigid internal (RIF) fixation to advance the mandible. Sixteen consecutive patients (12 females and 4 males, mean age 21.4 years) were available for re-examination 12.7 years (T5) after surgery. The preceding follow-ups were before (T1), and 5 days (T2), 7.3 months (T3), and 13.9 months (T4) after surgery. Lateral cephalograms were traced by hand, digitized, and evaluated with the Dentofacial Planner program. The x-axis for the system of co-ordinates ran through sella (point zero) and the line NSL -7 degrees. Thus, the program determined the x- and y-values of each variable and the usual angles and distances. Statistical analysis was carried out using Wilcoxon's matched-pair signed-ranks test with Bonferroni adjustments. The relationships between the examined variables were analysed by Spearman rank correlation coefficients. The backward relapse at point B (T5) was 2.42 mm, or 50 per cent, and at pogonion 3.21 mm, or 60 per cent of the initial advancement. The mean net effect at T5 on the labial fold (soft tissue point B) was 94 per cent of the advancement at point B. For the soft tissue chin (soft tissue pogonion), it was 119 per cent of the advancement at pogonion. The net effect on the lower lip (labrale inferior) was 55 per cent of the advancement at incision inferior. The amount of the surgical advancement of the mandible was correlated with the long-term relapse in point B. Among possible reasons for this relapse are the initial soft tissue profile, the initial growth direction, and the remodelling processes of the hard tissue.

Stability of hard tissue profile after mandibular setback in sagittal split osteotomies: a longitudinal and long-term follow-up study

The aim of the study was to conduct a long-term follow-up on the stability of the hard tissues after bilateral sagittal split osteotomy (BSSO) with rigid internal fixation (RIF)to set back the mandible and to compare it with that of mandibular advancement performed by the same team of surgeons and with the same examination protocol. Seventeen consecutive patients (6 females and 11 males) could be re-examined 12.7 years (T5) after surgery. The previous examinations were before surgery (T1), 5 days (T2), and 6.6 (T3) and 14.4 (T4) months after surgery. Lateral cephalograms were traced by hand, digitized, and evaluated with the Dentofacial Planner software program. The x-axis for the system of co-ordinates ran through sella (point zero) and the line nasion-sella-line minus 7 degrees. The program determined the x- and y-values of each variable and the usual angles and distances. The effects of treatment were determined with Wilcoxon matched pairs, signed ranks test, with Bonferroni adjustment, and the relationship between variables with Spearman rank correlation coefficient. Relapse at point B was 0.94 mm or 15 per cent and at pogonion 1.46 mm or 21 per cent of the initial setback at T5. Relapse was mainly short-term (T4-T2), 13 per cent for point B and 17 per cent for pogonion. Gender correlated significantly with relapse (T5-T2) at point B (P = 0.002) and pogonion (P = 0.021), i.e. females in contrast to males showed further distalization of the mandible instead of relapse. No correlations were seen for age or the amount of surgical setback. The long-term results in mandibular setback patients were more stable when compared with the mandibular advancement patients examined previously. The initial soft tissue profile, the initial growth direction, and the remodelling processes of the hard tissues must be considered as reasons for long-term relapse. Growth direction positively influenced the long-term results in females: further distalization of the mandible occurred.

Long-term trends of HIV type 1 drug resistance prevalence among antiretroviral treatment-experienced patients in Switzerland

BACKGROUND:Accurate quantification of the prevalence of human immunodeficiency virus type 1 (HIV-1) drug resistance in patients who are receiving antiretroviral therapy (ART) is difficult, and results from previous studies vary. We attempted to assess the prevalence and dynamics of resistance in a highly representative patient cohort from Switzerland. METHODS:On the basis of genotypic resistance test results and clinical data, we grouped patients according to their risk of harboring resistant viruses. Estimates of resistance prevalence were calculated on the basis of either the proportion of individuals with a virologic failure or confirmed drug resistance (lower estimate) or the frequency-weighted average of risk group-specific probabilities for the presence of drug resistance mutations (upper estimate). RESULTS:Lower and upper estimates of drug resistance prevalence in 8064 ART-exposed patients were 50% and 57% in 1999 and 37% and 45% in 2007, respectively. This decrease was driven by 2 mechanisms: loss to follow-up or death of high-risk patients exposed to mono- or dual-nucleoside reverse-transcriptase inhibitor therapy (lower estimates range from 72% to 75%) and continued enrollment of low-risk patients who were taking combination ART containing boosted protease inhibitors or nonnucleoside reverse-transcriptase inhibitors as first-line therapy (lower estimates range from 7% to 12%). A subset of 4184 participants (52%) had >or= 1 study visit per year during 2002-2007. In this subset, lower and upper estimates increased from 45% to 49% and from 52% to 55%, respectively. Yearly increases in prevalence were becoming smaller in later years. CONCLUSIONS:Contrary to earlier predictions, in situations of free access to drugs, close monitoring, and rapid introduction of new potent therapies, the emergence of drug-resistant viruses can be minimized at the population level. Moreover, this study demonstrates the necessity of interpreting time trends in the context of evolving cohort populations.

Episodic and long-lasting Paleozoic felsic magmatism in the pre-Alpine basement of the Suretta nappe (eastern Swiss Alps)

The Suretta nappe of eastern Switzerland contains a series of meta-igneous rocks, with the Rofna Porphyry Complex (RPC) being the most prominent member. We present LA-ICP-MS U–Pb zircon data from 12 samples representing a broad spectrum of meta-igneous rocks within the Suretta nappe, in order to unravel the pre-Alpine magmatic history of this basement unit. Fine-grained porphyries and coarse-grained augengneisses from the RPC give crystallization ages between 284 and 271 Ma, which either represent distinct magma pulses or long-lasting magmatic activity in a complex magma chamber. There is also evidence for an earlier Variscan magmatic event at ~320–310 Ma. Mylonites at the base of the Suretta nappe are probably derived from either the RPC augengneisses or another unknown Carboniferous–Permian magmatic protolith with a crystallization age between 320 and 290 Ma. Two polymetamorphic orthogneisses from the southern Suretta nappe yield crystallization ages of ~490 Ma. Inherited zircon cores are mainly of late Neoproterozoic age, with minor Neo- to Paleoproterozoic sources. We interpret the Suretta nappe as mainly representing a Gondwana-derived crustal unit, which was subsequently intruded by minor Cambrian–Ordovician and major Carboniferous–Permian magmatic rocks. Finally, the Suretta nappe was thrust into its present position during the Alpine orogeny, which hardly affected the U–Pb system in zircon.