Chemical interactions between Saturn's atmosphere and its rings.

The Pioneer and Voyager spacecraft made close-up measurements of Saturn's ionosphere and upper atmosphere in the 1970s and 1980s that suggested a chemical interaction between the rings and atmosphere. Exploring this interaction provides information on ring composition and the influence on Saturn's atmosphere from infalling material. The Cassini Ion Neutral Mass Spectrometer sampled in situ the region between the D ring and Saturn during the spacecraft's Grand Finale phase. We used these measurements to characterize the atmospheric structure and material influx from the rings. The atmospheric He/H2 ratio is 10 to 16%. Volatile compounds from the rings (methane; carbon monoxide and/or molecular nitrogen), as well as larger organic-bearing grains, are flowing inward at a rate of 4800 to 45,000 kilograms per second.

Left atrial appendage morphology and relative contrast agent concentration in patients undergoing coronary artery CTA.

AIM: To evaluate whether certain morphological features of the left atrial appendage (LAA) would influence the LAA/ascending aorta (AA) radiodensity ratio, as a reflection of the blood flow conditions in the LAA. MATERIALS AND METHODS: Eight-hundred and eight consecutive patients undergoing computed tomography angiography (CCTA) were evaluated. Of these, 749 had no history of atrial fibrillation and none had suffered acute stroke. The LAA/AA radiodensity ratio, and the length, lobe number, and morphological classification of LAAs were assessed. RESULTS: The distribution of morphological classes for LAAs were: windsock 62.3%, cactus 18.6%, chicken wing 10.0%, and cauliflower 9.2%. The mean LAA/AA radiodensity ratio was 0.87±0.14 (range 0.22-1.44). Female gender (p=0.001), elevated body mass index (BMI; r=-0.129; p=0.003), and diabetes (p=0.03) were associated with lower LAA/AA radiodensity ratios, while heart failure (p=0.017), significant coronary artery stenosis (p=0.010), and LAAs with multiple lobes (p=0.018), exhibited higher LAA/AA radiodensity ratios. Multiple regression analysis revealed that a short one-lobed cauliflower morphology was an independent predictor (p=0.007) of a decreased LAA/AA radiodensity ratio. CONCLUSION: A decline in the LAA/AA radiodensity ratio may reflect decreased blood flow in the LAA, paralleling spontaneous echo contrast in transoesophageal echocardiography. Thus, CCTA might be of value in recognising LAA structures that predispose to decreased blood flow.

Efficacy and safety of myocardial gene transfer of adenovirus, adeno-associated virus and lentivirus vectors in the mouse heart.

Gene therapy is a promising new treatment option for cardiac diseases. For finding the most suitable and safe vector for cardiac gene transfer, we delivered adenovirus (AdV), adeno-associated virus (AAV) and lentivirus (LeV) vectors into the mouse heart with sophisticated closed-chest echocardiography-guided intramyocardial injection method for comparing them with regards to transduction efficiency, myocardial damage, effects on the left ventricular function and electrocardiography (ECG). AdV had the highest transduction efficiency in cardiomyocytes followed by AAV2 and AAV9, and the lowest efficiency was seen with LeV. The local myocardial inflammation and fibrosis in the left ventricle (LV) was proportional to transduction efficiency. AdV caused LV dilatation and systolic dysfunction. Neither of the locally injected AAV serotypes impaired the LV systolic function, but AAV9 caused diastolic dysfunction to some extent. LeV did not affect the cardiac function. We also studied systemic delivery of AAV9, which led to transduction of cardiomyocytes throughout the myocardium. However, also diffuse fibrosis was present leading to significantly impaired LV systolic and diastolic function and pathological ECG changes. Compared with widely used AdV vector, AAV2, AAV9 and LeV were less effective in transducing cardiomyocytes but also less harmful. Local administration of AAV9 was safer and more efficient compared with systemic administration.

An observed correlation between plume activity and tidal stresses on Enceladus.

Saturn's moon Enceladus emits a plume of water vapour and micrometre-sized ice particles from a series of warm fissures located near its south pole. This geological activity could be powered or controlled by variations in the tidal stresses experienced by Enceladus as it moves around its slightly eccentric orbit. The specific mechanisms by which these varying stresses are converted into heat, however, are still being debated. Furthermore, it has proved difficult to find a clear correlation between the predicted tidal forces and measured temporal variations in the plume's gas content or the particle flux from individual sources. Here we report that the plume's horizontally integrated brightness is several times greater when Enceladus is near the point in its eccentric orbit where it is furthest from Saturn (apocentre) than it is when near the point of closest approach to the planet (pericentre). More material therefore seems to be escaping from beneath Enceladus' surface at times when geophysical models predict its fissures should be under tension and therefore may be wider open.

Predictive value of modelled tumour control probability based on individual measurements of in vitro radiosensitivity and potential doubling time.

OBJECTIVE: The aim of this study was to compare patient-specific radiobiological parameters with population averages in predicting the clinical outcome after radiotherapy (RT) using a tumour control probability (TCP) model based on the biological effective dose (BED). METHODS: A previously published study of 46 head and neck carcinomas with individually identified radiobiological parameters, radiosensitivity and potential doubling time (Tpot), and known tumour size was investigated. These patients had all been treated with external beam RT, and the majority had also received brachytherapy. The TCP for each individual based on the BED using patient-specific radiobiological parameters was compared with the TCP based on the BED using average radiobiological parameters (α=0.3 Gy(-1), Tpot=3 days). RESULTS: 43 patients remained in the final analysis. There was only a weak trend for increasing local tumour control with increasing BED in both groups. However, when the TCP was calculated, the use of patient-specific parameters was better for identifying local control correctly. The sensitivity and specificity for tumour-specific parameters were 63% and 80%, respectively. The corresponding values for population-based averages were 0% and 91%, respectively. The positive predictive value was 92% when tumour-specific parameters were used compared with 0% for population-based averages. A receiver operating characteristic curve confirmed the superiority of patient-specific parameters over population averages in predicting local control. CONCLUSION: Individual radiobiological parameters are better than population-derived averages when used in a mathematical model to predict TCP after curative RT in head and neck carcinomas. ADVANCES IN KNOWLEDGE: TCP based on individual radiobiological parameters is better than TCP based on population-based averages for identifying local control correctly.

10-year safety follow-up in patients with local VEGF gene transfer to ischemic lower limb.

Vascular endothelial growth factor (VEGF)-mediated gene therapy (GT) has shown promising results as a novel method in the treatment of severe cardiovascular diseases. VEGF GT has proved to be safe and well tolerated in short-term studies, but there is only very limited data available on long-term effects. In this study we examined the effects of VEGF GT on patients having received VEGF-A gene transfer for the treatment of symptomatic (that is, claudication or critical lower limb ischemia) peripheral arterial occlusive disease. Out of 54 patients, 25 (46%) were interviewed for this study and 26 (48%) had died during the follow-up. Interviewed patients were treated with adenoviral (n=8, mean age 76 (62.7-90.6) years) or plasmid/liposome (n=8, mean age 84.2 (71.9-94.7) years) vectors compared with a randomized control group (n=10, mean age 80.5 (70.7-88.1) years) using a local balloon catheter device. The follow-up time was 10 years. Causes of death were clarified from hospital records. There were no statistically significant differences between the study groups in the causes of death or in the incidence of cancer (VEGF-Adv 0/10 vs VEGF-p/l 1/8 vs Control 1/7, P=0.5), diabetes (3/10 vs 3/8 vs 2/7, P=1.00) or diabetic retinopathy (0/10 vs 1/8 vs 0/7, P=0.45). In addition, we found no differences in the number of amputations of the treated leg (0/10 vs 3/8 vs 1/7, P=0.17). We conclude that transient VEGF-A-mediated GT did not increase the incidence of cancer, diabetes, retinopathy or any other diseases during the 10-year follow-up time. No significant differences were detected in the number of amputations or causes of death. This study supports our previous findings that local adenovirus and plasmid/liposome-mediated VEGF-A GT is safe and well-tolerated treatment in elderly patients with cardiovascular diseases.

Saturn's curiously corrugated C ring.

In August 2009 the Sun illuminated Saturn's rings from almost exactly edge-on, revealing a subtle corrugation that extends across the entire C ring. This corrugation's amplitude is 2 to 20 meters and its wavelength is 30 to 80 kilometers. Radial trends in the corrugation's wavelength indicate that this structure--like a similar corrugation previously identified in the D ring--results from differential nodal regression within a ring that became tilted relative to Saturn's equator plane in 1983. We suggest that this initial tilt arose because interplanetary debris struck the rings. The corrugation's radial extent implies that the impacting material was a dispersed cloud of debris instead of a single object, and the corrugation's amplitude indicates that the debris' total mass was ~10(11) to 10(13) kilograms.

Progress and prospects: hurdles to cardiovascular gene therapy clinical trials.

Several gene therapy approaches have been designed for the treatment of cardiovascular diseases. A positive finding is that the safety of cardiovascular gene therapy has been excellent even in long-term follow-up. However, several hurdles to this field are still present. A major disappointing feature of the trials is that while preclinical and uncontrolled phase-I gene therapy trials have been positive, none of the randomized controlled phase-II/III cardiovascular gene therapy trials have shown clinically relevant positive effects. Low gene transfer efficiency seems to be associated with several trials. A sophisticated efficient delivery method for cardiovascular applications is still lacking and only low concentrations of the gene product are produced in the target tissues. Only a few gene therapy vectors can be produced in large scale. In addition, inflammatory reactions against vectors and inability to regulate gene expression are still present. Furthermore, a strong placebo effect is affecting the results in gene therapy trials, and long-term trials have become more difficult to conduct because of the multiplicity of therapies applied simultaneously on the patients. This review summarizes advances and obstacles of current cardiovascular clinical gene therapy trials.

Dissecting the Finnish male uniformity: the value of additional Y-STR loci.

The forensic use of Y-chromosomal markers can be hampered by reduced diversity and geographical subdivision in some populations. In Finland both of these confounding factors are well documented, but it is also shown that increase of data could resolve or at least alleviate these problems. In order to increase the forensic usability of Y-chromosomal data in Finland, we have here evaluated the diversity at a number of additional Y-STRs. A seven Y-STR locus panel ("FY7": DYS449, DYS460, DYS505, DYS522, DYS576, DYS612 and DYS627) was found to reveal higher diversity levels among Finns than the substantially larger commercial multiplexes commonly in use. The Y-STR data augmented with the FY7 panel shows substantially higher discrimination capacity and lower levels of geographical structure among Finns. Amplifiable in one multiplex, this set of loci offers an informative and easy-to-use supplementary for the commercial Y-STR kits.

An evolving view of Saturn's dynamic rings.

We review our understanding of Saturn's rings after nearly 6 years of observations by the Cassini spacecraft. Saturn's rings are composed mostly of water ice but also contain an undetermined reddish contaminant. The rings exhibit a range of structure across many spatial scales; some of this involves the interplay of the fluid nature and the self-gravity of innumerable orbiting centimeter- to meter-sized particles, and the effects of several peripheral and embedded moonlets, but much remains unexplained. A few aspects of ring structure change on time scales as short as days. It remains unclear whether the vigorous evolutionary processes to which the rings are subject imply a much younger age than that of the solar system. Processes on view at Saturn have parallels in circumstellar disks.

X-STR diversity patterns in the Finnish and the Somali population.

Autosomal and Y-chromosomal STR markers have been routinely used in kinship analyses already for over a decade, augmented by mitochondrial DNA in more complex cases questioning the maternal relationships of the samples. Recently, a commercial X-chromosome typing kit Mentype Argus X-8 was introduced to supplement the existing forensic toolkit. In this study, X-STR allele frequencies and population diversity indices in two ethnic groups, the Finnish and the Somali, are reported. Several previously unreported alleles and features in the allelic distribution were observed, some of which were further investigated with a small set of family data. Most notably, several alleles showed significant frequency differences between sexes, yet no obvious explanation for this discrepancy was found. As a demonstration of X-chromosome analysis in practice, we describe two family reunion cases, where the X-STR data was successfully utilized.

TGFBR1 variants TGFBR1(*)6A and Int7G24A are not associated with an increased familial colorectal cancer risk.

Variants of the transforming growth factor-beta receptor type 1 (TGFBR1) gene, TGFBR1*6A and Int7G24A, have been suggested to act as low-penetrance tumour susceptibility alleles with TGFBR1*6A being causally responsible for some cases of familial colorectal cancer (CRC). We performed a case-control study of 262 unrelated familial CRC cases; 83 hereditary non-polyposis colorectal cancer (HNPCC) and 179 non-HNPCC. Patients were genotyped for TGFBR1*6A and Int7G24A and compared with 856 controls. Further, we screened the coding region of TGFBR1 in affected members of a large family with CRC linked to 9q22.32-31.1. TGFBR1*6A allelic frequency was not significantly different in all of the familial cases compared with controls (0.107 and 0.106, respectively; P=0.915). In a subgroup analysis allele frequencies were, however, different between HNPCC and non-HNPCC familial cases (0.157 and 0.084, respectively; P=0.013). TGFBR1*6A genotype did not influence age of onset. Int7G24A allele frequencies were similar in cases and controls. No germ-line mutation was identified in the family with CRC linked to this chromosomal region. Our study provides no substantial support for the hypothesis that the polymorphic variants TGFBR1*6A or Int7G24A contribute to familial CRC risk. We cannot, however, exclude the possibility that TGFBR1 variants have a modifying effect on inherited risk per se.

Eight-year safety follow-up of coronary artery disease patients after local intracoronary VEGF gene transfer.

Vascular endothelial growth factor (VEGF) has been shown to stimulate angiogenesis and myocardial perfusion. The short-term safety of VEGF gene therapy is excellent. However, there are only limited results regarding the long-term effects. The Kuopio Angiogenesis Trial (KAT) studied the efficiency and short-term safety of the local VEGF-A(165) gene transfer in 103 patients with coronary artery disease. Three patient groups received either VEGF as an adenoviral (n=37), or as a plasmid/liposome vector (n=28), or as a placebo (n=38), during coronary angioplasty and stenting (percutaneous coronary intervention, PCI)AQ1. The aim of this study was to examine the long-term effects and safety of VEGF gene therapy. Patients were interviewed by telephone or with a questionnaire on their current status of health, coronary and other cardiovascular events and symptoms, working ability, exercise tolerance, other diseases, such as cancer and diabetes, as well as their personal experience of the treatment. Causes of death were clarified from hospital records. The total follow-up time was 8.1 years (range 6.9-9.7 years). Overall 82% of the patients were reached across the study. Eight (7.5%) of the patients died during the follow-up, but there was no significant difference in mortality between the groups (3/32 vs 2/26 vs 3/31 VEGF-adenovirus vs VEGF-plasmid/liposome vs placebo, respectively; P=0.88). The incidence of major adverse cardiovascular events (MACEs) (10 vs 11 vs 15; P=0.85), cancer (1 vs 4 vs 2; P=0.38) or diabetes (2 vs 2 vs 2; P=0.97) did not differ between the groups. Local intracoronary VEGF gene transfer is safe and does not increase the risk of MACE, arrhythmias, cancer, diabetes or other diseases.

Impaired CD4 and CD8 T cell phenotype and reduced chemokine secretion in recent-onset type 1 diabetic children.

Although the role of the T cell-mediated autoimmune reaction in type 1 diabetes (T1D) is conclusive, studies including data from human circulating CD4(+) and CD8(+) lymphocytes subsets during the disease onset and posterior development are scarce. Further, chemokines and chemokine receptors are key players in the migration of pathogenic T cells into the islets of non-obese diabetic mice developing T1D, but few studies have investigated these markers in human T1D patients. We studied the expression of T helper 1 (Th1)- and Th2-associated chemokine receptors, and the two isoforms of CD45 leucocyte antigen on CD4(+) and CD8(+) lymphocytes from T1D and healthy children, as well as the secretion of chemokines in cell supernatants in peripheral blood mononuclear cells. Our results showed increased expression of CCR7 and CD45RA and reduced CD45RO on CD8(+) cells among recent-onset T1D patients. The percentages of CD4(+) cells expressing CXC chemokine receptor 3 (CXCR3), CXCR6 and CCR5, and the secretion of interferon-gamma-induced protein-10, monocyte chemoattractant protein-1, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta was lower among diabetics. Low expression of Th1-associated receptors and secretion of chemokines, together with an increased amount of CD8(+) cells expressing CD45RA and CCR7 in T1D patients therefore might represent suboptimal Th function in T1D, leading to impaired T cytotoxic responses or alternatively reflect a selective recruitment of Th1 cells into the pancreas.

Finnish mitochondrial DNA HVS-I and HVS-II population data.

We have analyzed the two hypervariable regions HVS-I and HVS-II of 200 Finnish male individuals for forensic purposes. The distribution of the haplotypes within Finland was determined by the geographical knowledge of the donors' maternal ancestors. In our population sample, we identified 135 different mtDNA haplotypes. Different mtDNA sequences were further divided to haplogroups using the EMPOP software. The most common haplogroups were H (40.0%) and U (27.5%). Subgroup U5b, which contains earlier described "Saami motif", consisted majority (65.5%) of the sample in the U haplogroup. Analysis of the mtDNA sequence hypervariable regions I and II showed that the mtDNA diversity within the Finnish population sample was comparable to other European populations and uniformly distributed. This is contrary to the Y-STR "minimal haplotype" diversity, which in Finland is lower than in any of the other European populations studied so far.

Dose-hair concentration relationship and pigmentation effects in patients on low-dose clozapine.

Several hair components have been suggested as possible molecular sites for drug binding and interaction. Of these, keratin and melanin have been investigated in some detail in order to assess the mechanisms by which the binding occurs. Substances that are positively charged at physiological pH may interact by electrostatic forces between their cationic groups and the anionic carboxylic groups on the surface of the melanin polymer. Studies in human subjects with grey hair have shown that various drugs are detectable in both the coloured (melanin rich) and white (melanin free) hair shafts of these individuals. Again this supports the proposition that keratin and hair proteins play an important role in the binding of drugs in hair. However, drugs are often found in significantly higher concentrations in pigmented hair strands than in senile white hair strands. Another interesting question is if the concentration measured in hair reflects the dose taken. Previous reports have both verified and rejected this hypothesis, but most agree that many factors have impact on the incorporation rate, melanin being one. In this study we obtained blood and hair samples from 12 grey haired patients treated with low-dose clozapine as an adjunct medication in their treatment against Parkinson disease. Each patient's hair was divided into a pigmented and a non-pigmented portion and those were analyzed separately. Clozapine and desmethylclozapine were analyzed with LC-MS-MS after extraction of the analytes from hair and plasma. Paired results from the analysis of pigmented and white hair confirmed the preference for binding to pigmented hair for both clozapine and its metabolite. A majority of the incorporated clozapine was found in the pigmented hair but, as drugs could be detected in white hair, binding to hair protein or association with other hair matrix account for a significant part of drug accumulation in hair. High correlations between dose and the measured concentration of analyte were found for both clozapine (r = 0.91) and desmethylclozapine (r = 0.88).

The association of CTLA-4 and HLA class II autoimmune risk genotype with regulatory T cell marker expression in 5-year-old children.

Regulatory T cells (Treg) are involved in the maintenance of peripheral tolerance by suppression of autoreactive lymphocytes that have avoided thymic depletion. The defective function of Treg cells has recently attracted attention in autoimmune diseases such as type 1 diabetes (T1D), rheumatoid arthritis and multiple sclerosis. Susceptibility to these diseases is associated with specific human leucocyte antigen (HLA) class II and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) gene polymorphisms. This study aimed to investigate the relationship between HLA class II and CTLA +49 A/G polymorphisms associated with susceptibility to T1D and the number and characteristics of Treg cells in children. Samples from 47 5-year-old children who participated in the All Babies in South-east Sweden (ABIS) follow-up study were grouped according to the presence of the T1D risk-associated HLA genotype (DQA1*0501-DQB1*0201, DQA1*0301-DQB1*0302) or neutral HLA genotypes. Lower percentages of CD4+ T cells (P = 0.03) and CD4+ CD25high cells (P = 0.06) expressing intracellular CTLA-4 were detected in samples from children with CTLA-4 +49GG compared to children with the +49AA genotype. Similarly, lower percentages of CD4+ (P = 0.002) and CD4+ CD25high (P = 0.002) cells expressing CTLA-4 were observed in children positive for HLA DQA1*0501-DQB1*0201 and DQA1*0301-DQB1*0302 (P = 0.04 for CD4+ and P = 0.02 for CD4+ CD25high) risk haplotypes when compared to children without these alleles. The percentage of CD25high cells among CD4+ cells was correlated inversely with CTLA-4 mRNA expression in PBMC (r = -0.56, P = 0.03). Decreased levels of CTLA-4 in CD4+ and CD4+ CD25high cells in individuals with CTLA-4 and HLA class II alleles associated with T1D may contribute to the initiation and/or progression of autoimmune response.

A microarray system for genotyping 150 single nucleotide polymorphisms in the coding region of human mitochondrial DNA.

We established a genotyping system for a panel of 150 SNPs in the coding regions of mitochondrial DNA based on multiplex tag-array minisequencing. We show the feasibility of this system for simultaneous identification of individuals and prediction of the geographical origin of the mitochondrial DNA population lineage of the sample donors by genotyping the panel of SNPs in 265 samples representing nine different populations from Africa, Europe, and Asia. Nearly 40,000 genotypes were produced in the study, with an overall genotyping success rate of 95% and accuracy close to 100%. The gene diversity value of the panel of 150 SNPs was 0.991, compared to 0.995 for sequencing 500 nucleotides of the hypervariable regions I and II of mtDNA. For 17 individuals with identical sequences in the hypervariable regions of mtDNA, our panel of SNPs increased the power of discrimination. We observed 144 haplotypes that correspond to previously determined mitochondrial "haplogroups," and they allowed prediction of the origin of the maternal population lineage of 97% of the analyzed samples.

Periadventitial angiopoietin-1 gene transfer induces angiogenesis in rabbit carotid arteries.

This study was performed to evaluate angiogenic responses of angiopoietin-1 (Ang1) in vivo after adenovirus-mediated gene transfer in the periadventitial space of the rabbit carotid arteries using a collar technique. Adenoviruses encoding LacZ and vascular endothelial growth factor (VEGF) receptor-1-Ig fusion protein (VEGF-R1-Ig) adenoviruses were used as controls. Increased neovessel formation was seen in adventitia of the Ang1 transduced arteries 7 days after the gene transfer. Neovessels in the Ang1 transduced arteries were large in size and well perfused. Ang1 binds to Tie2 (tyrosine kinase with immunoglobulin and epidermal growth factor homology domain) receptors, which were expressed in the endothelium of the neovessels. When VEGF-R1-Ig was used with Ang1, it resulted in a decrease in the number of neovessels, which implies that VEGF-A or some other VEGF-R1 ligand(s) play a crucial role in angiogenesis occurring in response to Ang1. There were no significant differences in the total number of capillaries in the adventitia of the VEGF-R1-Ig transduced arteries as compared to LacZ controls. Neointima formation was not increased in the Ang1 transduced arteries as compared to the controls. We conclude that in the periadventitial space Ang1 shows angiogenic activity and is a potentially useful factor for the induction of therapeutic vascular growth in vivo.

Association between insulin resistance and GAD65-autoantibody levels--a pilot study in an adult non-diabetic population.

The aim of this pilot study was to investigate any association between insulin resistance (IR) and serum levels of autoantibodies against the glutamic acid decarboxylase (GAD65Ab) among adult non-diabetic subjects. Based on calculations of IR using the IR homeostasis model in a Swedish adult non-diabetic population (n = 756) participating in the WHO MONICA-study, an insulin sensitive group (n = 54, M/F:27/27) and an insulin resistant group (n = 46 M/F:24/22) were identified. Serum from the subjects were analysed for the presence of GAD65Ab. There was no significant difference in GAD65Ab levels between the groups. However, there was a correlation between IR and serum GAD65Ab within the insulin sensitive group (Spearman rho 0.4, p < 0.01). Our observation could indicate that IR could serve as an initiator or a progression factor in the autoimmune process in subjects predisposed to autoimmunity. This finding will be further investigated in a larger study including subjects with a continuum of IR.