Pluto's Interaction With Energetic Heliospheric Ions.

Pluto energies of a few kiloelectron volts and suprathermal ions with tens of kiloelectron volts and above. We measure this population using the Pluto Energetic Particle Spectrometer Science Investigation (PEPSSI) instrument on board the New Horizons spacecraft that flew by Pluto in 2015. Even though the measured ions have gyroradii larger than the size of Pluto and the cross section of its magnetosphere, we find that the boundary of the magnetosphere is depleting the energetic ion intensities by about an order of magnitude close to Pluto. The intensity is increasing exponentially with distance to Pluto and reaches nominal levels of the interplanetary medium at about 190R P distance. Inside the wake of Pluto, we observe oscillations of the ion intensities with a periodicity of about 0.2 hr. We show that these can be quantitatively explained by the electric field of an ultralow-frequency wave and discuss possible physical drivers for such a field. We find no evidence for the presence of plutogenic ions in the considered energy range.

Restoring functional neurofibromin by protein transduction.

In Neurofibromatosis 1 (NF1) germ line loss of function mutations result in reduction of cellular neurofibromin content (NF1+/-, NF1 haploinsufficiency). The Ras-GAP neurofibromin is a very large cytoplasmic protein (2818 AA, 319 kDa) involved in the RAS-MAPK pathway. Aside from regulation of proliferation, it is involved in mechanosensoric of cells. We investigated neurofibromin replacement in cultured human fibroblasts showing reduced amount of neurofibromin. Full length neurofibromin was produced recombinantly in insect cells and purified. Protein transduction into cultured fibroblasts was performed employing cell penetrating peptides along with photochemical internalization. This combination of transduction strategies ensures the intracellular uptake and the translocation to the cytoplasm of neurofibromin. The transduced neurofibromin is functional, indicated by functional rescue of reduced mechanosensoric blindness and reduced RasGAP activity in cultured fibroblasts of NF1 patients or normal fibroblasts treated by NF1 siRNA. Our study shows that recombinant neurofibromin is able to revert cellular effects of NF1 haploinsuffiency in vitro, indicating a use of protein transduction into cells as a potential treatment strategy for the monogenic disease NF1.

Influence of pelvic volume on surgical outcome after low anterior resection for rectal cancer.

BACKGROUND: Low anterior resection (LAR) for rectal cancer is a potentially challenging operation due to limited space in the pelvis. CT pelvimetry allows to quantify pelvic space, so that its relationship with outcome after LAR may be assessed. Studies investigating this, however, yielded conflicting results. We hypothesized that a small pelvis is associated with a higher rate of incomplete mesorectal excision, anastomotic leakages, and increased rate of urinary dysfunction in patients operated for rectal cancer. METHODS: In a single-center retrospective analysis, we studied 74 patients that underwent LAR for rectal cancer with primary anastomosis. Thin-layered multi-slice CT datasets were used for slice by slice depiction of the inner pelvic surface, and the inner pelvic volume was automatically compounded. The primary outcome was quality of total mesorectal excision (TME; Mercury grading); secondary outcomes were anastomotic leakage and urinary dysfunction with regard to pelvic dimensions. Univariate analyses and multiple logistic regression analyses were performed for the primary and the secondary outcomes. RESULTS: Shorter obstetric conjugate diameters were associated with a higher probability of a worse TME quality (110.8 ± 10.2 vs. 105.0 ± 8.6 mm; OR 0.85; 95% CI 0.73-0.99; p = 0.038). Short interspinous distance showed a trend towards an increased risk for deteriorated TME quality (OR 0.88; 95% CI 0.76-1.0; p = 0.06). Anastomotic leakage was associated with anemia (OR 2.77; 95% CI 1.0-7.7; p = 0.047). Association between pelvic diameters or pelvic volume and anastomotic leakage or urinary dysfunction was not observed. Perioperative blood transfusions were administered more often in patients with postoperative urinary dysfunction (OR 17.67; 95% CI 2.44-127.7; p = 0.004). CONCLUSION: Shorter obstetric conjugate diameter might be a risk factor for incompleteness of total mesorectal excision. Anastomotic leakage seems to be influenced more by clinical factors such as anemia rather than pelvic dimensions. Further studies have to prove the influence of pelvic diameter on local recurrence of rectal cancer after LAR.

The small satellites of Pluto as observed by New Horizons.

The New Horizons mission has provided resolved measurements of Pluto's moons Styx, Nix, Kerberos, and Hydra. All four are small, with equivalent spherical diameters of ~40 kilometers for Nix and Hydra and ~10 kilometers for Styx and Kerberos. They are also highly elongated, with maximum to minimum axis ratios of ~2. All four moons have high albedos (~50 to 90%) suggestive of a water-ice surface composition. Crater densities on Nix and Hydra imply surface ages of at least 4 billion years. The small moons rotate much faster than synchronous, with rotational poles clustered nearly orthogonal to the common pole directions of Pluto and Charon. These results reinforce the hypothesis that the small moons formed in the aftermath of a collision that produced the Pluto-Charon binary.

Modelling the growth of plants with a uniform growth logistics.

BACKGROUND AND AIMS: The increment model has previously been used to describe the growth of plants in general. Here, we examine how the same logistics enables the development of different superstructures. METHODS: Data from the literature are analyzed with the increment model. Increments are growth-invariant molecular clusters, treated as heuristic particles. This approach formulates the law of mass action for multi-component systems, describing the general properties of superstructures which are optimized via relaxation processes. RESULTS: The daily growth patterns of hypocotyls can be reproduced implying predetermined growth invariant model parameters. In various species, the coordinated formation and death of fine roots are modeled successfully. Their biphasic annual growth follows distinct morphological programs but both use the same logistics. In tropical forests, distributions of the diameter in breast height of trees of different species adhere to the same pattern. Beyond structural fluctuations, competition and cooperation within and between the species may drive optimization. CONCLUSION: All superstructures of plants examined so far could be reproduced with our approach. With genetically encoded growth-invariant model parameters (interaction with the environment included) perfect morphological development runs embedded in the uniform logistics of the increment model.

A comparative electrographic analysis of the effect of sec-butyl-propylacetamide on pharmacoresistant status epilepticus.

Better treatment of status epilepticus (SE), which typically becomes refractory after about 30 min, will require new pharmacotherapies. The effect of sec-butyl-propylacetamide (SPD), an amide derivative of valproic acid (VPA), on electrographic status epilepticus (ESE) was compared quantitatively to other standard-of-care compounds. Cortical electroencephalograms (EEGs) were recorded from rats during ESE induced with lithium-pilocarpine. Using a previously-published algorithm, the effects of SPD on ESE were compared quantitatively to other relevant compounds. To confirm benzodiazepine resistance, diazepam (DZP) was shown to suppress ESE when administered 15 min after the first motor seizure, but not after 30 min (100mg/kg). VPA (300 mg/kg) also lacked efficacy at 30 min. SPD (130 mg/kg) strongly suppressed ESE at 30 min, less after 45 min, and not at 60 min. At a higher dose (180 mg/kg), SPD profoundly suppressed ESE at 60 min, similar to propofol (100mg/kg) and pentobarbital (30 mg/kg). After 4-6h of SPD-induced suppression, EEG activity often overshot control levels at 7-12h. Valnoctamide (VCD, 180 mg/kg), an SPD homolog, was also efficacious at 30 min. SPD blocks pilocarpine-induced electrographic seizures when administered at 1h after the first motor seizure. SPD has a faster onset and greater efficacy than DZP and VPA, and is similar to propofol and pentobarbital. SPD and structurally similar compounds may be useful for the treatment of refractory ESE. Further development and use of automated analyses of ESE may facilitate drug discovery for refractory SE.

Partial Blindness to Submicron Topography in NF1 Haploinsufficient Cultured Fibroblasts Indicates a New Function of Neurofibromin in Regulation of Mechanosensoric.

Cells sense physical properties of their extracellular environment and translate them into biochemical signals. In this study, cell responses to surfaces with submicron topographies were investigated in cultured human NF1 haploinsufficient fibroblasts. Age-matched fibroblasts from 8 patients with neurofibromatosis type 1 (NF1(+/-)) and 9 controls (NF1(+/+)) were cultured on surfaces with grooves of 200 nm height and lateral distance of 2 µm. As cellular response indicator, the mean cell orientation along microstructured grooves was systematically examined. The tested NF1 haploinsufficient fibroblasts were significantly less affected by the topography than those from healthy donors. Incubation of the NF1(+/-) fibroblasts with the farnesyltransferase inhibitor FTI-277 and other inhibitors of the neurofibromin pathway ameliorates significantly the cell orientation. These data indicate that NF1 haploinsufficiency results in an altered response to specific surface topography in fibroblasts. We suggest a new function of neurofibromin in the sensoric mechanism to topographies and a partial mechanosensoric blindness by NF1 haploinsufficiency.

On the structure-bounded growth processes in plant populations.

If growing cells in plants are considered to be composed of increments (ICs) an extended version of the law of mass action can be formulated. It evidences that growth of plants runs optimal if the reaction-entropy term (entropy times the absolute temperature) matches the contact energy of ICs. Since these energies are small, thermal molecular movements facilitate via relaxation the removal of structure disturbances. Stem diameter distributions exhibit extra fluctuations likely to be caused by permanent constraints. Since the signal-response system enables in principle perfect optimization only within finite-sized cell ensembles, plants comprising relatively large cell numbers form a network of size-limited subsystems. The maximal number of these constituents depends both on genetic and environmental factors. Accounting for logistical structure-dynamics interrelations, equations can be formulated to describe the bimodal growth curves of very different plants. The reproduction of the S-bended growth curves verifies that the relaxation modes with a broad structure-controlled distribution freeze successively until finally growth is fully blocked thus bringing about "continuous solidification".

Correlation between critical temperature and strength of small-scale bcc pillars.

Microcompression tests were performed on focused-ion-beam-machined micropillars of several body-centered-cubic metals (W, Mo, Ta, and Nb) at room temperature. The relationship between yield strength and pillar diameter as well as the deformation morphologies were found to correlate with a parameter specific for bcc metals, i.e., the critical temperature T(c). This finding sheds new light on the phenomenon of small-scale plasticity in largely unexplored non-fcc metals.

Higher efficiency of thymine-adenine clamp-modified single-stranded oligonucleotides in targeted nucleotide sequence correction is not correlated with lower intracellular degradation.

Specific single-stranded oligonucleotides can induce targeted nucleotide sequence correction in eukaryotic genes in vitro and in vivo. Our model for investigating the reasons for the low correction rates achieved by this method is the correction of a point mutation in the hypoxanthine-guanine phosphoribosyltransferase gene (hprt) in the cell line V79-151. Using single-stranded phosphorothioate-modified oligonucleotides, the correction rates of this hprt mutation were low but always reproducible. One reason for low exchange rates may be fast intracellular degradation of the oligonucleotides. Therefore we compared the exchange rates of different 3' and 5' end-modified oligonucleotides with their degradation rates. Thymine-adenine (TA) repeat (clamp)-modified oligonucleotides showed higher correction rates than those with a guanine-cytosine (GC) clamp and 5' clamps induced higher correction rates than clamps at the 3' end. Experiments on the stability of the most effective 5'-TA and 3'-TA clamp-modified oligonucleotide indicated rapid cleavage and the occurrence of shortened oligonucleotides in the presence of cytoplasmic and nuclear extracts. The phosphorothioate-modified oligonucleotides were more stable, but their correction rates were lower. We suggest that there is no direct correlation between the biological stability of the full-length oligonucleotides and the exchange rates achieved.

Expression analysis of genes lying in the NF1 microdeletion interval points to four candidate modifiers for neurofibroma formation.

The hallmark of neurofibromatosis type 1 (NF1) are multiple dermal neurofibromas. They show high inter- and intrafamilial variability for which the influence of modifying genes is discussed. NF1 patients presenting microdeletions spanning NF1 and several contiguous genes have an earlier onset and higher number of dermal neurofibromas than classical NF1 patients, pointing to one of the deleted genes as modifier. Expression analysis of 13 genes of the microdeletion region in dermal neurofibromas and other tissues revealed four candidates for the modification of neurofibroma formation: CENTA2, RAB11FIP4, C17orf79, and UTP6.

The general growth logistics of cell populations.

An increment model based on thermodynamics lays bare that the cell size distributions of archaea, prokaryotes and eukaryotes are optimized and belong to the same universal class. Yet, when a cell absorbs mass or signals are processed, these conditions are disturbed. Relaxation re-installs ideal growth conditions via an exponential process with a rate that slows down with the cell size. In a growing ensemble, a distribution of relaxation modes comes in existence, exactly defined by the universal cell size distribution. The discovery of nano-mechanic acoustic activities in cells led us to assume that in a growing ensemble acoustic signals may contribute significantly to the transmission of essential information about growth-induced disturbances to all cells, initiating that way coordinated relaxation. The frequency increases with the cell number shortening the period between successive signals. The completion of rearrangements occurring at a constant rate is thus progressively impaired, until cellular growth stops, totally. Due to this phenomenon, the so-called "relaxation-frequency-dispersion" cell colonies should exhibit a maximum cell number. In populations with large cell numbers, subsystems, behaving similar-like colonies, should form network-like patterns. Based on these ideas, we formulate equations that describe the growth curves of all cell types, verifying that way the general nature of the growth logistics.

Structured treatment interruptions following immediate initiation of HAART in eight patients with acute HIV-1 seroconversion.

BACKGROUND: The immunological and clinical benefits of structured treatment interruptions (STIs) during primary HIV-1 infection remain largely unclear. PATIENTS AND METHODS: Eight patients identified during primary HIV-1 infection were immediately treated with HAART and underwent subsequent STIs after reaching complete viral suppression of HIV-RNA in peripheral plasma. HAART was re-initiated if either HIV-1 RNA >5000 copies/ml, CD4-cells <200 cells/microl or symptomatic HIV-1 disease was observed. RESULTS: After treatment discontinuation, four of eight patients were able to persistently control HIV-1 viremia below 5000 copies/ml until the last time point of follow-up (median 3 years). CD4-cell counts were within the interquartile range of untreated individuals compared to historical reference data from the MACS cohort. In the remaining study subjects persistent virological control was not reached despite repeated STIs. Moreover, compared to the MACS cohort repetitive virological failures during STIs appeared to induce an accelerated decline of CD4-cells. CONCLUSION: Spontaneous HIV-1 control after treated primary HIV-1 infection was possible in four out of eight individuals, however, if STIs after treated primary infection ameliorate the overall HIV-1 disease progression remains unknown. In the absence of viral control, repetitive viral exposure during STIs might be associated with accelerated decline of CD4-cell counts.

Stationary cell size distributions and mean protein chain length distributions of Archaea, Bacteria and Eukaryotes described with an increment model in terms of irreversible thermodynamics.

In terms of an increment model irreversible thermodynamics allows to formulate general relations of stationary cell size distributions observed in growing colonies. The treatment is based on the following key postulates: i) The growth dynamics covers a broad spectrum of fast and slow processes. ii) Slow processes are considered to install structural patterns that operate in short periods as temporary stationary states of reference in the sense of irreversible thermodynamics. iii) Distortion during growth is balanced out via the many fast processes until an optimized stationary state is achieved. The relation deduced identifies the numerous different stationary patterns as equivalents, predicting that they should fall on one master curve. Stationary cell size distributions of different cell types, like Hyperphilic archaea, E. coli (Prokaryotes) and S. cerevisiae (Eukaryotes), altogether taken from the literature, are in fact consistently described. As demanded by the model they agree together with the same master curve. Considering the "protein factories" as subsystems of cells the mean protein chain length distributions deduced from completely sequenced genomes should be optimized. In fact, the mean course can be described with analogous relations as used above. Moreover, the master curve fits well to the patterns of different species of Archaea, Bacteria and Eukaryotes. General consequences are discussed.

Urinary bladder cancer: preoperative nodal staging with ferumoxtran-10-enhanced MR imaging.

PURPOSE: To prospectively evaluate ferumoxtran-10-enhanced magnetic resonance (MR) imaging for nodal staging in patients with urinary bladder cancer. MATERIALS AND METHODS: Fifty-eight patients with proved bladder cancer were enrolled. Results of MR imaging performed before and after injection of ferumoxtran-10 were compared with histopathologic results in surgically removed lymph nodes. High-spatial-resolution three-dimensional T1-weighted magnetization-prepared rapid acquisition gradient-echo (voxel size, 1.4 x 1.4 x 1.4 mm) and T2*-weighted gradient-echo (voxel size, 0.8 x 0.8 x 3.0 mm) sequences were performed before and 24 hours after injection of ferumoxtran-10 (2.6 mg iron per kilogram of body weight). On precontrast images, lymph nodes were defined as malignant by using size and shape criteria (round node, >8 mm; oval, >10 mm axial diameter). On postcontrast images, nodes were considered benign if there was homogeneous decrease in signal intensity and malignant if decrease was absent or heterogeneous. Qualitative evaluation was performed on a node-to-node basis. Sensitivity, specificity, predictive values, and accuracy were evaluated with logistic regression analysis. RESULTS: In 58 patients, 172 nodes imaged with use of ferumoxtran-10 were matched and correlated with results of node dissection. Of these, 122 were benign and 50 were malignant. With nodal size and shape criteria, accuracy, sensitivity, specificity, and positive and negative predictive values on precontrast images were 92%, 76%, 99%, 97%, and 91%, respectively; corresponding values on postcontrast images were 95%, 96%, 95%, 89%, and 98%. In the depiction of pelvic metastases, sensitivity and negative predictive value improved significantly at postcontrast compared with those at precontrast imaging, from 76% to 96% (P < .001) and from 91% to 98% (P < .01), respectively. At postcontrast imaging, metastases (4-9 mm) were prospectively found in 10 of 12 normal-sized nodes (<10 mm); these metastases were not detected on precontrast images. Postcontrast images also showed lymph nodes that were missed at pelvic node dissection in two patients. CONCLUSION: Ferumoxtran-10-enhanced MR imaging significantly improves nodal staging in patients with bladder cancer by depicting metastases even in normal-sized lymph nodes.

Laryngopharyngitis by Corynebacterium ulcerans.

A 71-year-old female patient was hospitalized with membranous laryngopharyngitis typical of classical diphtheria. A toxigenic strain of Corynebacterium ulcerans was isolated from the throat. The patient was treated for 6 days with amoxicillin-clavulanic acid and recovered without complications. This second reported case of diphtheric laryngopharyngitis caused by C. ulcerans in Switzerland is a reminder that C. ulcerans should be included as a possible agent in patients with classical diphtheria symptoms.

Is the distribution of dermal neurofibromas in neurofibromatosis type 1 (NF1) related to the pattern of the skin surface temperature?

The formation of dermal neurofibromas is a hallmark of the neurofibromatosis type 1 (NF1). A total loss of the NF1 gene product by stochastic events inactivating the wild type allele in Schwann cells should precede the development of neurofibromas. Dermal neurofibromas tend to be located mainly on the surface of the trunk and not in the body periphery. This distribution partly resembles the density of sensitive nerve endings in the epidermis. Our hypothesis is that a better correlation concerns the pattern of normal body surface temperature. According to our clinical observations we assume that in skin areas with higher temperatures the number of visible dermal neurofibromas is higher than in colder areas such as the arms/legs or nose. It is known that differences in temperature are able to determine differentiation. We suggest that the regulation of skin temperature is also involved in the formation of NF1 dermal neurofibromas and is related to the intrafamilial variability in NF1.

Spinal neurofibromatosis without café-au-lait macules in two families with null mutations of the NF1 gene.

Spinal neurofibromatosis (SNF) is considered to be an alternative form of neurofibromatosis, showing multiple spinal tumors and café-au-lait macules. Involvement of the neurofibromatosis type 1 (NF1) locus has been demonstrated, by linkage analysis, for three families with SNF. In one of them, a cosegregating frameshift mutation in exon 46 of the NF1 gene was identified. In the present study, we report four individuals from two families who carry NF1 null mutations that would be expected to cause NF1. Three patients have multiple spinal tumors and no café-au-lait macules, and the fourth has no clinical signs of NF1. In the first family, a missense mutation (Leu2067Pro) in NF1 exon 33 was found, and, in the second, a splice-site mutation (IVS31-5A-->G) enlarging exon 32 by 4 bp at the 5' end was found. The latter mutation has also been observed in an unrelated patient with classical NF1. Both NF1 mutations cause a reduction in neurofibromin of approximately 50%, with no truncated protein present in the cells. This demonstrates that typical NF1 null mutations can result in a phenotype that is distinct from classical NF1, showing only a small spectrum of the NF1 symptoms, such as multiple spinal tumors, but not completely fitting the current clinical criteria for SNF. We speculate that this phenotype is caused by an unknown modifying gene that compensates for some, but not all, of the effects caused by neurofibromin deficiency.

Spinal cord ischaemia after stent-graft treatment for infra-renal abdominal aortic aneurysms. Analysis of the Eurostar database.

OBJECTIVES: to evaluate the prevalence and the possible causes of spinal cord ischaemia (SCI) following endovascular abdominal aneurysm repair (EVAR). Differences in the incidence of this complication between endovascular treatment and published series following conventional treatment were assessed. DESIGN: analysis of patients enrolled in the EUROSTAR collaborators registry. MATERIALS AND METHODS: 2862 patients operated between July 1994 and July 2000 were analysed. Patient characteristics, aneurysm morphology, procedure characteristics and potential causative factors with particular interference with pelvic circulation or pelvic embolisation were related to the risk of SCI. RESULTS: six patients (0.21%) were identified with postoperative symptoms of SCI: one complete spinal cord infarction (type I), two anterior spinal artery syndromes (type II) and three combinations of root lesions and centromedullary infarcts (type III). In the patients with type I or II lesions (3/6) no regression of neurological symptoms was noted, whereas the patients with type III lesions (3/6) had partial regression of symptoms in two cases and a full neurological recovery in one case. There was a significant correlation between emboli (p < 0.001) and coil embolisation of hypogastric or lumbar arteries (p < 0.029) and the development of SCI. CONCLUSIONS: SCI is equally rare following open aortic surgery or EVAR. Microembolism is the probable cause. SCI should be mentioned when taking informed consent.