Fine idiotype analysis of B cell precursors in the T-dependent and T-independent responses to alpha 1-3 dextran in BALB/c mice.
In this study BALB/c B cell precursors responsive to the T-independent (TI) type 2 (TI-2) antigen, dextran B1355S (DEX), and the T-dependent (TD) derivative, dextran-Limulus hemocyanin (DEX-Hy) were examined for isotype and idiotope expression using the splenic focus assay. The predominant isotype detected in the TI assay was IgM, while IgA was the predominant isotype expressed in the TD assay. There was also a fourfold increase in the number of foci secreting more than one isotype in the TD assay vs. the TI assay without an overall change in anti-DEX precursor frequency, suggesting that carrier-primed T cells enhance the expression of non-IgM isotypes possibly by increasing the frequency of isotype switching by individual B cell precursors. A panel of distinct monoclonal antiidiotype antibodies (MAIDs) was then used to examine idiotope expression by antibodies secreted in splenic foci responding to DEX and DEX-Hy. This analysis revealed considerable diversity in the idiotope profiles expressed by all isotypes tested. There appeared to be no differences in idiotope diversity among the various isotypes. A similar diversity of idiotope profiles was obtained from both TI and TD splenic foci, indicating that a comparable degree of diversity was associated with the antibodies generated by TI and TD precursors. Idiotype analysis of IgM-IgA-secreting foci with a panel of monoclonal antiidiotope antibodies revealed slight idiotypic differences between the two isotypes secreted in the same focus in about half the cases. These results suggest that somatic variation occurs during the antigen-driven maturation of B cell precursors, within the 15-d time frame of the splenic focus assay, and may be associated with isotype switching.


First insight in trace element distribution in the intestinal cytosol of two freshwater fish species challenged with moderate environmental contamination.
Cytosolic distribution of six essential elements and nonessential Cd among biomolecules of different molecular masses was investigated in the intestine of brown trout (Salmo trutta) from the karst Krka River and Prussian carp (Carassius gibelio) from the lowland Ilova River. Fish were sampled at two locations (reference and contaminated) and in two seasons (autumn and spring). Analyses were conducted by size exclusion high performance liquid chromatography and high resolution inductively coupled plasma mass spectrometry. Although studied salmonid and cyprinid fish have different biological characteristics, obtained profiles often showed mostly similar patterns in both species. Specifically, Cd and Cu were dominantly bound to metallothioneins in both species, but the same association was not observed for Zn, whereas Mo distribution was similar in the intestine of both fish species with two well shaped and clear peaks in HMM (100-400 kDa) and VLMM (2-8 kDa) range. In brown trout, Se was mostly associated with biomolecules of very low molecular masses (VLMM, <10 kDa), whereas significant additional elution in HMM region (30-303 kDa) was observed only in Prussian carp. Iron binding to VLMM biomolecules (1.8-14 kDa) was observed only in brown trouts, and of Zn in Prussian carps. Cobalt was mostly bound to HMM biomolecules (85-235 kDa) in brown trout and to VLMM biomolecules (0.7-18 kDa) in Prussian carp. Comparison of intestinal profiles with previously published data on liver and gills revealed some similarities in distribution, but also organ-specific differences due to the different function and composition of each organ. As so far there is no published data on intestinal trace metal distribution, the obtained results represent the novel findings, and the key point for the exact identification of specific metal-binding biomolecules which could eventually be used as biomarkers of metal exposure or effects.


After-potential of spinal axons in vivo.
A method is evolved whereby the after-potential sequence intrinsic to longitudinal dorsal column myelinated fibers may be studied in isolation from those events occurring in intact spinal cord subjected to an afferent volley. The recovery sequence intrinsic to dorsal column fibers, after refractoriness is over, is characterized by supernormality approximately four to five times greater than that seen in peripheral nerve. This supemormality averages 15.7 +/- 4 per cent (current calibration) at peak and decays exponentially with a half-time of 7.5 msecs. It is not followed by subnormality unless conditioning is repeated more than three times at frequencies greater than 100/sec. Characterization of the recovery curve of dorsal column fibers permits by exclusion, the allocation of the origin of DRV to structures more centrally located. DCV (the dorsal column counterpart of DRV) is seen to exist equally developed in active and passive dorsal column fibers.


Activation of aldose reductase by nonenzymatic glycosylation.
Incubation of human erythrocyte with 50 mM glucose results in glycosylation of aldose reductase besides hemoglobin A and other proteins. The glycosylation of aldose reductase is established by adsorption of the enzyme on phenyl boronate (PBA-60) column. Furthermore, the enzyme was purified to an apparent homogeneity from the erythrocytes incubated with 50 mM glucose and the glycosylation was quantitated by reduction with tritiated sodium borohydride. The glycosylated aldose reductase exhibits lower Km for glucose and NADPH as compared to unglycosylated enzyme and is not inhibited by phosphorylated intermediates such as ADP, 1,3-DPG, 2,3-DPG and 3-PGA, whereas physiological concentrations of these intermediates almost completely inhibit the unglycosylated enzyme. In addition, the glycosylated enzyme is less susceptible to aldose reductase inhibitors such as sorbinil and alrestatin. In hyperglycemia, blood glucose higher than 11 mM, almost all the aldose reductase is glycosylated.


Gaseous electron multiplier-based soft x-ray plasma diagnostics development: Preliminary tests at ASDEX Upgrade.
A Gaseous Electron Multiplier (GEM)-based detector is being developed for soft X-ray diagnostics on tokamaks. Its main goal is to facilitate transport studies of impurities like tungsten. Such studies are very relevant to ITER, where the excessive accumulation of impurities in the plasma core should be avoided. This contribution provides details of the preliminary tests at ASDEX Upgrade (AUG) with a focus on the most important aspects for detector operation in harsh radiation environment. It was shown that both spatially and spectrally resolved data could be collected, in a reasonable agreement with other AUG diagnostics. Contributions to the GEM signal include also hard X-rays, gammas, and neutrons. First simulations of the effect of high-energy photons have helped understanding these contributions.


Melamine-barbiturate/cyanurate binary organogels possessing rigid azobenzene-tether moiety.
Binary organogels were prepared from coaggregates of azobenzene-tethered melamine dimer and cyanurate/barbiturates. In the gels of hydrocarbon liquids, the coaggregates formed heavily entangled nanofibers, morphologies of which are dramatically different from the previously reported coaggregates based on flexible dodecamethylene-tethered melamine dimers. In the present systems, the rigidity of the azobenzene tether may induce regular packing of molecules. In addition, UV-vis and IR spectroscopic measurements provided unequivocal evidence for the contribution of the central amide groups and the azobenzene chromophores in the tether moiety upon forming well-defined nanofibers by hydrogen-bonding and face-to-face (H-type) pi-pi stacking interactions, respectively. As a result of tight molecular packing in the self-assembled nanofibers, the azobenzene moiety in the gel state showed remarkable resistance to trans --> cis isomerization upon irradiation with UV light.


Inhibition of Initial Attachment of Injured Salmonella Typhimurium onto Abiotic Surfaces.
Following sanitation interventions in food processing facilities, sublethally injured bacterial cells can remain on food contact surfaces. We investigated whether injured Salmonella Typhimurium cells can attach onto abiotic surfaces, which is the initial stage for further biofilm development. We utilized heat, UV, hydrogen peroxide, and lactic acid treatments, which are widely utilized by the food industry. Our results showed that heat, UV, and hydrogen peroxide did not effectively change populations of attached Salmonella Typhimurium. Cells treated with hydrogen peroxide had a slightly higher tendency to adhere to abiotic surfaces, although there was no significant difference between the populations of control and hydrogen peroxide-treated cells. However, lactic acid effectively reduced the number of Salmonella Typhimurium cells attached to stainless steel. We also compared physicochemical changes of Salmonella Typhimurium after application of lactic acid and used hydrogen peroxide as a positive control because only lactic acid showed a decreased tendency for attachment and hydrogen peroxide induced slightly higher numbers of attached bacteria cells. Extracellular polymeric substance produced by Salmonella Typhimurium was not detected in any treatment. Significant differences in hydrophobicity were not observed. Surface charges of cell membranes did not show relevant correlation with numbers of attached cells, whereas autoaggregation showed a positive correlation with attachment to stainless steel. Our results highlight that when lactic acid is applied in a food processing facility, it can effectively interfere with adhesion of injured Salmonella Typhimurium cells onto food contact surfaces.


Chondrocyte cells respond mechanically to compressive loads.
Many studies have illustrated the effect of mechanical loading on articular cartilage and the corresponding changes in chondrocyte metabolism, yet the mechanism through which the cells respond to loading still is unclear. The purpose of this study was to evaluate the change in shape of chondrocytes under a statically applied uniaxial compressive load. Isolated chondrocytes from rat chondrosarcoma were embedded in 2% agarose gel. Strains of 5, 10, and 15% were applied, and images of the cell were recorded from initial loading to equilibrium (15 minutes). A finite-element model was used to model the experimental setup and to estimate the mechanical properties of the chondrocyte at equilibrium. The transient behavior of the composite in the experiment was analyzed with use of a standard linear viscoelastic model. We found that all cells decreased in cross-sectional area under each of the applied compressive strains. In the finite-element model, the elasticity of the chondrocyte was similar to that of the surrounding agarose gel (4.0 kPa) and had a Poisson's ratio of 0.4. Viscoelastic analysis showed that the chondrocytes contributed a significant viscoelastic component to the behavior of the composite in comparison with the agarose gel alone. If a decrease in cell volume proportional to the decrease in cross-sectional area is assumed, the decrease observed was greater than would be predicted by a passive cellular response due to an equivalent osmotic pressure. This indicates that the chondrocyte may be altering its intracellular composition by cellular processes in response to mechanical loading.


The anti-arrhythmic efficacy of perhexiline maleate, disopyramide and mexiletine in ventricular ectopic activity.
The anti-arrhythmic efficacy of perhexiline maleate, disopyramide and mexiletine has been evaluated in 27 patients with chronic ischaemic heart disease who exhibited frequent ventricular ectopic beats (i.e. greater than or equal to 8/h). Holter tape recordings were made during normal working hours before, during and after the sequential administration of the three drugs. Each drug was administered to each patient for a 2-month period. The drug had to be discontinued in 4 cases because of side-effects. A significant reduction (P less than 0,001) in ectopic beat frequency occurred with all three drugs. No significant difference in anti-arrhythmic potency could be demonstrated between the drugs.


The hexokinase isoenzyme PII of Saccharomyces cerevisiae ia a protein kinase.
The HXK2 gene product has an important role in controlling carbon catabolite repression in Saccharomyces cerevisiae. We have raised specific antibodies against the hexokinase PII protein and have demonstrated that it is a 58 kDa phosphoprotein with protein kinase activity. The predicted amino acid sequence of the HXK2 gene product has significant homology to the conserved catalytic domain of mammalian and yeast protein kinases. Protein kinase activity was located in a different domain of the protein from the hexose-phosphorylating activity. The hexokinase PII protein level remained unchanged in P2T22D mutant cells (hxk1 HXK2 glk1) growing in a complex medium with glucose. The protein kinase activity of hexokinase PII is regulated by the glucose concentration of the culture medium. Exit from the carbon catabolite repression phase and entry into derepression phase may be controlled, in part, by modulation of the 58 kDa protein kinase activity by changes in cyclic AMP concentration.


[Transvascular fluid movement into the brain in response to an increase in venous pressure].
An increase in pressure of the venous outflow under conditions of perfusion with constant blood flow of hemodynamically isolated brain, led to filtration of fluid from the cerebral vascular bed in anesthetized cats. Velocity of the transvascular translocation of fluid was proportional to the pressure increase by 50, 75 and 100 mm Hg in cerebral veins. The capillary filtration coefficient (CFC) was about 0.11-0.12 ml/100 g of tissue/mm Hg/min. Reasons for a relatively great CFC found in the brain, are discussed.


First Report of Infection of Cherry Rusty Mottle Associated Virus in Portuguese Laurel (Prunus lusitanica) in Washington State.
During late spring of 2012 in Snohomish County of Washington State, chlorotic yellow leaf blotch symptoms suggestive of a virus infection were observed on Portuguese laurel (Prunus lusitanica) planted in a hedge row. Leaf samples from representative trees were initially tested for the presence of Cherry leaf roll virus (CLRV) and Plum pox virus (PPV) by ELISA with antibodies specific to CLRV and general potyvirus, respectively (Agdia, Inc., Elkhart, IN). The ELISA test yielded negative results for both viruses. Reverse transcription (RT)-PCR was pursued to detect other viruses known to infect Prunus spp., namely American plum line pattern virus (APLPV), Apple chlorotic leafspot virus (ACLSV), Cherry mottle leaf virus (CMLV), Cherry raspleaf virus (CRLV), Cherry virus A (CVA), Prune dwarf virus (PDV), and Prunus necrotic ringspot virus (PNRSV), as well as CLRV and PPV. None of these viruses were detected. However, RT-PCR with a generic primer pair Fovea2/AdPr (3) that amplifies the coat protein (CP) coding sequence and 3'-untranslated regions (3'-UTR) of several members of the family Betaflexiviridae yielded a 1.4-kb amplicon that was cloned into pCR2.1 (Invitrogen, Carlsbad, CA) and sequenced (GenBank Accession No. KF356396). The sequences from three clones were 99.8% identical to each other at the nucleotide level. Comparison of the consensus CP coding region with the nucleotide sequence database revealed 86 to 93% identity to Cherry rusty mottle associated virus (CRMaV), and only 73 to 75% identities to Cherry necrotic rusty mottle virus (CNRMV) (1) and 71 to 76% identities to Cherry green ring mottle virus (CGRMV) (4) isolates from sweet cherry (P. avium). This result suggested that the cloned fragment represents a strain of CRMaV. Prunus avium 'Bing' and 'Sam,' and P. serrulata 'Kwanzan' were grafted with bark patches from the symptomatic tree and observed for induction of cherry rusty mottle disease (CRMD) symptoms. Ninety days after grafting, symptoms typical of CRMD consisting of chlorotic yellow mottle appeared on 'Bing,' 'Sam,' and 'Kwanzan' indicators. Small necrotic spots also appeared on the leaves of the latter. Angular necrotic lesions on 'Sam' and epinasty of 'Kwanzan' that are diagnostic symptoms of cherry necrotic rusty mottle disease (CNRMD) and cherry green ring mottle disease (CGRMD), respectively, were absent from graft inoculated indicators. Further RT-PCR tests on the indicators using primers specific to CNRMV, CGRMV, and CRMaV (2) yielded negative results for CNRMV and CGRMV but showed positive amplification for CRMaV. The results of the woody indexing corroborate the presence of CRMaV but the absence of CNRMV and CGRMV in the symptomatic Portuguese laurel. To our knowledge, this is the first report of CRMaV in Portuguese laurel in the United States and the first description of symptoms associated with CRMaV in this host. As a potential reservoir of CRMaV, Portuguese laurel could play an important component in management of CRMD in cherry production areas where this ornamental cherry is also present. References: (1) M. E. Rott and W. Jelkmann. Arch. Virol. 146:395, 2001. (2) D. E. V. Villamor and K. C. Eastwell. Phytopathology 103:1287, 2012. (3) D. V. Villamor et al. Arch. Virol. 158:1805, 2013. (4) Y. P. Zhang et al. J. Gen. Virol. 79:2275, 1998.


[Geography of effective size in the rural population of northern Eurasia: effective size and the intensity of random genetic drift].
On the basis of 655 direct and indirect estimations of effective size (Ne) of rural populations, a map of the geographic distribution of Ne in northern Eurasia was constructed. A geographic cline of Ne was found, with its value decreasing by three orders of magnitude from the direction of southwest (the western Caucasus and Central Asia) to northeast (the coasts of the Sea of Okhotsk and the Bering Sea). The area of highest distribution density of mean Ne values was situated meridionally between the Ob and Yenisei rivers from the Arctic coast of Taimyr Peninsula to the eastern Sayany and the south Baikal regions. Another similar area covered the south Baltic region, Belarus, and northwestern Ukraine. The average effective population size in northern Eurasia was Ne = 211.6, the geometrical mean G = 176, the harmonic mean H = 147, and the modal value Mo = 102. These characteristics of effective population size indicate a considerable contribution of stochastic gene drift to the differentiation of the northern Eurasian gene pool and the geographic cline of the rate of gene drift in the subcontinent. By means of transformation of the Ne map, a map for the rate of stochastic gene drift (1/4Ne) in northern Eurasia was obtained.


One-year glycemic control with a sulfonylurea plus pioglitazone versus a sulfonylurea plus metformin in patients with type 2 diabetes.
The goal was to assess the 1-year efficacy and safety of the addition of pioglitazone or metformin to existing sulfonylurea (SU) therapy in patients with inadequately controlled type 2 diabetes. In this multicenter, double-blind study, patients were randomized to receive either pioglitazone 15 mg (n = 319) or metformin 850 mg (n = 320) and up to 45 mg/day and 2,550 mg/day, respectively. The primary efficacy endpoint was HbA(1c) at week 52. Fasting plasma glucose, insulin, and lipid profiles were also measured. HbA(1c) was reduced by 1.20% in the SU plus pioglitazone group and 1.36% in the SU plus metformin group, and fasting plasma glucose was reduced by 2.2 and 2.3 mmol/l in the respective groups. Fasting insulin levels were also reduced (pioglitazone arm -1.3 micro IU/ml; metformin arm -0.8 micro IU/ml). There were no significant between-treatment differences in these three parameters. Pioglitazone addition to SU significantly reduced triglycerides (-16 vs. -9%; P = 0.008) and increased HDL cholesterol (14 vs. 8%; P < 0.001) compared with metformin addition. LDL cholesterol was increased 2% by the addition of pioglitazone and decreased 5% by the addition of metformin to SU (P < 0.001). Urinary albumin-to-creatinine ratio was reduced by 15% in the SU plus pioglitazone group and increased 2% in the SU plus metformin group (P = 0.017). Both combinations were well tolerated with no evidence of hepatic or cardiac toxicity in either group. Clinically equivalent improvements in glycemic control were observed for both combinations. Compared with metformin plus SU, addition of pioglitazone to SU resulted in a reduction of the urinary albumin-to-creatinine ratio, a small but significant rise in LDL cholesterol, and significantly greater improvements in triglyceride levels and HDL cholesterol levels. Metformin plus SU was associated with a significant reduction in LDL cholesterol. SU plus pioglitazone is an effective and well-tolerated combination regimen that may provide additional beneficial effects for patients with type 2 diabetes.


The effects of packaging materials on the fatty acid composition, organic acid content, and texture profiles of Tulum cheese.
In this research, Erzincan Tulum cheese was packaged in its original packaging material, the skin bag, small intestine, and appendix to observe the changes in its physical, chemical, and textural properties during storage day. Lactic acid% values increased in all Tulum cheeses throughout storage stage. At the end of the storage period, the highest value was determined in the sample filled in the small intestine (20.10%). All fatty acid values were increased, and the highest increase was identified in oleic acid (C 18:1) (skin bag 2.18%), linoleic acid (18:2) (appendix 0.41%), and palmitic acid (C 16:0) (small intestine 0.34%), respectively. All organic acids increased in stored sample. The highest increase among organic acids was determined to be 4.47% in lactic acid. As a result of the Texture Profile Analyses (TPA), the hardness, and adhesiveness of Tulum cheeses increased during storage periods, whereas the springiness, cohesiveness, and chewiness values decreased. Gumminess value declined in the sample filled into the appendix (with a value of 36.01), whereas it increased in the other two samples. The highest increase in hardness values was 2,520.27 N at given storage time was in the samples filled into appendix while the highest adhesive values of -49.82 were determined in the sample filled into small intestine. PRACTICAL APPLICATION: Tulum cheese is usually produced by filling sheep or goat skin bag. Goat or sheep skin bag are not always available, and the amount of cheese produced in them is excessive. Therefore, cheeses were also filled to small intestine and appendix. At the end of the study, there were no negative effects on cheeses filled with intestine and appendix. The use of small intestine and appendix has helped to develop a product that will be appreciated by the consumers with no adverse effects in the physicochemical and textural properties of cheese.


Insights into the Enhancement of MOF/Polymer Adhesion in Mixed-Matrix Membranes via Polymer Functionalization.
MOF-based mixed-matrix membranes (MMMs) prepared using standard routes often exhibit poor adhesion between polymers and MOFs. Herein, we report an unprecedented systematic exploration on polymer functionalization as the key to achieving defect-free MMMs. As a case study, we explored computationally MMMs based on the combination of the prototypical UiO-66(Zr) MOF with polymer of intrinsic porosity-1 (PIM-1) functionalized with various groups including amidoxime, tetrazole, and N-((2-ethanolamino)ethyl)carboxamide. Distinctly, the amidoxime-derivative PIM-1/UiO-66(Zr) MMM was predicted to express the desired enhanced MOF/polymer interfacial interactions and thus subsequently prepared and evaluated experimentally. Prominently, high-resolution transmission electron microscopy confirmed optimal adhesion between the two components in contrast to the nanometer-sized voids/defects shown by the pristine PIM-1/UiO-66(Zr) MMM. Notably, single-gas permeation measurements further corroborated the need of optimal MOF/polymer adhesion in order to effectively enable the MOF to play a role in the gas transport of the resulting MMM.


What Lesbian, Gay, Bisexual, Transgender, Queer, and Intersex Patients Say Doctors Should Know and Do: A Qualitative Study.
This qualitative study explored the experiences of lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI) people in health care and their recommendations for physicians. Six focus groups were conducted with LGBTQI people (N = 48) in four U.S. cities between October 2013 and April 2014. Five overarching themes emerged regarding patients' suggestions for providers: be comfortable with LGBTQI patients; share medical decision-making; avoid assumptions; apply LGBTQI-related knowledge; and address the social context of health disparities. These core competencies differed in meaningful ways from competencies created by national organizations such as the Association of American Medical Colleges. Community-derived competencies1 stressed the importance of collaborative patient-physician partnerships, particularly in the setting of hormone prescription for transgender patients, and prioritized addressing social determinants of health and focusing on marginalized subpopulations2 and stigmatized needs of the community. Limitations, particular of sampling, were considered. Community input could improve medical education interventions to reduce health disparities in marginalized communities.


[The readaptation problems of cancer patients].
The paper discusses certain problems involved in communication between physician, cancer patient and society. The authors suggest that information given to a cancer patient on his or her diagnosis should be determined by the patient's willingness to know and prognosis. Also, suggestions on improvement of treatment of cancer patients of clinical group 4 are made.


The diagnostic accuracy of endoscopic ultrasound vs. contrast-enhanced computed tomography in local staging of pancreatic adenocarcinoma: a bi-national multicenter study.
Identification of pancreatic cancer (PC) local invasion is crucial to optimize patients' selection for surgery. To determine the diagnostic accuracy of contrast-enhanced computed tomography (CECT) and endoscopic ultrasound (EUS) in local staging of PC. We performed a multicenter study including all patients with PC who underwent surgery. One hundred twelve patients were included. Surgical findings of peri-pancreatic lymph nodes (LN), vascular and adjacent organ involvement were seen in 67 (59.8%), 33 (29.5%) and 19 patients (17%), respectively. The diagnostic performance of EUS was better than CECT in peri-pancreatic LN. The sensitivity, specificity, positive predictive value (PPV) and negative predictive (NPV) of CECT vs. EUS were 28.4%, 80%, 67.9% and 42.9% vs. 70.2%, 75.6%, 81% and 63%, respectively. For vascular and adjacent organ involvement, the sensitivity, specificity, PPV and NPV were 45.5%, 93.7%, 75%, 80.4% and 31.6%, 89.2%, 37.5% and 86.5% for CECT, respectively, vs. 63.6%, 93.7%, 80.8%, 86.1% and 36.8%, 94.6%, 58.3% and 88% for EUS, respectively. Combining both CECT and EUS, the sensitivity for peri-pancreatic LN, vascular and adjacent organ involvement improved (76.1%, 78.8% and 42%), respectively. EUS was superior to CECT in local staging. Combined EUS and CECT had a higher sensitivity than either alone.


Studies on vision. The nature of the retinal-opsin linkage.
1. Convenient methods for the preparation of tritiated 11-cis-retinol, 11-cis-retinal and rhodopsin are described. Irradiation of labelled rhodopsin in the presence of sodium borohydride resulted in the irreversible binding of the retinyl moiety to the active site. Degradative studies established that the retinyl moiety in this reduced derivative of rhodopsin was attached to the in-amino group of lysine. In connexion with this investigation the synthesis of a number of N-retinylidene- and N-retinyl-amino acids was achieved. Derivatives of lysine with the retinyl moiety attached either to the alpha-amino group or to the in-amino group were also synthesized and characterized. 2. It is suggested that the involvement of a charge-transfer interaction between the retinylidene chromophore and a suitable group -X or -X.H on the opsin best explains the spectroscopic properties of rhodopsin and other visual proteins.


A convenient alignment approach for x-ray imaging experiments based on laser positioning devices.
This study presents a two-laser alignment approach for facilitating the precise alignment of various imaging and measuring components with respect to the x-ray beam. The first laser constantly pointed to the output window of the source, in a direction parallel to the path along which the components are placed. The second laser beam, originating from the opposite direction, was calibrated to coincide with the first laser beam. Thus, a visible indicator of the direction of the incident x-ray beam was established, and the various components could then be aligned conveniently and accurately with its help.


Vegetation increases abundances of ground and canopy arthropods in Mediterranean vineyards.
The decline of arthropod populations observed in many parts of the world is a major component of the sixth mass extinction with intensive agriculture being one of its main drivers. Biodiversity-friendly farming practices are taking centre stage in the recovery process. In vineyards, vegetation cover is commonly used for production purposes, to reduce soil compaction by machinery use and soil erosion. Here we examined the effects of vegetation cover and soil management on the abundance of ground- (spiders, beetles, Hemiptera and harvestmen) and canopy-dwelling (wild bees, green lacewings, beetles and Hemiptera) arthropods in three categories of vineyards: (i) vineyards with no vegetation, (ii) partially vegetated (every second inter-row is vegetated) and (iii) all inter-rows are vegetated. We recorded a general positive effect of a decrease in soil perturbation intensity and corresponding higher vegetation cover on arthropod abundance. Plant species richness was the most important vegetation parameter, with a positive effect on spiders, harvestmen, hemipterans and beetles (ground and canopy) abundances. Using a path analysis, we also highlighted the central role of inter-row vegetation management in trophic and non-trophic relationships between vegetation and arthropods, and between arthropod groups. Our results demonstrate the benefits of a softer soil management preserving a diverse vegetation cover for the conservation of arthropods in Mediterranean vineyards.


Computerized tomographic scan findings in facial fractures associated with blindness.
A retrospective study of 379 consecutive patients who underwent operative repair of facial fractures at the West Virginia University Medical Center was carried out. Blindness developed in at least one eye in 21 (6%) of the 379 patients studied. Le Fort II and Le Fort III fractures, frontal bone and frontal sinus fractures, severe fractures of the zygoma, and fractures of the orbital floor were associated with fractures of the lesser sphenoid wing and optic canal in 5 of the patients studied. These 5 patients had indirect optic nerve injuries, as determined by CT scan and clinical criteria, which included visual loss with afferent pupillary defect and an otherwise normal ophthalmologic examination. In addition, one other patient who was not one of the 379 patients who underwent operative repair gradually developed ipsilateral blindness as a result of indirect optic nerve injury following minimal frontal bone trauma without a fracture. The usual mechanism of injury was trauma at the level of the orbital roof. The principal findings on CT scan were those of fracture of the lesser sphenoid wing and subdural hematoma of the optic nerve sheath. The association between sphenoethmoid sinus hemorrhage and fracture of the optic canal (31%) in cases of facial trauma has been presented. The indications for optic nerve decompression have been discussed. To the authors' knowledge, there is no previous report of an optic canal fracture as diagnosed by computerized tomography in the literature.


KCa 3.1 channels maintain endothelium-dependent vasodilatation in isolated perfused kidneys of spontaneously hypertensive rats after chronic inhibition of NOS.
The purpose of the study was to investigate renal endothelium-dependent vasodilatation in a model of severe hypertension associated with kidney injury. Changes in perfusion pressure were measured in isolated, perfused kidneys taken from 18-week-old Wistar-Kyoto rat (WKY), spontaneously hypertensive rats (SHR) and SHR treated for 2 weeks with N(ω) -nitro-L-arginine methyl ester in the drinking water (L-NAME-treated SHR, 6 mg·kg(-1) ·day(-1) ). Acetylcholine caused similar dose-dependent renal dilatation in the three groups. In vitro administration of indomethacin did not alter the vasodilatation, while the addition of N(w) -nitro-L-arginine (L-NA) produced a differential inhibition of the vasodilatation, (inhibition in WKY > SHR > L-NAME-treated SHR). Further addition of ODQ, an inhibitor of soluble guanylyl cyclase, abolished the responses to sodium nitroprusside but did not affect the vasodilatation to acetylcholine. However, the addition of TRAM-34 (or charybdotoxin) inhibitors of Ca(2+) -activated K(+) channels of intermediate conductance (K(Ca) 3.1), blocked the vasodilatation to acetylcholine, while apamin, an inhibitor of Ca(2+) -activated K(+) channels of small conductance (K(Ca) 2.3), was ineffective. Dilatation induced by an opener of K(Ca) 3.1/K(Ca) 2.3 channels, NS-309, was also blocked by TRAM-34, but not by apamin. The magnitude and duration of NS-309-induced vasodilatation and the renal expression of mRNA for K(Ca) 3.1, but not K(Ca) 2.3, channels followed the same ranking order (WKY < SHR < L-NAME-treated SHR). In SHR kidneys, an EDHF-mediated response, involving activation of K(Ca) 3.1 channels, contributed to the mechanism of endothelium-dependent vasodilatation. In kidneys from L-NAME-treated SHR, up-regulation of this pathway fully compensated for the decrease in NO availability.


Bacillus clausii and gut homeostasis: state of the art and future perspectives.
The intestinal barrier is a complex system responsible for the host health. Many gastrointestinal and extra-intestinal diseases are associated to gut barrier disruption. An increasing interest on nutritional supplements and functional foods focused on the hypothesis that specific prebiotics and probiotics may modulate and interact with gut barrier, re-establishing gut homeostasis. The application of preparations containing B. clausii in the treatment or prevention of gut phisiology impairment has been largely supported in the last years and has driven its clinical applications. This review focuses on B. clausii clinical applications and speculates on the possible interactions among B. clausii, gut barrier and immune system and on the consequences of this interplay in modulating human health. Expert commentary: Its favorable effects have been linked to several properties, such as antimicrobial and immunomodulatory activity, regulation of cell growth and differentiation, cell-cell signaling, cell adhesion, signal transcription and transduction, production of vitamins and gut protection from genotoxic agents. In this scenario, future studies will need to better clarify its mechanisms of action and focus on the possible role of B. clausii in modulating gut immune system.


Allergy to LTP: to eat or not to eat sensitizing foods? A follow-up study.
Background. Follow-up data about the onset of novel food allergies in patients allergic to lipid transfer protein (LTP) are missing. We investigated the occurrence of novel allergies over time in LTP hypersensitive patients. Methods. Sixty-seven LTP-allergic patients recommended to avoid foods responsible for systemic reactions and encouraged to eat other sensitizing foods avoiding the association with known co-factors, were re-evaluated after ≥ 1 year to assess the occurrence of allergy to novel foods. IgE to rPru p 3, rBet v 1, and r Phl p 12 were measured. Results. At baseline, the most frequent offending foods were Rosaceae / Prunoideae, tree nuts, and peanut. Most patients reacted to > 1 food, and 77% experienced systemic allergic reactions. Those monosensitized to LTP showed a higher prevalence of food-induced systemic reactions than patients co-sensitized to profilin and/or PR-10 (p < 0.01). Baseline Pru p 3 IgE levels did not differ between patients with local symptoms or systemic symptoms. 1-16 years after the baseline evaluation 18/67 (27%) patients had experienced new food allergies; 8 and 10 reported local or systemic symptoms following the ingestion of previously tolerated foods. Again, most new allergies were caused by Rosaceae / Prunoideae, tree nuts, and peanut. The clinical evolution did not depend on baseline total IgE, co-sensitization to PR-10 and/or profilin, or Pru p 3 IgE levels. Conclusions.Rosaceae / Prunoideae, nuts and peanut are the most frequent cause of new food allergies in the long term. Their exclusion from patient's diets at baseline should be considered on an individual basis.


Amplification of granulopoiesis by T cell subpopulations.
Regulation of granulopoiesis by activated splenic T lymphocyte subpopulations was investigated. The addition of syngeneic T cells activated by the mitogen concanavalin A or by mixed lymphocyte response (MLR) to normal bone marrow cultures stimulated granulopoiesis, while, in contrast, resting T cells did not. Functional analyses of Fluorescence Activated Cell Sorter (FACS) purified subpopulations of MLR activated T cells showed that both subsets enhanced granulocyte colony forming cells (CFUc) differentiation. Further studies using Ly 23+ T cells stimulated in vitro to suppress the primary generation of plaque forming cells (PFC) showed that these "suppressor cells" simultaneously enhanced CFUc differentiation. These results show that T cell "helper" function in hematopoietic regulation is not restricted to the inducer subset of T cells.


Polyamines are essential for cell transformation by pp60v-src: delineation of molecular events relevant for the transformed phenotype.
Ornithine decarboxylase (ODC), the key enzyme of polyamine biosynthesis, becomes upregulated during cell proliferation and transformation. Here we show that intact ODC activity is needed for the acquisition of a transformed phenotype in rat 2R cells infected with a temperature-sensitive mutant of Rous sarcoma virus. Addition of the ODC inhibitor alpha-difluoromethyl ornithine (DFMO) to the cells (in polyamine-free medium) before shift to permissive temperature prevented the depolymerization of filamentous actin and morphological transformation. Polyamine supplementation restored the transforming potential of pp60v-src. DFMO did not interfere with the expression of pp60v-src or its in vitro tyrosine kinase activity. The tyrosine phosphorylation of most cellular proteins, including ras GAP, did not either display clear temperature- or DFMO-sensitive changes. A marked increase was, however, observed in the tyrosine phosphorylation of phosphatidylinositol 3-kinase and proteins of 33 and 36 kD upon the temperature shift, and these hyperphosphorylations were partially inhibited by DFMO. A DFMO-sensitive increase was also found in the total phosphorylation of calpactins I and II. The well-documented association of GAP with the phosphotyrosine-containing proteins p190 and p62 did not correlate with transformation, but a novel 42-kD tyrosine phosphorylated protein was complexed with GAP in a polyamine- and transformation-dependent manner. Further, tyrosine phosphorylated proteins of 130, 80/85, and 36 kD were found to coimmunoprecipitate with pp60v-src in a transformation-related manner. Altogether, this model offers a tool for sorting out the protein phosphorylations and associations critical for the transformed phenotype triggered by pp60v-src, and implicates a pivotal role for polyamines in cell transformation.


Metabolism of garlic constituents in the isolated perfused rat liver.
The metabolic and kinetic behaviour of different garlic (Allium sativum L., Alliaceae) constituents were investigated in the isolated perfused rat liver, using aqueous extracts of garlic powder as well as isolated allicin, the main product of the enzymatic degradation of alliin. Allicin (allyl thiosulfinate) showed a remarkable first pass effect and passed the liver unmetabolized only at high concentrations which caused considerable cell injuries. Diallyl disulfide and allyl mercaptan were identified as metabolites of allicin, whereby diallyl disulfide probably is the metabolic precursor of allyl mercaptan as shown by perfusion with diallyl disulfide alone. The metabolites diallyl disulfide and allyl mercaptan could be determined in the perfusion medium as well as in the bile and the liver tissue. Other degradation products of garlic were also investigated in this model. Ajoenes and vinyldithiins were detected in perfusion medium after liver passage but no metabolites of them could be identified up to now.


Programs in cytopathology: how do you evaluate performance and how can you improve?
The need to cut costs complicates the challenge of providing quality assurance. QA in cytopathology presents still another dilemma: deciding which QA mechanism to use. Here, in an article adapted from his presentation before the New York State Society of Pathologists (Orlando, Fla., 1983), the author discusses various QA mechanisms and a program designed to improve diagnostic performance.


Ssssh for Handover: protected medical handover; optimising quality and prioritising safety-a regional initiative.
Medical handover is one of the most commonly performed actions in the healthcare system today. While it is performed regularly, it is often not done as effectively as it could or should be. 1 Many organisations have implemented systems and structures to improve the quality and impact of their handover process. These include advocating senior presence, introducing validated handover tools and an emphasis on multidisciplinary involvement. 2 A protected handover prioritises safety, enhances communication and encourages improvement in handover effectiveness. Our local pilot and subsequent regional initiative has begun actively addressing this issue using a low-cost, interprofessional, multispeciality quality improvement initiative.


[Pathogenesis and prevention of spastic hip dislocation].
Based on retrospective analysis of 82 hips of 41 patients with cerebral palsy, a pathogenetic model of spastic paralytic dislocation of the hip is introduced including recent observations of the normal hip development. According to this model the reduced activity of the gluteus maximus, medius, minimus and quadriceps femoris muscles, which normally cause a decrease of valgus and anteversion, results in an increased subluxating coxa valga antetorta with a consecutive dislocation. In order to prevent a dislocation, these muscle groups have to undergo increased activation. Since walking has to be to undergo increased activation. Since walking has to be considered the strongest stimulus for the dislocation-preventing hip abductors, hip extensors, outward rotators and knee extensors, the erect gait should be encouraged with statomotorically favored children early as possible. This can be supported by muscle relaxing surgery of the antagonistically effective hip flexors, hip adductors and inward rotators as well as the knee flexors. These muscle release operations will counteract, although to a limited extent, a dislocation even with a severely handicapped child who is unable to walk.


FOXM1, a typical proliferation-associated transcription factor.
FOXM1 is a typical proliferation-associated transcription factor: it stimulates proliferation by promoting S-phase entry as well as M-phase entry and is involved in proper execution of mitosis. Accordingly, FOXM1 regulates genes that control G1/S-transition, S-phase progression, G2/M-transition and M-phase progression. Consistently, its expression and its activity are antagonistically regulated by many important proliferation and anti-proliferation signals. Furthermore, FOXM1 is implicated in tumorigenesis and contributes to both tumor initiation and progression. In addition to its function as a conventional transcription factor, FOXM1 transactivates the human c-myc P1 and P2 promoters directly via their TATA-boxes by a new transactivation mechanism, which it also employs for transactivation of the human c-fos, hsp70 and histone H2B/a promoters. This review summarizes the current knowledge on FOXM1, in particular its two different transactivation mechanisms, the regulation of its transcriptional activity by proliferation versus anti-proliferation signals and its function in normal cell cycle progression and tumorigenesis.


Ulcerative colitis associated with Takayasu's disease.
A 25-year-old Japanese woman had both ulcerative colitis and Takayasu's disease and was positive for HLA-A24, BW52, and DR2. She was found to have thickening of the wall of the carotid artery on contrast-enhanced computerized tomography of the neck and chest. Prednisolone, beraprost, and sulfapyridine achieved rapid remission of both diseases.


H-Bonded and metal(ii)-organic architectures assembled from an unexplored aromatic tricarboxylic acid: structural variety and functional properties.
This study reports the application of an aromatic tricarboxylic acid, 2,5-di(4-carboxylphenyl)nicotinic acid (H3dcna) as a versatile and unexplored organic building block for assembling a new series of metal(ii) (M = Co, Ni, Zn, Fe, and Mn) complexes and coordination polymers, namely [M(Hdcna)(phen)2(H2O)]·H2O (M = Co (1), Ni (2)), [Zn(μ-Hdcna)(phen)]n (3), [Co(μ-Hdcna)(bipy)(H2O)2]n·nH2O (4), [Zn2(μ-Hdcna)2(bipy)2(H2O)4]·6H2O (5), [Zn(μ3-Hdcna)(H2biim)]n (6), [Ni2(Hdcna)2(μ-bpb)(bpb)2(H2O)4] (7), [Fe(μ4-Hdcna)(μ-H2O)]n·nH2O (8), and [Mn3(μ5-dcna)2(bipy)2(H2O)2]n·2nH2O (9). Such a diversity of products was hydrothermally prepared from the corresponding metal(ii) salts, H3dcna as a principal multifunctional ligand, and N-donor mediators of crystallization (1,10-phenanthroline, phen; 2,2'-bipyridine, bipy; 2,2'-biimidazole, H2biim; or 1,4-bis(pyrid-4-yl)benzene, bpb). The obtained products 1-9 were fully characterized by standard methods (elemental analysis, FTIR, TGA, PXRD) and the structures were established by single-crystal X-ray diffraction. These vary from the discrete monomers (1, 2) and dimers (5, 7) to the 1D (3, 4, 6) and 2D (8, 9) coordination polymers (CPs). Structural and topological characteristics of hydrogen-bonded or metal-organic architectures in 1-9 were highlighted, revealing that their structural multiplicity depends on the type of metal(ii) source and crystallization mediator. Thermal stability as well as luminescent, magnetic, or catalytic properties were explored for selected compounds. In particular, the zinc(ii) derivatives 3, 5, and 6 were applied as efficient heterogeneous catalysts for the cyanosilylation of aldehydes with trimethylsilyl cyanide at room temperature. The catalytic reactions were optimized by tuning the different reaction parameters (solvent composition, time, catalyst loading) and the substrate scope was also explored. Compound 5 revealed superior catalytic activity leading to up to 75% product yields, while maintaining its original performance upon recycling for at least four reaction cycles. Finally, the obtained herein products represent the unique examples of coordination compounds derived from H3dcna, thus opening up the use of this multifunctional tricarboxylic acid for generating complexes and coordination polymers with interesting structures and functional properties.


Using bifactor exploratory structural equation modeling to examine global and specific factors in measures of sports coaches' interpersonal styles.
In the present work we investigated distinct sources of construct-relevant psychometric multidimensionality in two sport-specific measures of coaches' need-supportive (ISS-C) and controlling interpersonal (CCBS) styles. A recently proposed bifactor exploratory structural equation modeling (ESEM) framework was employed to achieve this aim. In Study 1, using a sample of floorball players, the results indicated that the ISS-C can be considered as a unidimensional measure, with one global factor explaining most of the variance in the items. In Study 2, using a sample of male ice hockey players, the results indicated that the items in the CCBS are represented by both a general factor and specific factors, but the subscales differ with regard to the amount of variance in the items accounted for by the general and specific factors. These results add further insight into the psychometric properties of these two measures and the dimensionality of these two constructs.


Development and validation of the Durham Risk Score for estimating suicide attempt risk: A prospective cohort analysis.
Worldwide, nearly 800,000 individuals die by suicide each year; however, longitudinal prediction of suicide attempts remains a major challenge within the field of psychiatry. The objective of the present research was to develop and evaluate an evidence-based suicide attempt risk checklist [i.e., the Durham Risk Score (DRS)] to aid clinicians in the identification of individuals at risk for attempting suicide in the future. Three prospective cohort studies, including a population-based study from the United States [i.e., the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) study] as well as 2 smaller US veteran cohorts [i.e., the Assessing and Reducing Post-Deployment Violence Risk (REHAB) and the Veterans After-Discharge Longitudinal Registry (VALOR) studies], were used to develop and validate the DRS. From a total sample size of 35,654 participants, 17,630 participants were selected to develop the checklist, whereas the remaining participants (N = 18,024) were used to validate it. The main outcome measure was future suicide attempts (i.e., actual suicide attempts that occurred after the baseline assessment during the 1- to 3-year follow-up period). Measure development began with a review of the extant literature to identify potential variables that had substantial empirical support as longitudinal predictors of suicide attempts and deaths. Next, receiver operating characteristic (ROC) curve analysis was utilized to identify variables from the literature review that uniquely contributed to the longitudinal prediction of suicide attempts in the development cohorts. We observed that the DRS was a robust prospective predictor of future suicide attempts in both the combined development (area under the curve [AUC] = 0.91) and validation (AUC = 0.92) cohorts. A concentration of risk analysis found that across all 35,654 participants, 82% of prospective suicide attempts occurred among individuals in the top 15% of DRS scores, whereas 27% occurred in the top 1%. The DRS also performed well among important subgroups, including women (AUC = 0.91), men (AUC = 0.93), Black (AUC = 0.92), White (AUC = 0.93), Hispanic (AUC = 0.89), veterans (AUC = 0.91), lower-income individuals (AUC = 0.90), younger adults (AUC = 0.88), and lesbian, gay, bisexual, transgender, and queer or questioning (LGBTQ) individuals (AUC = 0.88). The primary limitation of the present study was its its reliance on secondary data analyses to develop and validate the risk score. In this study, we observed that the DRS was a strong predictor of future suicide attempts in both the combined development (AUC = 0.91) and validation (AUC = 0.92) cohorts. It also demonstrated good utility in many important subgroups, including women, men, Black, White, Hispanic, veterans, lower-income individuals, younger adults, and LGBTQ individuals. We further observed that 82% of prospective suicide attempts occurred among individuals in the top 15% of DRS scores, whereas 27% occurred in the top 1%. Taken together, these findings suggest that the DRS represents a significant advancement in suicide risk prediction over traditional clinical assessment approaches. While more work is needed to independently validate the DRS in prospective studies and to identify the optimal methods to assess the constructs used to calculate the score, our findings suggest that the DRS is a promising new tool that has the potential to significantly enhance clinicians' ability to identify individuals at risk for attempting suicide in the future.


Factors predicting treatment responsiveness and prognosis in node-negative breast cancer. The International (Ludwig) Breast Cancer Study Group.
An international trial (formerly Ludwig Trial V) has been conducted in 1,275 subjects to ascertain if perioperative chemotherapy is beneficial for node-negative breast cancer patients and to identify subgroups of patients who benefit from this therapy. Node-negative breast cancer patients were randomized to receive either one cycle of perioperative chemotherapy or no adjuvant treatment. A detailed pathology review was conducted in 1,203 of the 1,275 patients enrolled. Stepwise Cox regression analysis was used to search for factors either predicting chemotherapeutic responsiveness and/or influencing disease-free survival (DFS). As expected, primary tumor size, grade, and the presence of peritumoral vascular invasion are the most important prognostic factors. Perioperative chemotherapy provides a DFS advantage at 5 years of median follow-up and such treatment is more effective for estrogen receptor-negative than for estrogen receptor-positive tumors, for histologic grade 2 and 3 than for grade 1 tumors, and for patients in whom no axillary lymph node metastases were found even after serial sectioning and review by the Central Pathology Laboratory. Hormone receptor status and tumor grade are important factors for predicting responsiveness to perioperative chemotherapy in node-negative breast cancer.


A Promising Method for Calculating True Steady-State Metabolite Concentrations in Large-Scale Metabolic Reaction Network Models.
The calculation of steady-state metabolite concentrations in metabolic reaction network models is the first step in the sensitivity analysis of a metabolic reaction system described by differential equations. However, this calculation becomes very difficult when the number of differential equations is more than 100. In the present study, therefore, we investigated a calculation procedure for obtaining true steady-state metabolite concentrations both efficiently and accurately even in large-scale network models. For convenience, a linear pathway model composed of a simple Michaelis-Menten rate law and two TCA cycle models were used as case studies. The calculation procedure is as follows: first solve the differential equations by a numerical method for solving initial-value problems until the upper several digits of the calculated values stabilize, and then use these values as initial guesses for a root-finding technique. An intensive investigation indicates that the S-system technique, finding roots in logarithmic space and providing a broader convergence region, is superior to the Newton-Raphson technique, and the algorithm using the S-system technique successfully provides true steady-state values with machine accuracy even with 1,500 differential equations. The complex-step method is also shown to contribute to shortening the calculation time and enhancing the accuracy. The program code has been deposited to https://github.com/BioprocessdesignLab/Steadystateconc.


Variations in humanized and defined culture conditions supporting derivation of new human embryonic stem cell lines.
The evolution of "humanized" (i.e., free of animal sourced reagents) and ultimately chemically defined culture systems for human embryo stem cell (hESC) isolation and culture is of importance to improving their efficacy and safety in research and therapeutic applications. This can be achieved by integration of a multitude of individual approaches to replace or eliminate specific animal sourced reagents into a single comprehensive protocol. In the present study our objective was to integrate strategies obviating reliance on some of the most poorly defined and path-critical factors associated with hESC derivation, namely the use of animal immune compliment to isolate embryo inner cell mass, and animal sourced serum products and feeder cells to sustain hESC growth and attachment. As a result we report the derivation of six new hESC lines isolated by outgrowth from whole blastocysts on an extracellular matrix substrate of purified human laminin (Ln) with transitional reliance on mitotically inactivated human fibroblast (HDF) feeder cells. With this integrated system hESC lines were isolated using either HDF conditioned medium supplemented with a bovine-sourced serum replacement (bSRM), or a defined serum-free medium (SFM) containing only human sourced and recombinant protein. Further, outgrowth of embryonic cells from whole blastocysts in both media could be achieved for up to 1 week without reliance on feeder cells. All variant conditions sustained undifferentiated cell status, a stable karyotype and the potential to form cells representative of all three germinal lineages in vitro and in vivo, when transitioned off of feeders onto Laminin or Matrigel. Our study thus demonstrates the capacity to integrate derivation strategies eliminating a requirement for animal immune compliment and serum products, with a transitional requirement for human feeder cells. This represents another sequential step in the generation of therapeutic grade stem cells with reduced risk of zoonotic pathogen transmission.


Effects of symbiotic preparations on constipated irritable bowel syndrome symptoms.
Prebiotic and probiotic therapies are new strategies that are being used to treat different gastrointestinal diseases, such as irritable bowel syndrome, diverticular disease and inflammatory bowel diseases. Evaluating the effects of a symbiotic preparation on symptoms and colonic transit in patients with irritable bowel syndrome and significant bloating. We carried out an open-label, prospective, uncontrolled, multicenter trial on 129 patients meeting Rome II criteria for irritable bowel syndrome who did not have lactose malabsorption, abdominal surgery, overt psychiatric disorders and ongoing psychotropic drug therapy or ethanol abuse. For three months, the patients were treated with a symbiotic preparation and were investigated trough questionnaires on symptoms. Data on bloating and abdominal pain were obtained using the McNemar-Bowker's test, while data on stool frequency were evaluated using the t-test. The administration of a symbiotic preparation to these patients modified the clinical picture and intestinal function, with a significant increase of stool frequency. Our data, although the study had an open design, represent a further analysis of positive symbiotic effects on clinical manifestations and intestinal function in patients with irritable bowel syndrome.


A novel therapeutic technology of specific RNA inhibition for acute promyelocytic leukemia: improved design of maxizymes against PML/RARalpha mRNA.
Targeting of PML/RARalpha using a loss of function strategy in acute promyelocytic leukemia (APL) is a direct therapeutic approach for patients and may be the basis of future gene therapy for this leukemia. To achieve this, we designed specific maxizymes, novel allosterically controllable ribozymes, against both short and long PML/RARalpha isoforms. The maxizyme has sensor arms that can only recognize target sequences, and it can form a cavity that captures catalytically indispensable Mg2+. We deleted 1 base nucleotide in the Mg2+-binding pocket designed MzPRT50 and MzPRK55. The distance from the PML/RARalpha junction site to the center of effectors is only 2 bases, and there are 8 and 9 complementary bases in their inactive forms, respectively. Both maxizymes specifically cleaved PML/RARalpha mRNA but not wild-type RARalpha mRNA in a cell-free system. Modification of the sequence of the Mg2+-binding pocket will be important in designing the sequence-specific maxizymes against oncogenic genes.


A partially folded intermediate conformation is induced in pectate lyase C by the addition of 8-anilino-1-naphthalenesulfonate (ANS).
Addition of 8-anilino-1-naphthalenesulfonate (ANS) to acid-denatured pectate lyase C (pelC) leads to a large increase in the fluorescence quantum yield near 480 nm. The conventional interpretation of such an observation is that the ANS is binding to a partially folded intermediate such as a molten globule. Far-ultraviolet circular dichroism demonstrates that the enhanced fluorescence results from the induction of a partially folded protein species that adopts a large fraction of native-like secondary structure on binding ANS. Thus, ANS does not act as a probe to detect a partially folded species, but induces such a species. Near-ultraviolet circular dichroism suggests that ANS is bound to the protein in a specific conformation. The mechanism of ANS binding and structure induction was probed. The interaction of acid-unfolded pelC with several ANS analogs was investigated. The results strongly indicate that the combined effects of hydrophobic and electrostatic interactions account for the relatively high binding affinity of ANS for acid-unfolded pelC. These results demonstrate the need for caution in interpreting enhancement of ANS fluorescence as evidence for the presence of molten globule or other partially folded protein intermediates.


Universal Map of Gas-Dependent Kinetic Selectivity in Carbon Nanotube Growth.
Single-walled carbon nanotubes have been a candidate for outperforming silicon in ultrascaled transistors, but the realization of nanotube-based integrated circuits requires dense arrays of purely semiconducting species. In order to directly grow such nanotube arrays on wafers, control over kinetics and thermodynamics in tube-catalyst systems plays a key role, and further progress requires a comprehensive understanding of seemingly contradictory reports on the growth kinetics. Here, we propose a universal kinetic model that decomposes the growth rates of nanotubes into the adsorption and removal of carbon atoms on the catalysts, and we provide its quantitative verification by ethanol-based isotope labeling experiments. While the removal of carbon from catalysts dominates the growth kinetics under a low supply of precursors, resulting in chirality-independent growth rates, our kinetic model and experiments demonstrate that chiral angle-dependent growth rates emerge when sufficient amounts of carbon and etching agents are cosupplied. The kinetic maps, as a product of generalizing the model, include five types of kinetic selectivity that emerge depending on the absolute quantities of gases with opposing effects. Our findings not only resolve discrepancies existing in the literature but also offer rational strategies to control the chirality, length, and density of nanotube arrays for practical applications.


HPMA copolymer conjugates of paclitaxel and docetaxel with pH-controlled drug release.
In this paper we describe the synthesis, physicochemical characteristics and data on the biological activity of polymer prodrugs based on the anticancer drugs paclitaxel (PTX) and docetaxel (DTX) conjugated with a water-soluble N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer drug carrier. The drugs were derivatized and then attached to the polymer backbone via a spacer that is stable under physiological conditions (pH 7.4) and hydrolytically degradable in mild acidic environments (e.g., endosomes, pH approximately 5). Polymer-drug conjugates were designed to achieve prolonged blood circulation and release of the active compound in target cells. Six types of conjugates differing in the structure of the keto acid (levulic, 3-(acetyl)acrylic acid) and 4-(2-oxopropyl)benzoic acid-containing spacer or in the amount of drug bound to the HPMA copolymer were synthesized. In all the conjugates, the linkage susceptible to hydrolytic cleavage was formed by the reaction of the carbonyl group of a drug derivative with the hydrazide group-terminated side chains of the polymer. In vitro incubation of the conjugates in buffers resulted in much faster release of drugs or their derivatives from the polymer at pH 5 than at pH 7.4 with the rate depending on the detailed structure of the spacer. Conjugates containing drugs acylated with levulic acid were tested for their anticancer activity in vivo using two murine models. The PTX-containing conjugate showed better antitumor efficacy in the 4T1 model of mammary carcinoma than the parent drug and its derivative. The DTX-containing conjugate demonstrated high activity in treating EL4 T cell lymphoma. The treatment with the polymer conjugates was devoid of side toxicity. In both models, we achieved complete regression of established tumors accompanied by a durable tumor resistance in most of the cured animals.


In vivo evidence for a non-T cell origin of interleukin-5.
Eosinophil myelopoiesis is to a great extent regulated by interleukin (IL)-5. Analysis of IL-5 mRNA in spleen cell preparations by reverse transcription-polymerase chain reaction (RT-PCR) revealed the presence of message for this cytokine in uninfected severe combined immunodeficiency (SCID) mice. This message was increased following Mycobacterium avium infection. Normal BALB/c mice had higher levels of expression of IL-5 but the expression of this cytokine was reduced during M. avium infection. Anti-IL-5 monoclonal antibody administration in vivo to SCID mice reduced the number of peritoneal and splenic eosinophils. Gamma interferon (IFN-gamma) had an inhibitory effect of eosinophilopoiesis during infection of SCID mice by M. avium since neutralization of this cytokine increased the number of eosinophils detected in the peritoneal cavity of infected animals. Our results suggest that IL-5 may be produced by cells other than T cells that are both able to respond to infection and are under the control of IFN-gamma.


[The capacity for reactive DNA synthesis of the myocytes in the heart conduction system in experimental and clinical myocardial pathology].
The DNA synthesis has been studied in the conductive system (CS) myocytes, compared to that in atrial and ventricular myocytes: 1) in the left ventricular myocardial infarction induced in two- and three-week-old and adult rats, 2) after isoproterenol injections to adult rats and mice, and 3) in the hypertrophied human heart. The extent of DNA synthesis reactivation was evaluated by the cumulative labeling indices in experiments with multiple 3HTdR injections to rats and mice. In the human cardiac myocyte nuclei, the DNA content was determined by the Feulgen-cytophotometry. The difference between the control and experimental mean values of the labeling indices for CS myocyte nuclei was statistically significant only for atrioventricular part of the CS in the infarcted hearts of adult rats. In the human heart CS the ability of myocytes to polyploidization varies from one cell type to another, the lowest being in nodal cells.


GABA(C) receptors modulate the rod-driven ERG b-wave of the skate retina.
Studies characterizing the types of GABA receptors present on cells isolated from the skate retina have allowed us to develop a working model of possible GABA interactions at the level of the outer plexiform layer (OPL). Earlier studies have shown an electrogenic GABA transport mechanism in horizontal cells presents a source of GABA in the OPL which could modulate feedback onto photoreceptors. GABA(A) receptors on Müller cells, or GABA(A) and/or GABA(C) receptors on bipolar cells. This model has been used for the interpretation of results of experiments in this study designed to test the role these interactions may exert on the electroretinogram (ERG). Simultaneous intracellular recording of the horizontal cell response (the S-potential) was used to monitor effects on photoreceptor transmitter release which would be altered if GABAergic photoreceptor feedback mechanisms were involved. Picorotoxin (50 microM), a chloride channel blocker which suppresses the responses of both GABA(A)Rs and GABA(C)Rs, reduced the ON (b-wave) component of the ERG substantially. Simultaneous intracellular horizontal cell recordings, however, showed no effect on their light-evoked response, suggesting that photoreceptor feedback is not involved in the picrotoxin effect on the ERG. On the other hand, even 100 microM bicuculline, a GABA(A)R antagonist produced no change in either the ERG or the horizontal cell response. This observation leads to the conclusion that the GABAARs on Miller cells and bipolar cells are not involved. Thus, there remains a distinct possibility that the ERG changes produced by picrotoxin are due to its ability to block the GABA(C)Rs on retinal bipolar cells.


Hydroxyethyl Starch for Fluid Management in Patients Undergoing Major Abdominal Surgery: A Systematic Review With Meta-analysis and Trial Sequential Analysis.
In critically ill patients, warnings about a risk of death and acute kidney injury (AKI) with hydroxyethyl starch (HES) solutions have been raised. However, HES solutions may yet have a role to play in major abdominal surgery. This meta-analysis and trial sequential analysis (TSA) aimed to investigate the effect of HES intravascular volume replacement on the risk of AKI, intraoperative blood transfusion, and postoperative intra-abdominal complications compared to crystalloid intravascular volume replacement. In this meta-analysis and TSA, we searched for randomized controlled trials (RCTs) comparing intraoperative HES intravascular volume replacement to crystalloid intravascular volume replacement in adult patients undergoing major abdominal surgery. Primary outcome was 30-day AKI, defined as a binary outcome according to Kidney Disease Improving Global Outcomes (KDIGO) criteria, combining stages 1, 2, and 3 into an AKI category versus no AKI category (stage 0). Secondary outcomes included rates of intraoperative blood transfusion and postoperative intra-abdominal complications. We used random effects models to calculate summary estimates. We used relative risk (RR) as summary measure for dichotomous outcomes, with corresponding 95% confidence intervals (CIs) for the primary outcome (P value <.05 was considered statistically significant) and 99% CI after Bonferroni correction for the secondary outcomes (P value <.01 was considered statistically significant). Seven RCTs including 2398 patients were included. HES intravascular volume replacement was not associated with an increased risk of 30-day AKI (RR = 1.22, 95% CI, 0.94-1.59; P = .13), when compared to crystalloid intravascular volume replacement. According to TSA, this analysis was underpowered. HES intravascular volume replacement was associated with higher rates of blood transfusion (RR = 1.57 99% CI, 1.10-2.25; P = .001), and similar rates of postoperative intra-abdominal complications (RR = 0.76 99% CI, 0.57-1.02; P = .02). In this meta-analysis to focus on HES intravascular volume replacement in major abdominal surgery, HES intravascular volume replacement was not associated with a higher risk of 30-day AKI when compared to crystalloid intravascular volume replacement. However, CI and TSA do not exclude harmful effects of HES intravascular volume replacement on the renal function.


Molecular biology of chronic myeloid leukemia.
Detailed information on the crystal structure of the pharmacologically targeted domains of the BCR-ABL molecule and on its intracellular signaling, which are potentially involved in growth, anti-apoptosis, metabolism and stemness, has made the study of chronic myeloid leukemia the most successful field in tumor biology. However, we now face the issue of drug resistance due to deregulation in the quality control of both DNA and protein. BCR-ABL is basically a misfolded protein with intrinsically disordered regions, which not only produces endoplasmic reticulum stress followed by unfolded protein response in some settings, but also conformational plasticity that may affect the structure of the whole molecule. The intercellular signaling derived from the leukemic cell microenvironment may influence the intracellular responses that take place in a manner both dependent on and independent of BCR-ABL tyrosine kinase activity.


Antibodies: can they protect against HIV infection?
More than 20 million people have died since the discovery of human immunodeficiency virus (HIV), yet a broadly reactive AIDS vaccine remains elusive. Neutralizing antibody (nAb) response-based vaccine strategies were the first to be tested; however, when the difficulty in neutralizing primary HIV isolates was recognized, vaccine development focused instead on generating cytotoxic T-lymphocyte (CTL) responses. Recently, interest in anti-HIV nAbs has been revived by the impressive protection achieved in primates given passive immunization with neutralizing monoclonal antibodies (nmAbs) isolated from HIV clade B-infected individuals. The nmAbs used in these studies target conserved, functionally important epitopes in HIV gp120 and gp41. Regimens involving combinations of such human nmAbs or high-dose single-agent nmAb protected monkeys against intravenous (iv) and mucosal challenges with simian-human immunodeficiency virus (SHIV) strains encoding X4, X4R5 or R5 HIV env genes. In several such studies, sterilizing immunity was achieved, thus providing proof-of-concept that nAbs targeting conserved epitopes can be fully protective. The existence of these broadly reactive nmAbs suggests that it may be possible to design immunogens capable of inducing similar nAb responses by active vaccination. Unraveling the three-dimensional structures involved in the nmAb-HIV Env epitope interactions may facilitate the future development of a potent AIDS vaccine. This review is focused on the importance of nAbs in protecting against HIV infection or in containing viral spread, with particular emphasis on the successful use of nmAbs in passive immunization studies. The implications of the data from these studies on AIDS vaccine design in general are also discussed.


Clinical Subtypes of Dementia with Lewy Bodies Based on the Initial Clinical Presentation.
Dementia with Lewy bodies (DLB) is a heterogeneous disease in which clinical presentation, symptoms, and evolution widely varies between patients. To investigate the existence of clinical subtypes in DLB based on the initial clinical presentation. 81 patients with a clinical diagnosis of probable DLB were consecutively included. All patients underwent a neurological evaluation including a structured questionnaire about neuropsychiatric symptoms and sleep, an assessment of motor impairment (Unified Parkinson Disease Rating Scale subscale III), and a formal neuropsychological evaluation. Onset of core symptoms (hallucinations, parkinsonism, and fluctuations) and dementia were systematically reviewed from medical records. We applied a K-means clustering method based on the initial clinical presentation. Cluster analysis yielded three different groups. Patients in cluster I (cognitive-predominant, n = 46) presented more frequently with cognitive symptoms (95.7%, n = 44, p < 0.001), and showed a longer duration from onset to DLB diagnosis (p < 0.001) than the other clusters. Patients in cluster II (neuropsychiatric-predominant, n = 22) were older at disease onset (78.1±5 versus 73.6±6.1 and 73.6±4.2 in clusters I and III, respectively, both p < 0.01), presented more frequently with psychotic symptoms (77.3%, n = 17), and had a shorter duration until the onset of hallucinations (p < 0.001). Patients in cluster III (parkinsonism-predominant, n = 13) showed a shorter time from onset to presence of parkinsonism (p < 0.001) and dementia (0.008). Three clinical subtypes of DLB can be defined when considering the differential initial presentations. The proposed subtypes have distinct clinical profiles and progression patterns.


Histidine 20, the crucial proximal axial heme ligand of bacterial heme oxygenase Hmu O from Corynebacterium diphtheriae.
The hemin complex of Hmu O, a 24-kDa soluble heme degradation enzyme in Corynebacterium diphtheriae, is coordinated axially to a neutral imidazole of a proximal histidine residue in Hmu O. To identify which of the eight histidines in Hmu O is the proximal heme ligand, we have constructed and expressed the plasmids for eight His --> Ala Hmu O mutants. Reconstituted with hemin, the active site structures and enzymatic activity of these mutants have been examined by EPR, resonance Raman, and optical absorption spectroscopy. EPR of the NO-bound ferrous heme-Hmu O mutant complexes reveals His(20) as the proximal heme ligand in Hmu O, and this is confirmed by resonance Raman results from the ligand-free ferrous heme-H20A. All eight His --> Ala mutants bind hemin stoichiometrically, proving that none of the histidines is essential for hemin-Hmu O formation. However, His(20) is crucial to Hmu O catalysis. Its absence by point mutation has inhibited the conversion of hemin to biliverdin. The ferric heme-H20A complex is pentacoordinate. Resonance Raman of the CO-bound ferrous heme-H20A corroborates this and reveals an Fe-C-O bending mode, delta(Fe-C-O), the first reported for a pentacoordinate CO-bound hemeprotein. The appearance of delta(Fe-C-O) in C. diphtheriae Hmu O H20A but not mammalian HO-1 mutant H25A indicates that the heme environment between the two heme oxygenases is different.


Continuous venovenous hemofiltration versus extended daily hemofiltration in patients with septic acute kidney injury: a retrospective cohort study.
Whether continuous venovenous hemofiltration (CVVHF) is superior to extended daily hemofiltration (EDHF) for the treatment of septic AKI is unknown. We compared the effect of CVVHF (greater than 72 hours) with EDHF (8 to 12 hours daily) on renal recovery and mortality in patients with severe sepsis or septic shock and concurrent acute kidney injury (AKI). A retrospective analysis of 145 septic AKI patients who underwent renal replacement therapy (RRT) between July 2009 and May 2013 was performed. These patients were treated by CVVHF or EDHF with the same polyacrylonitrile membrane and bicarbonate-based buffer. The primary outcomes measured were occurrence of renal recovery and all-cause mortality by 60 days. Sixty-five and eighty patients were treated with CVVHF and EDHF, respectively. Patients in the CVVHF group had significantly higher recovery of renal function (50.77% of CVVHF group versus 32.50% in the EDHF group, P = 0.026). Median time to renal recovery was 17.26 days for CVVHF patients and 25.46 days for EDHF patients (P = 0.039). Sixty-day all-cause mortality was similar between CVVHF and EDHF groups (44.62%, and 46.25%, respectively; P = 0.844). 55.38% of patients on CVVHF and 28.75% on EDHF developed hypophosphatemia (P = 0.001). The other adverse events related to RRT did not differ between groups. On multivariate analysis, including physiologically clinical relevant variables, CVVHF therapy was significantly associated with recovery of renal function (HR 3.74; 95% CI 1.82 to 7.68; P < 0.001), but not with mortality (HR 0.69; 95% CI 0.34 to 1.41; P = 0.312). Patients undergoing CVVHF therapy had significantly improved renal recovery independent of clinically relevant variables. The patients with septic AKI had similar 60-day all-cause mortality rates, regardless of type of RRT.


Improving network approaches to the study of complex social-ecological interdependencies.
Achieving effective, sustainable environmental governance requires a better understanding of the causes and consequences of the complex patterns of interdependencies connecting people and ecosystems within and across scales. Network approaches for conceptualizing and analyzing these interdependencies offer one promising solution. Here, we present two advances we argue are needed to further this area of research: (i) a typology of causal assumptions explicating the causal aims of any given network-centric study of social-ecological interdependencies; (ii) unifying research design considerations that facilitate conceptualizing exactly what is interdependent, through what types of relationships, and in relation to what kinds of environmental problems. The latter builds on the appreciation that many environmental problems draw from a set of core challenges that re-occur across contexts. We demonstrate how these advances combine into a comparative heuristic that facilitates leveraging case-specific findings of social-ecological interdependencies to generalizable, yet context-sensitive, theories based on explicit assumptions of causal relationships.


The association of new-onset diabetes with subsequent diagnosis of pancreatic cancer-novel use of a large administrative database.
Screening options for pancreatic ductal adenocarcinoma (PDAC) are limited. New-onset type 2 diabetes (NoD) is associated with subsequent diagnosis of PDAC in observational studies and may afford an opportunity for PDAC screening. We evaluated this association using a large administrative database. Patients were identified using claims data from the OptumLabs® Data Warehouse. Adult patients with NoD diagnosis were matched 1:3 with patients without NoD using age, sex and chronic obstructive pulmonary disease (COPD) status. The event of PDAC diagnosis was compared between cohorts using the Kaplan-Meier method. Factors associated with PDAC diagnosis were evaluated with Cox's proportional hazards modeling. We identified 640 421 patients with NoD and included 1 921 263 controls. At 3 years, significantly more PDAC events were identified in the NoD group vs control group (579 vs 505; P < 0.001). When controlling for patient factors, NoD was significantly associated with elevated risk of PDAC (HR 3.474, 95% CI 3.082-3.920, P < 0.001). Other factors significantly associated with PDAC diagnosis were increasing age, increasing age among Black patients, and COPD diagnosis (P ≤ 0.05). NoD was independently associated with subsequent diagnosis of PDAC within 3 years. Future studies should evaluate the feasibility and benefit of PDAC screening in patients with NoD.


The validity and reliability of the Violence Risk Scale-Sexual Offender version: assessing sex offender risk and evaluating therapeutic change.
The Violence Risk Scale-Sexual Offender version (VRS-SO) is a rating scale designed to assess risk and predict sexual recidivism, to measure and link treatment changes to sexual recidivism, and to inform the delivery of sexual offender treatment. The VRS-SO comprises 7 static and 17 dynamic items empirically or conceptually linked to sexual recidivism. Dynamic items with higher ratings identify treatment targets linked to sexual offending. A modified stages of change model assesses the offender's treatment readiness and change. File-based VRS-SO ratings were completed on 321 sex offenders followed up an average of 10 years post-release. VRS-SO scores predicted sexual and nonsexual violent recidivism post-release and demonstrated acceptable interrater reliability and concurrent validity. A factor analysis of the dynamic items generated 3 factors labeled Sexual Deviance, Criminality, and Treatment Responsivity, all of which predicted sexual recidivism and were differentially associated with different sex offender types. The dynamic items together made incremental contributions to sexual recidivism prediction after static risk was controlled for. Positive changes in the dynamic items, measured at pre- and posttreatment, were significantly related to reductions in sexual recidivism after risk and follow-up time were controlled for, suggesting that dynamic items are indeed dynamic or changeable in nature.


Immediate implant placement with simultaneous guided bone regeneration in the esthetic zone: 10-year clinical and radiographic outcomes.
To associate the dimension of the facial bone wall with clinical, radiological, and patient-centered outcomes at least 10 years after immediate implant placement with simultaneous guided bone regeneration in a retrospective study. Primary endpoint was the distance from the implant shoulder (IS) to the first bone-to-implant contact (IS-BIC10y ). Secondary endpoints included the facial bone thickness (BT10y ) 2, 4, and 6 mm apical to the IS, and the implant position. At baseline, the horizontal defect width (HDWBL ) from the implant surface to the alveolar wall was recorded. At recall, distance from the IS to the mucosal margin (IS-MM10y ), degree of soft tissue coverage of the mesial and distal aspects of the implants (PISm10y , PISd10y ; Papilla Index), pocket probing depth (PPD10y ), and patient-centered outcomes were determined. Width of the keratinized mucosa (KM), Full-Mouth Plaque and Bleeding Score (FMPS, FMBS) were available for both time points. Of the 20 patients who underwent immediate implant placement with simultaneous guided bone regeneration and transmucosal healing, nine males and eight females with a median age of 62 years (42 min, 84 max) were followed up for a median period of 10.5 y (min 10.1 max 11.5). The 10-year implant survival rate was 100%. Multivariate regression analysis revealed a correlation of the IS-BIC10y , controlled for age and gender, with four parameters: HDWBL (P = 0.03), KMBL -10 (P = 0.02), BT10 4 mm (P = 0.01), and BT10 6 mm (P = 0.01). Within the conditions of the present study, the horizontal defect width was the main indicator for the vertical dimension of the facial bone. The facial bone dimension was further associated with a reduction in the width of the keratinized mucosa and the dimension of the buccal bone.


Panretinal, high-resolution color photography of the mouse fundus.
To analyze high-resolution color photographs of the mouse fundus. A contact fundus camera based on topical endoscopy fundus imaging (TEFI) was built. Fundus photographs of C57 and Balb/c mice obtained by TEFI were qualitatively analyzed. High-resolution digital imaging of the fundus, including the ciliary body, was routinely obtained. The reflectance and contrast of retinal vessels varied significantly with the amount of incident and reflected light and, thus, with the degree of fundus pigmentation. The combination of chromatic and spherical aberration favored blue light imaging, in term of both field and contrast. TEFI is a small, low-cost system that allows high-resolution color fundus imaging and fluorescein angiography in conscious mice. Panretinal imaging is facilitated by the presence of the large rounded lens. TEFI significantly improves the quality of in vivo photography of retina and ciliary process of mice. Resolution is, however, affected by chromatic aberration, and should be improved by monochromatic imaging.


Core outcomes for adult burn survivors: a clinical overview.
Burn trauma ranges from the minor burn to the devastating injury, which can impact on all aspects of a person's life including aesthetic appearance, relationships with others and psychological, social and physical functioning. Measurement of outcome in burns patients is therefore complex and multi-faceted. The increasing numbers of major burn survivors implies that understanding health outcomes in these patients has assumed high priority. This paper sets out a conceptual framework for unifying outcome measurement, which may be useful to all members of the multidisciplinary team who are contemplating outcome assessment in their burn patients. It outlines seven core domains of assessment which are (i) skin; (ii) neuromuscular function; (iii) sensory and pain; (iv) psychological function; (v) physical role function; (vi) community participation; and (vii) perceived quality of life. Within each domain, we present a brief clinical review of the most commonly administered measurement tools that have been, or potentially could be, used to assess aspects of these core domains. Where possible, the psychometric properties and clinical utility of these tools are presented. A concise discussion of key methodological issues which should be addressed in this assessment process is then provided, together with suggestions for future research.


Associations among hypertension, dementia biomarkers, and cognition: The MEMENTO cohort.
Approximately 40% of dementia cases could be delayed or prevented acting on modifiable risk factors including hypertension. However, the mechanisms underlying the hypertension-dementia association are still poorly understood. We conducted a cross-sectional analysis in 2048 patients from the MEMENTO cohort, a French multicenter clinic-based study of outpatients with either isolated cognitive complaints or mild cognitive impairment. Exposure to hypertension was defined as a combination of high blood pressure (BP) status and antihypertensive treatment intake. Pathway associations were examined through structural equation modeling integrating extensive collection of neuroimaging biomarkers and clinical data. Participants treated with high BP had significantly lower cognition compared to the others. This association was mediated by higher neurodegeneration and higher white matter hyperintensities load but not by Alzheimer's disease (AD) biomarkers. These results highlight the importance of controlling hypertension for prevention of cognitive decline and offer new insights on mechanisms underlying the hypertension-dementia association. Paths of hypertension-cognition association were assessed by structural equation models. The hypertension-cognition association is not mediated by Alzheimer's disease biomarkers. The hypertension-cognition association is mediated by neurodegeneration and leukoaraiosis. Lower cognition was limited to participants treated with uncontrolled blood pressure. Blood pressure control could contribute to promote healthier brain aging.


Patterns of sexual behaviour and reported symptoms of STI/RTIs among young people in Croatia--implications for interventions' planning.
This paper describes some of the results of the first national-level survey on sexual behaviour and the distribution of risks to sexually transmitted infections (STIs), including human immunodeficiency virus infection (HIV), among youth in Croatia, and the nature and the extent of their vulnerability to these adverse health outcomes. The study was a cross-sectional, probability-based household survey conducted in 2005, and included 1093 respondents aged 18-24. This paper aims to describe the findings related to the knowledge of HIV transmission, key behavioural outcomes relevant for potential transmission of HIV and STIs, and correlates of genital discharge in young men and young women. More than 80% of young people know that the correct use of condoms protects against HIV and that HIV can be transmitted by someone who looks healthy. Fifty-nine percent of young men and 52.4% of young women reported using condoms during the first sexual intercourse, and 59.3% of men and 46.1% of women used condoms during the last sexual intercourse with a casual partner. This points to the gap between knowledge of condom use and the actual use of condoms as a high proportion of risky sexual contact remain unprotected. Having sexual intercourse frequently or regularly while consuming alcohol was reported by 19.2% of men and 7.6% of women. Much lower proportion are using drugs frequently or regularly during sexual intercourse (3.7% of men and 2.1% of women). Among those sexually experienced, 11.8% of men and 44.1% of women reported ever having a genital discharge. Higher presence of genital discharge in women is suggestive of reproductive tract infections that are not necessarily sexually transmitted. In the multivariate analysis, the lack of knowledge of whether chlamydial infections is an STI and having more than five partners in life were correlates of genital discharge in men, while in women the correlates included having more than five partners in life and not using condoms during the first sexual intercourse. Higher burden of STI-related symptoms was found among men who have men as sexual partners, those who paid for sex, and those with concurrent partnerships. These findings point out to the immediate need to strengthen sexual health education among young people and to the necessity for further development of other broad-based interventions to prevent adverse sexual health outcomes among both men and women, as well as those targeted towards more vulnerable subgroups.


[Correction of sinus rate by inhibitors of If-channels in patients with acute decompensated heart failure].
The aim of the study was to assess heart rate reduction for a acute decompensated heart failure in patients with reduced left ventricular systolic function and in patients with heart failure without significant reduction in ejection fraction. Were examined 79 patients with an ejection fraction less than 40%. 38 of them took If-channel blocker, ivabradine, 41 amounted to a control group. A group of patients with diastolic dysfunction was 48 patients (23 in the treatment of ivabradine and 25 subgroups of control). During the 14 days of observation it was found that the positive effect of reducing the sinus rate by ivabradine was observed in patients with diastolic dysfunction. In this group of patients on the background of decreasing heart rate, improves the passive diastolic properties of the left ventricle and an increase in the distance traveled by the patients during 6-minute walk test compared with the control group. The data obtained in our study support the use of ivabradine in patients with acute decompensated heart failure. The most significant changes in hemodynamic parameters and functional status were obtained in patients with diastolic dysfunction. Given the small sample, the results need to be further confirmed in larger clinical trials.


Biomechanics of calcaneal fractures: a model for the motor vehicle.
Changes in legislation, availability of passive or active restraint systems, or both, together with increased public awareness for safety and the need for use of restraint, have shifted the spectrum of trauma in motor vehicle crashes from the head and torso to other regions. Lower extremity trauma in motor vehicle crashes continues to be a significant problem. The objective of this study was to investigate the biomechanics of the human foot and ankle complex under impact loading and replicate calcaneal fractures routinely seen in motor vehicle crashes. Twenty-two unembalmed cadaver lower extremity specimens were subjected to dynamic loads using a minisled pendulum device. Input and output forces and results of pathologic analysis were obtained using load cell data, radiographs obtained before and after testing, and gross dissection. The intraarticular fracture patterns produced were similar to those seen clinically and described in the literature. Maximum forces ranged from 3.6 to 11.4 kN for the fracture, and 0.5 to 7.3 kN for the nonfracture groups. Logistic regression analysis revealed a 50% probability of calcaneal fracture at 5.5 kN and a 25% probability at 4.0 kN. These studies will lead to an understanding of the tolerance of the lower extremity in sustaining calcaneal fractures under impact. Implications of the work are in the design of crash test dummies, data acquisition, and modifications in motor vehicle design and safety.


In vivo amyloid imaging with PET in frontotemporal dementia.
N-methyl[11C]2-(4'methylaminophenyl)-6-hydroxy-benzothiazole (PIB) is a positron emission tomography (PET) tracer with amyloid binding properties which allows in vivo measurement of cerebral amyloid load in Alzheimer's disease (AD). Frontotemporal dementia (FTD) is a syndrome that can be clinically difficult to distinguish from AD, but in FTD amyloid deposition is not a characteristic pathological finding. The aim of this study is to investigate PIB retention in FTD. Ten patients with the diagnosis of FTD participated. The diagnosis was based on clinical and neuropsychological examination, computed tomography or magnetic resonance imaging scan, and PET with 18 Fluoro-2-deoxy-d-glucose (FDG). The PIB retention, measured in regions of interest, was normalised to a reference region (cerebellum). The results were compared with PIB retention data previously obtained from 17 AD patients with positive PIB retention and eight healthy controls (HC) with negative PIB retention. Statistical analysis was performed with a students t-test with significance level set to 0.00625 after Bonferroni correction. Eight FTD patients showed significantly lower PIB retention compared to AD in frontal (p < 0.0001), parietal (p < 0.0001), temporal (p = 0.0001), and occipital (p = 0.0003) cortices as well as in putamina (p < 0.0001). The PIB uptake in these FTD patients did not differ significantly from the HC in any region. However, two of the 10 FTD patients showed PIB retention similar to AD patients. The majority of FTD patients displayed no PIB retention. Thus, PIB could potentially aid in differentiating between FTD and AD.


Impact of Tyrosine Kinase Inhibitors Applied for First-Line Chronic Myeloid Leukemia Treatment on Platelet Function in Whole Blood of Healthy Volunteers In Vitro.
The tyrosine kinase inhibitors (TKIs) imatinib, dasatinib, bosutinib, and nilotinib are established for first-line treatment of chronic myeloid leukemia (CML) but may cause side effects such as bleeding and thrombotic complications. We investigated the impact of TKIs on platelet function ex vivo in anticoagulated whole blood (WB) samples from healthy adults by lumiaggregometry and PFA-100 test. Samples (n = 15 per TKI) were incubated for 30 minutes with TKI at therapeutically relevant final concentrations. Aggregation and ATP release were induced by collagen (1 µg/mL), arachidonic acid (0.5 mmol/L), and thrombin (0.5 U/mL). Imatinib, bosutinib, and nilotinib significantly increased collagen-induced aggregation compared with controls. In addition, for bosutinib and nilotinib, a significant increase in aggregation after induction with arachidonic acid was detected. ATP-release and PFA-100 closure times were not influenced significantly by these three TKI. In contrast, dasatinib demonstrated a concentration-dependent inhibition of collagen-induced aggregation and ATP release and a significant prolongation of the PFA-100 closure time with the collagen/epinephrine cartridge. Aggregation and ATP release by other agonists as well as closure time with the collagen/ADP cartridge were not influenced significantly. In conclusion, we clearly show a concentration-dependent inhibition of collagen-induced platelet function in WB by dasatinib confirming prior results obtained in platelet-rich plasma. Bosutinib and nilotinib exerted no impairment of platelet activation. On the contrary, both TKI showed signs of platelet activation. When comparing our results with existing data, imatinib in therapeutic relevant concentrations does not impair platelet function.