Human tear lipocalin exhibits antimicrobial activity by scavenging microbial siderophores.
Human tear lipocalin (TL; also known as Lcn1) is a secretory protein present in large amounts in fluids that cover epithelial surfaces such as tears and respiratory secretions. It is supposed to act as a physiological scavenger of hydrophobic, potentially harmful molecules, but there is evidence that it also inhibits bacterial growth. In the present study, we reconsidered the possibility that TL might interfere with microbial growth by scavenging of siderophores, as described for human neutrophil gelatinase-associated lipocalin (NGAL). Indeed, our experiments revealed that TL binds to microbial siderophores with high affinities. In contrast to NGAL, which was shown to have some specificity for bacterial catecholate-type siderophores, TL binds to a broad array of siderophores, including bacterial catecholate-type enterobactin and hydroxamate-type desferrioxamine B, and all major classes of fungal siderophores. By adding exogenous TL, bacterial and fungal growth could be inhibited under iron-limiting conditions. Thus, TL might be a novel member of the innate immune system especially involved in mucosal defense against fungal infections.


Microporosity enhances bioactivity of synthetic bone graft substitutes.
This paper describes an investigation into the influence of microporosity on early osseointegration and final bone volume within porous hydroxyapatite (HA) bone graft substitutes (BGS). Four paired grades of BGS were studied, two (HA70-1 and HA70-2) with a nominal total porosity of 70% and two (HA80-1 and HA80-2) with a total-porosity of 80%. Within each of the total-porosity paired grades the nominal volume fraction of microporosity within the HA struts was varied such that the strut porosity of HA70-1 and HA80-1 was 10% while the strut-porosity of HA70-2 and HA80-2 was 20%. Cylindrical specimens, 4.5 mm diameter x 6.5 mm length, were implanted in the femoral condyle of 6 month New Zealand White rabbits and retrieved for histological, histomorphometric, and mechanical analysis at 1, 3, 12 and 24 weeks. Histological observations demonstrated variation in the degree of capillary penetration at 1 week and bone morphology within scaffolds 3-24 weeks. Moreover, histomorphometry demonstrated a significant increase in bone volume within 20% strut-porosity scaffolds at 3 weeks and that the mineral apposition rate within these scaffolds over the 1-2 week period was significantly higher. However, an elevated level of bone volume was only maintained at 24 weeks in HA80-2 and there was no significant difference in bone volume at either 12 or 24 weeks for 70% total-porosity scaffolds. The results of mechanical testing suggested that this disparity in behaviour between 70 and 80% total-porosity scaffolds may have reflected variations in scaffold mechanics and the degree of reinforcement conferred to the bone-BGS composite once fully integrated. Together these results indicate that manipulation of the levels of microporosity within a BGS can be used to accelerate osseointegration and elevate the equilibrium volume of bone.


FMS-like tyrosine kinase 3 ligand treatment does not ameliorate experimental rapidly progressive glomerulonephritis.
Fms-like tyrosine kinase 3-ligand (FL) is a growth factor that may expand dendritic cell and regulatory T cell populations. We hypothesised that FL-induced regulatory T cells would protect mice from experimental rapidly progressive glomerulonephritis. To determine if FL was able to enhance regulatory T cell populations, C57BL/6 mice received 10 days of daily intraperitoneal injections of either FL or phosphate buffered saline. To induce accelerated autologous-phase anti-mouse glomerular basement membrane glomerulonephritis, mice were sensitized to sheep globulin 4 days prior to the induction of glomerulonephritis with sheep anti-mouse glomerular basement membrane globulin, and experiments ended 10 days later. FL was administered before, throughout and during the sensitization phase of this glomerulonephritis model. Renal disease and systemic immunity to the nephritogenic antigen were assessed. FL increased regulatory T cell and plasmacytoid dendritic cell proportions within spleen and lymph nodes. FL administration prior to glomerulonephritis did not protect mice from renal injury. When FL was given throughout the model, FL treated mice had reduced survival, with more interstitial neutrophils and glomerular CD11c+ cells than controls. Systemic immune responses showed increased IL-17A production from splenocytes, with more CD11c+ cells, but reduced plasmacytoid dendritic cell proportions in spleen and lymph nodes, despite increased regulatory T cell proportions. Under homeostatic conditions, FL expanded regulatory T cell and plasmacytoid dendritic cell populations, but FL enhanced systemic inflammatory responses and conventional dendritic cell populations when given during experimental glomerulonephritis, suggesting selective attempts to suppress pathogenic immunity by dendritic cell manipulation may be harmful.


Modification of dose-response curves by effector blockade and uncompetitive antagonism.
Kinetic equations were derived for simple models of agonist-antagonist-receptor interaction and used to predict theoretical dose-response curves for the situation where there exists "receptor reserve" and a simple rectangular hyperbolic relation between tissue response and receptor occupancy by agonist, generated by an "effector chain" that links final response to receptor activation. Drug action within this chain, or an "uncompetitive" antagonism exerted by a reversible agonist that combines primarily with the active agonist-receptor complex, may give the appearance of classical noncompetitive or competitive antagonism, depending upon the amount of receptor reserve and upon the rate constants involved in both agonist-receptor and antagonist-receptor interaction. The apparent potency and nature of antagonism by such an uncompetitive antagonist may depend upon the particular agonist against which it is tested. The phenomenon whereby true competitive antagonists reduce the maximal response to a partial agonist can be explained if the partial agonist, in addition to activating receptors, also acts as an uncompetitive antagonist.


Psychophysics with junctions in real images.
Junctions, formed at the intersection of image contours, are thought to play an important and early role in vision. The interest in junctions can be attributed in part to the notion that they are local image features that are easy to detect but that nonetheless provide valuable information about important events in the world, such as occlusion and transparency. Here I test the notion that there are locally defined junctions in real images that might be detected with simple, early visual mechanisms. Human observers were used as a tool to measure the visual information available in local regions of real images. One set of observers was made to label all the points in a set of real images where one edge occluded another. A second set of observers was presented with variable-size circular subregions of these images, and was asked to judge whether the regions were centered on an occlusion point. This task is easy if junctions are visible, but I found performance to be poor for small regions, not approaching ceiling levels until observers were given fairly large (approximately 50 pixels in diameter) regions over which to make the judgment. Control experiments ruled out the possibility that the effects are just due to junctions at multiple scales. Experiments reported here suggest that, although some junctions in real images are locally defined and can be detected with simple mechanisms, a substantial fraction necessitate the use of more complex and global processes. This raises the possibility that junctions in such cases may not be detected prior to scene interpretation.


Peripheral arterial disease affects ground reaction forces during walking.
Claudication is the most common manifestation of peripheral arterial disease (PAD), producing significant ambulatory compromise. The gait of claudicating patients has been evaluated using primarily temporal and spatial parameters. With the present study, we used advanced biomechanical measures to further delineate the ambulatory impairment of claudicating patients. We hypothesized that the claudicating legs of PAD patients have an altered kinetic gait pattern compared with normal legs from control subjects. Ambulation kinetics (ground reaction forces) were evaluated in claudicating patients and compared with age-matched healthy controls. Forces were analyzed in the vertical, anterior-posterior, and medial-lateral directions. Time from heel touch-down to toe-off (stance time) and time spent in double-limb support were also evaluated. The study recruited 14 PAD patients (age, 58 +/- 3.4 years; weight, 80.99 +/- 15.64 kg) with femoropopliteal occlusive disease (ankle-brachial index [ABI], 0.56 +/- 0.03) and five controls (age, 53 +/- 3.4 years; weight, 87.38 +/- 12.75 kg; ABI, >or=1.00). Vertical force curve evaluation demonstrated significant flattening in claudicating patients resulting in a lower and less fluctuant center of mass when ambulating. In the anterior-posterior direction, claudicating patients demonstrated significantly decreased propulsion forces. In the medial-lateral direction, they had significantly increased forces consistent with wider steps and an inability to swing their legs straight through. Claudicating patients demonstrated a greater stance time and time in double limb support compared with healthy controls. Most importantly, gait abnormalities were present before the onset of claudication, with gait worsening after the onset of claudication. Claudicating patients demonstrate significant gait impairments that are present even before they experience any limb discomfort. These alterations may make them feel more stable and secure while attempting to minimize use of the affected limb. Advanced biomechanical analysis, using ambulation kinetics, permits objective and quantitative evaluation of the gaits of claudicating patients. Such evaluation may point to new rehabilitation strategies and provide objective measurement of functional outcomes after medical and surgical therapy.


[Constipation and fecal incontinence in the elderly].
Alterations of anorectal functions (constipation and fecal incontinence) are very frequent in the elderly. The patient's global evaluation with his past medical history, comorbidities, medications, as well as social environment and physical dependence, is more than ever necessary in this high risk population to guide the explorations and the medical care of these disorders.


Impact of polyelectrolyte adsorption on the rheology of concentrated poly(N-isopropylacrylamide) microgel suspensions.
We explore the impact of three water-soluble polyelectrolytes (PEs) on the flow of concentrated suspensions of poly(N-isopropylacrylamide) (PNIPAm) microgels with thermoresponsive anionic charge density. By progressively adding the PEs to a jammed suspension of swollen microgels, we show that the rheology of the mixtures is remarkably influenced by the sign of the PE charge, PE concentration and hydrophobicity only when the temperature is increased above the microgel volume phase transition temperature Tc, namely when microgels collapse, they are partially hydrophobic and form a volume-spanning colloidal gel. We find that the original gel is strengthened close to the isoelectric point, attained when microgels are mixed with cationic PEs, while PE hydrophobicity rules the gel strengthening at very high PE concentrations. Surprisingly, we find that polyelectrolyte adsorption or partial embedding of PE chains inside the microgel periphery occurs also when anionic polymers of polystyrene sulfonate with a high degree of sulfonation are added. This gives rise to colloidal stabilization and to the melting of the original gel network above Tc. Contrastingly, the presence of polyelectrolytes in suspensions of swollen, jammed microgels results in a weak softening of the original repulsive glass, even when an apparent isoelectric condition is met. Our study puts forward the crucial role of electrostatics in thermosensitive microgels, unveiling an exciting new way to tailor the flow of these soft colloids and highlighting a largely unexplored path to engineer soft colloidal mixtures.


Robustness and evolvability of heterogeneous cell populations.
Biological systems are endowed with two fundamental but seemingly contradictory properties: robustness, the ability to withstand environmental fluctuations and genetic variability; and evolvability, the ability to acquire selectable and heritable phenotypic changes. Cell populations with heterogeneous genetic makeup, such as those of infectious microbial organisms or cancer, rely on their inherent robustness to maintain viability and fitness, but when encountering environmental insults, such as drug treatment, these populations are also poised for rapid adaptation through evolutionary selection. In this study, we develop a general mathematical model that allows us to explain and quantify this fundamental relationship between robustness and evolvability of heterogeneous cell populations. Our model predicts that robustness is, in fact, essential for evolvability, especially for more adverse environments, a trend we observe in aneuploid budding yeast and breast cancer cells. Robustness also compensates for the negative impact of the systems' complexity on their evolvability. Our model also provides a mathematical means to estimate the number of independent processes underlying a system's performance and identify the most generally adapted subpopulation, which may resemble the multi-drug-resistant "persister" cells observed in cancer.


Treatment of lower respiratory infections in outpatients with ofloxacin compared with erythromycin.
To assess the safety and efficacy of a ten-day oral course of ofloxacin (400 mg 12 hourly) as compared with erythromycin (400 mg every 6 hours) for treatment of lower respiratory tract infections, fifty-two adult outpatients with pulmonary infiltrates (pneumonia) or with a cough and purulent sputum (bronchitis) were evaluated. Expectorated sputum specimens were Gram-stained and cultured, and antibody titres to Mycoplasma pneumoniae, Legionella pneumophilia, and in most cases Chlamydia pneumoniae were measured on acute and convalescent serum samples. Patients were evaluated clinically, microbiologically and radiographically three to five days after concluding therapy; the incidence of adverse reactions was monitored throughout the study period. The ofloxacin group (N = 25) was comprised of nineteen patients with pneumonia and six patients with bronchitis. The erythromycin group (N = 27) was comprised of thirteen patients with pneumonia and fourteen patients with bronchitis. All fifty-two patients were either clinically improved or cured after therapy. Microbiological cure was documented in all fourteen cases (27%) in which causative pathogens were identified. Clinical cure was achieved with ofloxacin in 68% of patients with pneumonia and in 83% of patients with bronchitis, while clinical cure with erythromycin was achieved in 46% of patients with pneumonia and 54% of patients with bronchitis. Adverse reactions (mostly mild gastrointestinal or central nervous system symptoms) were reported by eight patients receiving ofloxacin and four patients receiving erythromycin. While the types of adverse effects were similar, ofloxacin showed a trend toward a higher rate of cure than erythromycin. Ofloxacin is a promising new antibiotic for the treatment of acute lower respiratory infections.


One haplotype is associated with the Swiss type of hereditary persistence of fetal hemoglobin in the Yugoslavian population.
Blood samples from normal adults and from members of seven families with the Swiss type of hereditary persistence of fetal hemoglobin (HPFH) from Yugoslavia were analyzed for their fetal hemoglobin (Hb F) and G gamma levels, while haplotyping defined the chromosomes at eight or nine polymorphic restriction sites. The data indicate that Swiss-HPFH, characterized by slightly elevated Hb F and G gamma levels and no recognizable hematological abnormality, is associated with a chromosome whose restriction enzyme haplotype is identical to the no. 3 (Senegal) haplotype found in black sickle cell (SS) patients. Many adults with this chromosome have high G gamma but normal Hb F levels. It is suggested that the Swiss-HPFH phenotype results from the action of more than one factor; one is linked to the beta-globin gene cluster and causes high G gamma values, while others result in an increased Hb F production and are perhaps of different origins.


Therapeutic targets in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease. After many drugs failed in clinical trials, improvements in the understanding of the pathogenesis of IPF led to the approval of two drugs that slow the progression of the disease. However, the prognosis for patients with IPF remains poor and the search continues for drugs that inhibit the pathogenic pathways active in IPF to reduce or even halt the progression of the disease. In this article, we review the mechanisms of action of the two approved therapies for IPF (nintedanib and pirfenidone) and of the investigational compounds that are in Phase II trials and discuss the potential for combination therapy in the treatment of IPF.


Augmentation of sarcolemmal Ca by anionic amphiphile: contractile response of three ventricular tissues.
The anionic amphiphile dodecyl sulfate was used at the concentration of 100 microM, below the concentration at which membrane permeability is compromised. In rat myocardial tissue culture dodecyl sulfate induced a large increase in Ca uptake in the intact cells, of which 84% was distributed in a rapidly exchangeable (t1/2 less than 18 s) and 16% in a slowly exchangeable (t1/2 = 17 min) compartment. Dodecyl sulfate induced a large increase in Ca bound to isolated sarcolemmal membrane of these cells. This increase in membrane binding and the distribution in whole cells is consistent with insertion of dodecyl sulfate in the sarcolemma (SL) with subsequent Ca binding to its anionic head group. With perfusate extracellular calcium concentration ([Ca]o) equal to 1 mM, dodecyl sulfate produced greater than 60% increase in active force in ventricular tissue from adult rabbit and neonatal rat but virtually no increase in adult rat ventricle. Preperfusion with 0.1 mM [Ca]o or 10(-6) M ryanodine markedly increased the relative response of adult rat ventricle to dodecyl sulfate. After a quiescent period in rabbit ventricle, dodecyl sulfate caused a progressive increase of force of each beat compared with control; i.e., the treppe response was increased at each successive beat. This did not occur in adult rat ventricle. These results further clarify the different quantitative role of SL-bound versus sarcotubular Ca in the hearts of different species.


Morbidity and mortality in infant mountain gorillas (Gorilla beringei beringei): A 46-year retrospective review.
Long-term studies of morbidity and mortality in free-ranging primates are scarce, but may have important implications for the conservation of extant populations. Infants comprise a particularly important age group, as variation in survival rates may have a strong influence on population dynamics. Since 1968, the Mountain Gorilla Veterinary Project (MGVP, Inc.) and government partners have conducted a comprehensive health monitoring and disease investigation program on mountain gorillas (Gorilla beringei beringei) in Rwanda, Uganda, and the Democratic Republic of the Congo. In an effort to better understand diseases in this species, we reviewed reliable field reports (n = 37), gross post-mortem (n = 66), and histopathology (n = 53) reports for 103 infants (less than 3.5 years) mountain gorillas in the Virunga Massif. Our aim was to conduct the first comprehensive analysis of causes of infant mortality and to correlate histological evidence with antemortem morbidity in infant mountain gorillas. Causes of morbidity and mortality were described, and compared by age, sex, and over time. Trauma was the most common cause of death in infants (56%), followed by respiratory infections and aspiration (13%). Gastrointestinal parasitism (33%), atypical lymphoid hyperplasia (suggestive of infectious disease) (31%), and hepatic capillariasis (25%) were the most significant causes of antemortem morbidity identified post-mortem. Identifying the causes of mortality and morbidity in infants of this critically endangered species will help to inform policy aimed at their protection and guide ante- and post-mortem health monitoring and clinical decision-making in the future.


Activation of acid sphingomyelinase by protein kinase Cdelta-mediated phosphorylation.
Although important for cellular stress signaling pathways, the molecular mechanisms of acid sphingomyelinase (ASMase) activation remain poorly understood. Previous studies showed that treatment of MCF-7 mammary carcinoma cells with the potent protein kinase C (PKC) agonist, phorbol 12-myristate 13-acetate (PMA), induces a transient drop in sphingomyelin concomitant with an increase in cellular ceramide levels (Becker, K. P., Kitatani, K., Idkowiak-Baldys, J., Bielawski, J., and Hannun, Y. A. (2005) J. Biol. Chem. 280, 2606-2612). Here we show that PMA selectively activates ASMase and that ASMase accounts for the majority of PMA-induced ceramide. Pharmacologic inhibition and RNA interference experiments indicated that the novel PKC, PKCdelta, is required for ASMase activation. Immunoprecipitation experiments revealed the formation of a novel PKCdelta-ASMase complex after PMA stimulation, and PKCdelta was able to phosphorylate ASMase in vitro and in cells. Using site-directed mutagenesis, we identify serine 508 as the key residue phosphorylated in response to PMA. Phosphorylation of Ser(508) proved to be an indispensable step for ASMase activation and membrane translocation in response to PMA. The relevance of the proposed mechanism of ASMase regulation is further validated in a model of UV radiation. UV radiation also induced phosphorylation of ASMase at serine 508. Moreover, when transiently overexpressed, ASMase(S508A) blocked the ceramide formation after PMA treatment, suggesting a dominant negative function for this mutant. Taken together, these results establish a novel direct biochemical mechanism for ASMase activation in which PKCdelta serves as a key upstream kinase.


Needs-based primary medical care capitation: development and evaluation of alternative approaches.
To develop and evaluate alternative methods of adjusting primary medical care capitation payments for variations in relative need for health care among enrolled practice populations. We developed alternative needs-based capitation formulae and applied them to a sample of capitation-funded primary care practices to assess each formula's performance against a reference standard of capitation payments based on age, sex and self-assessed health status of the enrolled populations. The alternative formulae were based on: (1) age and sex; (2) age, sex and individually-measured socioeconomic characteristics; (3) age, sex and socioeconomic characteristics imputed from census data for enrollees' neighbourhood of residence; (4) age, sex and standardized mortality ratio for enrollees' neighbourhood of residence. Age/sex-adjusted capitation payments for the six practices studied ranged from 10% higher to 18% lower than the reference standard payments. Capitation formulae based on socioeconomic and mortality data did not perform consistently better than the current age/sex-based formula. Primary medical care capitation payments adjusted only for age and sex do not reflect the relative health care needs of enrolled practice populations. Our alternative formulae based on socioeconomic and mortality data also failed to reflect relative needs. Methods that use other approaches to adjusting for differences in relative need among enrolled populations should be investigated.


Effect of Denture Cleansers on Surface Roughness and Flexural Strength of Heat Cure Denture Base Resin-An In vitro Study.
Denture cleansing is essential for maintaining the prosthesis and oral health, so choosing an appropriate cleanser which is not only efficient but also not adversely affects the properties of denture base resin itself with prolonged use is important. Hence, the present study was undertaken. To evaluate the effect of different chemical cleansers on surface roughness and flexural strength of heat cure denture base resin when used daily for three months. A total of 40 rectangular specimens (65 mm x 10 mm x 2.5 mm) and 32 disc shaped specimens (10 mm x 2 mm) were fabricated from heat cure denture base resin (DPI Heat Cure) for evaluation of flexural strength and surface roughness respectively. The specimens not subjected to cleansing served as control whereas other specimens were subjected to daily cleansing with one of the three cleansers (1% sodium hypochlorite, fittydent tablets, 100% vinegar) daily and stored in distilled water for three months. Surface analyser (Surftest SJ-210, Mitutoyo, USA) was used to evaluate change in surface roughness of the specimens (ΔRa) before and after cleansing. Also, flexural strength (S) of specimens after cleansing was evaluated by subjecting the specimens to load of 50 kgf at a crosshead speed of 5 mm/min in universal testing machine (INSTRON). Data obtained by testing was compiled and analysed using statistical software SPSS version 17.5. ANOVA and Post-hoc Tukey's tests were used and p-value <0.05 was considered significant in all tests. Results showed that the surface roughness of the specimens was significantly increased and flexural strength significantly decreased after immersion in 1% sodium hypochlorite solution for three months (p<0.05). No statistically significant difference were observed in flexural strength and surface roughness of the specimens cleaned with fittydent and 100% vinegar for three months (p>0.05). Within the limitations of this in vitro study, it was concluded that immersion in 1% sodium hypochlorite solutions for three months influences the surface roughness and flexural strength of heat cure denture base resin; hence it should be used with caution when used for long period. Fittydent and 100% vinegar can be recommended as a routine chemical cleansing agent for long term use.


Oral bioavailability and pharmacokinetic study of cetrizine HCl in Iranian healthy volunteers.
The objective of the present study was to evaluate the pharmacokinetic parameters and bioavailability of a selective histamine (H1)-receptor antagonist, cetirizine hydrochloride (CTZ), following administration of a single oral dose of the drug. The properties of a test compound were compared with those of a reference product in a randomized cross-over study in 12 volunteers. Blood samples were collected at selected time intervals up to 24 h and plasma concentrations of CTZ were determined using a validated HPLC method. Pharmacokinetic parameters including T(1/2), T(1/2)(abs), K, K(a), T(max), C(max), V(d)/F, Cl/F, AUC(0-24), AUC (0-∞) and MRT were determined from plasma concentration-time profiles for tested products and found to be in good agreement with previous reports. The analysis of variance did not show any significant differences between the test and reference products. The confidence intervals for the ratio of C(max) (95-110%), AUC(0-24) (91-112%) and AUC(0-∞) (92-109%) for the test and reference products were within the acceptable interval of 80-125%. ANOVA assessment of logarithmically transformed data did not reveal any significant subject, period or sequence effects. It was, therefore, concluded that the two products were bioequivalent and could be used interchangeably.


Cephalometry with a video display computer.
A new technique to develop cephalometric analyses for orthodontic problems is illustrated. A digital analyzer of images is employed in our laboratory, and this allows us to get the X-ray picture digitized and displayed on both a black and white and a colour TV screen. All the cephalometric points are selected by an operator who watches a coloured cross which can be moved on the colour TV screen by means of a keyboard. A suitable software was developed to calculate linear and angular measurements. The cephalometric coloured lines appear at the top of the X-ray image and the data are displayed on a monitor, from which a print-out is obtained. Such a technique has some advantages: the X-ray image can be processed before the cephalometric analysis to enhance details, thus making the analysis more accurate; the cephalometric lines can be seen on the X-ray image displayed on the colour TV screen and can be photographed or stored on floppy or rigid disc.


Airway management and hemodynamic response to laryngoscopy and intubation in supine and left lateral positions.
Intubation in the lateral position is desirable in several conditions. We compared the technical ease and hemodynamic response to laryngoscopy and intubation in the lateral (group L) and supine (group S) positions in 120 patients with normal airway in a prospective randomized controlled study. This was a randomized, controlled observational study. All intubations were performed by a single investigator experienced in lateral intubation. Ventilation score with bag and mask ventilation, laryngoscopy duration and attempts, application of external pressure and Cormac & Lehane grade were measured. Blood pressure and heart rate were observed before and after induction of anesthesia, after laryngoscopy/intubation and then at one minute interval for 6 minutes. 90% of patients in group S were ventilated by a single operator compared to 17% in group L. Duration oflaryngoscopy was significantly longer in group L (32 seconds) compared to group S (12 seconds) [p < 0.001]. 78% of the patients in group S had Cormack and Lehane grade 1 versus nil in group L. External pressure was required in 58% patients in group L and 5% in group S. In intra-group comparison at specified time lines no difference was observed in HR but the changes in BP were significantly higher in the lateral position (P-value < 0.001). Ventilation and intubation in lateral position was more difficult technically than in the suprine position, and the BP response was exaggerated in the lateral position.


One-electron oxidation of ds(5'-GGG-3') and ds(5'-G(8OG)G-3') and the nature of hole distribution: a density functional theory (DFT) study.
Of particular interest in radiation-induced charge transfer processes in DNA is the extent of hole localization immediately after ionization and subsequent relaxation. To address this, we considered double stranded oligomers containing guanine (G) and 8-oxoguanine (8OG), i.e., ds(5'-GGG-3') and ds(5'-G8OGG-3') in B-DNA conformation. Using DFT, we calculated a variety of properties, viz., vertical and adiabatic ionization potentials, spin density distributions in oxidized stacks, solvent and solute reorganization energies and one-electron oxidation potential (E0) in the aqueous phase. Calculations for the vertical state of the -GGG- cation radical showed that the spin was found mainly (67%) on the middle G. However, upon relaxation to the adiabatic -GGG- cation radical, the spin localized (96%) on the 5'-G, as observed in experiments. Hole localizations on the middle G and 3'-G were higher in energy by 0.5 kcal mol-1 and 0.4 kcal mol-1, respectively, than that of 5'-G. In the -G8OGG- cation radical, the spin localized only on the 8OG in both vertical and adiabatic states. The calculated vertical ionization potentials of -GGG- and -G8OGG- stacks were found to be lower than that of the vertical ionization potential of a single G in DNA. The calculated E0 values of -GGG- and -G8OGG- stacks are 1.15 and 0.90 V, respectively, which owing to stacking effects are substantially lower than the corresponding experimental E0 values of their monomers (1.49 and 1.18 V, respectively). SOMO to HOMO level switching is observed in these oxidized stacks. Consequently, our calculations predict that local double oxidations in DNA will form triplet diradical states, which are especially significant for high LET radiations.


[Clinical aspects of diagnostics and surgical treatment of acute primary purulent destructive pyelonephritis].
79 patients with the acute primary non-obstructive pyelonephritis were treated during 2003-2006. 24 (30.3%) patients were operated on with the diagnosis of acute primary purulent destructive pyelonephritis. Organopreserving operations were performed in 23 (95.8%) of patients. The early diagnostics of purulent destructive complications of pyelonephritis, using the developed diagnostic algorithm, and modified operative technique allowed to increase the rate of organopreserving operations, avoid reinterventions and decrease the risk of intraoperative complications.


Ryanodine receptor mutations in malignant hyperthermia and central core disease.
Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that manifests in response to anesthetic triggering agents. Central core disease (CCD) is a myopathy closely associated with MH. Both MH and CCD are primarily disorders of calcium regulation in skeletal muscle. The ryanodine receptor (RYR1) gene encodes the key channel which mediates calcium release in skeletal muscle during excitation-contraction coupling, and mutations in this gene are considered to account for susceptibility to MH (MHS) in more than 50% of cases and in the majority of CCD cases. To date, 22 missense mutations in the 15,117 bp coding region of the RYR1 cDNA have been found to segregate with the MHS trait, while a much smaller number of these mutations is associated with CCD. The majority of RYR1 mutations appear to be clustered in the N-terminal amino acid residues 35-614 (MH/CCD region 1) and the centrally located residues 2163-2458 (MH/CCD region 2). The only mutation identified outside of these regions to date is a single mutation associated with a severe form of CCD in the highly conserved C-terminus of the gene. All of the RYR1 mutations result in amino acid substitutions in the myoplasmic portion of the protein, with the exception of the mutation in the C-terminus, which resides in the lumenal/transmembrane region. Functional analysis shows that MHS and CCD mutations produce RYR1 abnormalities that alter the channel kinetics for calcium inactivation and make the channel hyper- and hyposensitive to activating and inactivating ligands, respectively. The likely deciding factors in determining whether a particular RYR1 mutation results in MHS alone or MHS and CCD are: sensitivity of the RYR1 mutant proteins to agonists; the level of abnormal channel-gating caused by the mutation; the consequential decrease in the size of the releasable calcium store and increase in resting concentration of calcium; and the level of compensation achieved by the muscle with respect to maintaining calcium homeostasis. From a diagnostic point of view, the ultimate goal of development of a simple non-invasive test for routine diagnosis of MHS remains elusive. Attainment of this goal will require further detailed molecular genetic investigations aimed at solving heterogeneity and discordance issues in MHS; new initiatives aimed at identifying modulating factors that influence the penetrance of clinical MH in MHS individuals; and detailed studies aimed at describing the full epidemiological picture of in vitro responses of muscle to agents used in diagnosis of MH susceptibility.


Designing a fall prediction model for inpatient rehabilitation facilities using readily available data.
To create a fall risk assessment tool for inpatient rehabilitation facilities (IRFs) using available data and compare its predictive accuracy to that of the Morse Fall Scale (MFS). We conducted a secondary analysis from a retrospective cohort study. Using a nomogram that displayed the contributions of QI codes associated with falls in a multivariable logistic regression model, we created a novel fall risk assessment, the Inpatient Rehabilitation Fall Scale (IRF Scale). To compare the predictive accuracy of the IRF Scale and MFS, we used receiver operator characteristic (ROC) curve analysis. We included data from 4 IRFs owned and operated by Intermountain Health. Data came from the medical records of 1699 patients. All participants were over the age of 14 and were admitted and discharged from 1 of the 4 sites between January 1 and December 31, 2020. Not applicable MAIN OUTCOME MEASURE(S): We assigned point values on the IRF Scale based on the adjusted associations of QI codes with falls. Using ROC curve analysis, we discovered an optimal cutoff score, sensitivity, specificity, and overall AUC of the IRF Scale and MFS. Receiver operator characteristic curve analysis revealed the optimal IRF Scale cutoff score of 22.4 yielded a sensitivity of 0.74 and a specificity of 0.63. With an AUC of 0.72, the IRF Scale demonstrated acceptable accuracy at identifying patients who fell in our retrospective cohort. Because the IRF Scale uses readily available data, it minimizes staff assessment and outperforms the MFS at identifying patients who previously fell. Prospective research is needed to investigate if it can adequately identify in advance which patients will fall during their IRF stay.


Hand-assisted laparoscopic low anterior resection: initial experience with a new procedure.
Laparoscopic low anterior resection for rectal cancer has never gained wide acceptance among general surgeons, mainly due to the technical difficulties encountered during pelvic dissection. It has therefore been stated that these patients should undergo open rather than laparoscopic surgery. Hand-assisted laparoscopic surgery (HALS) is a new technique that has the potential to overcome many of the existing limitations of pure laparoscopy. In the treatment of rectal cancer, HALS could reproduce an operative setting similar to that of the open approach. To assess the technical feasibility of hand-assisted laparoscopic low anterior resection for rectal cancer and evaluate potential benefits and drawbacks of this new procedure, a pilot study was conducted at a university hospital on 16 consecutive patients during a 12-month period. Only patients with extraperitoneal rectal cancer were included in this series. Patients' clinical data, operative time, conversion rate, complications, and early outcome measures were prospectively examined. There were 9 men and 7 women. The average +/- SD operation time was 238 +/- 38 min. Conversion to open surgery was never required. Ten of 16 patients were off pain medication on the third postoperative day. Eight were able to walk the day after surgery. Three minor postoperative complications were recorded. Mean postoperative stay for patients without complications was 5.6 +/- 1.4 days. From a technical standpoint, the reported hand-assisted procedure makes pelvic dissection during laparoscopic low anterior resection almost equivalent to the laparotomic operation. The incision for hand access that is needed with this technique does not seem to compromise the quick recovery of patients undergoing purely laparoscopic procedures.


Anticancer Activity of Cordia dichotoma against a Panel of Human Cancer Cell Lines and Their Phytochemical Profiling via HPLC and GCMS.
The current study was conducted to examine the in vitro anticancer potential of Cordia dichotoma (bark, leaves, pulp and seed). The plant material was collected from UT of J&K and methodical bioassays were carried out on ten human cancer cell lines (Michigan Cancer Foundation-7 (MCF-7), M.D. Anderson-Metastatic Breast (MDA-MB-231), Neuroblastoma-2a (N2A), SH-SY5Y, U-251, HCT-116, SW-620, A-549, MIA PaCa-2, Panc-1) from five different origins (breast, CNS, colon, lung, pancreas) respectively. Methanolic extracts were produced and fractions were then obtained from the extracts and evaluated for cytotoxicity. Mechanistic assays, HPLC, and GCMS profiling were performed on the highest active fraction. The Sulforhodamine B (SRB) assay determined the in vitro cytotoxicity. The findings revealed that the bark portion had in vitro cytotoxicity against the A-549 human lung cancer cell line. To our knowledge, this is the first study to show that the plant's bark has anticancer properties and induced chromatin condensation, confirmed cell death via ROS generation, and significantly decreased colony formation in A-549 cell line from lung origin in a dose-dependent manner. Furthermore, HPLC and GCMS investigations indicated the presence of a number of bioactive molecules such as gallic acid (144,969.86) uV*sec, caffeic acid (104.26) uV*sec, ferulic acid (472.87) uV*sec, vanillic acid (13,775.39) uV*sec, palmitic acid (18.34%), cis vaccenic acid (28.81%), etc. and one of the compounds was reported for the first time from the bark. As a result of its promising efficacy, it may become an essential cancer chemopreventive or chemotherapeutic medication for patients with lung carcinoma.


Efficacy of carcass electrical stimulation in meat quality enhancement: a review.
The use of electrical stimulation (ES) as a management tool to improve meat quality and efficiency of meat processing is reviewed. The basis of the efficacy of ES is its ability to fast track postmortem glycolysis, which in turn stimulates myriad histological, physical, biochemical, biophysical and physiological changes in the postmortem muscle. Electrical stimulation hastens the onset and resolution of rigor mortis thereby reducing processing time and labor and plays a vital role in improving meat tenderness and other meat quality traits. However, ES may have negative impacts on some meat quality traits such as color stability and water holding capacity in some animals. Electrical stimulation is not an end in itself. In order to achieve the desired benefits from its application, the technique must be properly used in conjunction with various intricate antemortem, perimortem and postmortem management practices. Despite extensive research on ES, the fundamental mechanisms and the appropriate commercial applications remained obscured. In addition, muscles differ in their response to ES. Thus, elementary knowledge of the various alterations with respect to muscle type is needed in order to optimize the effectiveness of ES in the improvement of meat quality.


Rodents as a reservoir of infection caused by multiple zoonotic species/genotypes of C. parvum, C. hominis, C. suis, C. scrofarum, and the first evidence of C. muskrat genotypes I and II of rodents in Europe.
Cryptosporidium spp. is an important causative agent of intestinal parasitoses-induced diarrhoea in humans and animals worldwide. Rodents (small mammals), the main reservoir of infections, are globally expanded and overpopulated, which increases the risk of transfer of human and zoonotic pathogens from the genus Cryptosporidium. In this study, Cryptosporidium was detected in wild immunocompetent asymptomatic small mammals. Altogether 262 fecal samples were collected from five areas in Eastern Slovakia from four different rodent species (Myodes glareolus, Apodemus agrarius, Apodemus flavicollis, Rattus norvegicus), eight samples originated from two insectivore species (Sorex araneus, Crocidura suaveolens), and two sample from a carnivore Mustela nivalis. The samples were examined using a method modified in our laboratory, based on the use of specific primers on a small subunit rRNA (18S rRNA) gene for species identification, and amplification of GP60 gene coding 60-kDa glycoprotein for genotype determination. The following species were identified: Cryptosporidium parvum (n=15), genotypes IIaA18G3R1 (n=11; KU311673), IIaA10G1R1 (n=1; KU311670), IIcA5G3a (n=1; KU311669), IIiA10 (n=2; KU311672); Cryptosporidium suis (n=4; KU311671); Cryptosporidium scrofarum (n=28); Cryptosporidium environment sp. (n=12; KU311677); Cryptosporidium muskrat genotype I (n=3; KU311675); Cryptosporidium muskrat genotype II (n=3; KU311676). From one of the rodent, the species Cryptosporidium hominis genotype IbA10G2 (KU311668) was identified for the first time. The results of this study indicate low host specificity of the detected Cryptosporidium species and imply the importance of free-living small mammals in urban and suburban habitats as a potential source of human cryptosporidiosis.


Neutrophils drive type I interferon production and autoantibodies in patients with Wiskott-Aldrich syndrome.
Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in Wiskott-Aldrich syndrome protein (WASp), a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients experience autoimmunity caused by a breakdown in T- and B-cell tolerance. Moreover, excessive production of type I interferon (IFN-I) by plasmacytoid dendritic cells (pDCs) contributes to autoimmune signs; however, the factors that trigger excessive innate activation have not been defined. Neutrophil extracellular traps (NETs) emerged as major initiating factors in patients with diseases such as systemic lupus erythematosus and rheumatoid arthritis. In this study we explored the possible involvement of aberrant neutrophil functions in patients with WAS. We evaluated the expression of a set of granulocyte genes associated with NETs in a cohort of patients with WAS and the presence of NET inducers in sera. Using a mouse model of WAS, we analyzed NET release by WASp-null neutrophils and evaluated the composition and homeostasis of neutrophils in vivo. By using depletion experiments, we assessed the effect of neutrophils in promoting inflammation and reactivity against autoantigens. Transcripts of genes encoding neutrophil enzymes and antimicrobial peptides were increased in granulocytes of patients with WAS, and serum-soluble factors triggered NET release. WASp-null neutrophils showed increased spontaneous NETosis, induced IFN-I production by pDCs, and activated B cells through B-cell activating factor. Consistently, their depletion abolished constitutive pDC activation, normalized circulating IFN-I levels, and, importantly, abolished production of autoantibodies directed against double-stranded DNA, nucleosomes, and myeloperoxidase. These findings reveal that neutrophils are involved in the pathogenic loop that causes excessive activation of innate cells and autoreactive B cells, thus identifying novel mechanisms that contribute to the autoimmunity of WAS.


The French Observational Cohort of Usual Smokers (FOCUS) cohort: French smokers perceptions and attitudes towards smoking cessation.
Despite increasing governmental anti-smoking measures, smoking prevalence remains at a high level in France. The objectives of this panel study were (1) to estimate smoking prevalence in France, (2) to identify smokers' profiles according to their perceptions, attitudes and behaviour in relation to smoking cessation, (3) to determine predictive factors of quit attempts, and (4) to assess tobacco-related behaviours and their evolutions according to the changes in the smokers' environments. A representative sample of French population was defined using the quota method. The identified cohort of smokers was assessed, in terms of smoking behaviour, previous quit attempts, and intention to quit smoking. A response rate of 66% for the screening enabled to identify a representative sample of the French population (N = 3 889) comprising 809 current smokers (21%). A majority of current smokers (63%) had made an attempt to quit smoking. Main reasons for having made the last attempt were cost (44%), social pressure (39%), wish to improve physical fitness (36%), fear of a future smoking-related disease (24%), and weariness of smoking (21%). Few attempts (16%) were encouraged by a physician. In those who used some kind of support (38%), NRT was the mostly used. Relapse was triggered by craving (45%), anxiety/stress (34%), a significant life event (21), weight gain (18%), and irritability (16%). Depression was rarely quoted (5%). Forty percent of smokers declared they intended to quit smoking permanently. Main reasons were cost (65%), physical fitness improvement (53%), fear of a future smoking-related disease (43%), weariness of tobacco (34%), and social pressure (30%). Using a smoking cessation treatment was considered by 43% of smokers that intended to quit. Barriers to smoking cessation were mainly fear of increased stress (62%), irritability (51%), and anxiety (42%), enjoying smoking (41%), and weight concerns (33%). Smoking prevalence and smoking cessation attempts rate were lower in this survey than in previous reports. Cost and social pressure were the main reasons for quitting smoking, maybe an effect of dramatic tax increases and smoking ban.


Risk of second primary malignancies in a population-based study of adult patients with essential thrombocythemia.
To determine the risk of second primary malignancy (SPM) and survival of patients with essential thrombocythemia (ET). We identified all patients with ET diagnosed during 2001 to 2011 from the Surveillance, Epidemiology and End Results (SEER) 18 database. Actuarial and relative survival methods were used to calculate the survival statistics. We utilized the SEER 13 database to calculate SPM. We used multiple primary standardized incidence ratio (SIR) session of the SEER*Stat software (version 8.1.5) to calculate SIR and excess risk of SPM for ET patients. Age standardized five-year cause-specific survival was greater for patients < 50 years vs those ≥ 50 years (99.4% vs 93.5%, P < 0.01). Five-year cause-specific survival was lower for men vs women (70.2% vs 79.7%). A total of 201 patients (2.46%) developed SPM at a median age of 75 years. SPMs occurred at an observed/expected (O/E) ratio of 1.26 (95%CI: 1.09-1.45, P = 0.002) with an absolute excess risk (AER) of 37.44 per 10000 population. A significantly higher risk was noted for leukemia (O/E 3.78; 95%CI: 2.20-6.05, P < 0.001; AER 11.28/10000). ET patients have an excellent cause-specific five-year survival but are at an increased risk of SPM, particularly leukemia, which may contribute to excess deaths.


Transition of Neural Activity From the Chaotic Bipolar-Disorder State to the Periodic Healthy State Using External Feedback Signals.
Chronotherapy is a treatment for mood disorders, including major depressive disorder, mania, and bipolar disorder (BD). Neurotransmitters associated with the pathology of mood disorders exhibit circadian rhythms. A functional deficit in the neural circuits related to mood disorders disturbs the circadian rhythm; chronotherapy is an intervention that helps resynchronize the patient's biological clock with the periodic daily cycle, leading to amelioration of symptoms. In previous reports, Hadaeghi et al. proposed a non-linear dynamic model composed of the frontal and sensory cortical neural networks and the hypothalamus to explain the relationship between deficits in neural function in the frontal cortex and the disturbed circadian rhythm/mood transitions in BD (hereinafter referred to as the Hadaeghi model). In this model, neural activity in the frontal and sensory lobes exhibits periodic behavior in the healthy state; while in BD, this neural activity is in a state of chaos-chaos intermittency; this temporal departure from the healthy periodic state disturbs the circadian pacemaker in the hypothalamus. In this study, we propose an intervention based on a feedback method called the "reduced region of orbit" (RRO) method to facilitate the transition of the disturbed frontal cortical neural activity underlying BD to healthy periodic activity. Our simulation was based on the Hadaeghi model. We used an RRO feedback signal based on the return-map structure of the simulated frontal and sensory lobes to induce synchronization with a relatively weak periodic signal corresponding to the healthy condition by applying feedback of appropriate strength. The RRO feedback signal induces chaotic resonance, which facilitates the transition to healthy, periodic frontal neural activity, although this synchronization is restricted to a relatively low frequency of the periodic input signal. Additionally, applying an appropriate strength of the RRO feedback signal lowered the amplitude of the periodic input signal required to induce a synchronous state compared with the periodic signal applied alone. In conclusion, through a chaotic-resonance effect induced by the RRO feedback method, the state of the disturbed frontal neural activity characteristic of BD was transformed into a state close to healthy periodic activity by relatively weak periodic perturbations. Thus, RRO feedback-modulated chronotherapy might be an innovative new type of minimally invasive chronotherapy.


Temporal bone study of Down's syndrome.
To study temporal bone histopathologic characteristics of the inner ear and middle ear cleft of patients with Down's syndrome. Sixteen temporal bones from eight patients with Down's syndrome were studied. Ten temporal bones from subjects without pathologic ear lesions but with congenital heart disease served as controls. The two-dimensional graphic reconstruction method proposed by Guild and modified by Schuknecht was used to study the cochleas; measurement of the vestibules was based on Igarashi's method. The temporal bone collection of the Otitis Media Research Center, Department of Otolaryngology, University of Minnesota School of Medicine, Minneapolis. Six bones showed short cochlea, and four of six had Mondini's cochlea. The overall cochlear lengths in this study group were notably shorter than those of the controls. The spiral ganglion cell population and two of three vestibular dimensions also were notably less than the controls. Middle ear findings included residual mesenchyme, stapes abnormality, otitis media, and large facial canal dehiscence. The difficulties encountered in rehabilitation of patients with Down's syndrome caused by mental retardation can be compounded by the hearing loss caused by middle and inner ear abnormalities. A complete evaluation of hearing loss and therapy before starting the rehabilitation gives the most favorable outcome.


The HSV1 Tail-Anchored Membrane Protein pUL34 Contains a Basic Motif That Supports Active Transport to the Inner Nuclear Membrane Prior to Formation of the Nuclear Egress Complex.
Herpes simplex virus type 1 nucleocapsids are released from the host nucleus by a budding process through the nuclear envelope called nuclear egress. Two viral proteins, the integral membrane proteins pUL34 and pUL31, form the nuclear egress complex at the inner nuclear membrane, which is critical for this process. The nuclear import of both proteins ensues separately from each other: pUL31 is actively imported through the central pore channel, while pUL34 is transported along the peripheral pore membrane. With this study, we identified a functional bipartite NLS between residues 178 and 194 of pUL34. pUL34 lacking its NLS is mislocalized to the TGN but retargeted to the ER upon insertion of the authentic NLS or a mimic NLS, independent of the insertion site. If co-expressed with pUL31, either of the pUL34-NLS variants is efficiently, although not completely, targeted to the nuclear rim where co-localization with pUL31 and membrane budding seem to occur, comparable to the wild-type. The viral mutant HSV1(17+)Lox-UL34-NLS mt is modestly attenuated but viable and associated with localization of pUL34-NLS mt to both the nuclear periphery and cytoplasm. We propose that targeting of pUL34 to the INM is facilitated by, but not dependent on, the presence of an NLS, thereby supporting NEC formation and viral replication.


Chloroplast Genome of Rambutan and Comparative Analyses in Sapindaceae.
Rambutan (Nephelium lappaceum L.) is an important fruit tree that belongs to the family Sapindaceae and is widely cultivated in Southeast Asia. We sequenced its chloroplast genome for the first time and assembled 161,321 bp circular DNA. It is characterized by a typical quadripartite structure composed of a large (86,068 bp) and small (18,153 bp) single-copy region interspersed by two identical inverted repeats (IRs) (28,550 bp). We identified 132 genes including 78 protein-coding genes, 29 tRNA and 4 rRNA genes, with 21 genes duplicated in the IRs. Sixty-three simple sequence repeats (SSRs) and 98 repetitive sequences were detected. Twenty-nine codons showed biased usage and 49 potential RNA editing sites were predicted across 18 protein-coding genes in the rambutan chloroplast genome. In addition, coding gene sequence divergence analysis suggested that ccsA, clpP, rpoA, rps12, psbJ and rps19 were under positive selection, which might reflect specific adaptations of N. lappaceum to its particular living environment. Comparative chloroplast genome analyses from nine species in Sapindaceae revealed that a higher similarity was conserved in the IR regions than in the large single-copy (LSC) and small single-copy (SSC) regions. The phylogenetic analysis showed that N. lappaceum chloroplast genome has the closest relationship with that of Pometia tomentosa. The understanding of the chloroplast genomics of rambutan and comparative analysis of Sapindaceae species would provide insight into future research on the breeding of rambutan and Sapindaceae evolutionary studies.


[Canine dirofilariasis in the canton of Ticino and in the neighboring areas of northern Italy].
The distribution of canine dirofilariosis in Southern Ticino (Switzerland) and in the neighbouring provinces of Varese and Como (Italy) was investigated. Blood samples were collected from 308 dogs which had remained in the local area and were outdoor-housed, older than 1.5 years and had not been treated previously with preventive or microfilaricidal drugs. Microfilariae of Dirofilaria immitis and D. repens were found in 33 (10.7%) and 17 (5.5%) dogs, respectively. Ten more dogs (3.2%) tested positive for circulating antigens. Four infected dogs lived in Southern Ticino: two harboured D. immitis, one D. repens and one had a mixed infection. In addition, 3887 mosquitoes were captured in five sample sites by means of dog-baited traps. Culex pipiens, Aedes geniculatus and Ae. vexans were the most abundant species. Infective stages of D. immitis were observed in local strains of Ae. geniculatus and Cx. pipiens, following engorgement on a microfilaraemic dog and the successive rearing in laboratory conditions. A chemo-prophylactic scheme in four administrations between July and October is recommended for Southern Switzerland.


Neuroanatomy of Halobiotus crispae (Eutardigrada: Hypsibiidae): Tardigrade brain structure supports the clade Panarthropoda.
The position of Tardigrada in the animal tree of life is a subject that has received much attention, but still remains controversial. Whereas some think tardigrades should be categorized as cycloneuralians, most authors argue in favor of a phylogenetic position within Panarthropoda as a sister group to Arthropoda or Arthropoda + Onychophora. Thus far, neither molecular nor morphological investigations have provided conclusive results as to the tardigrade sister group relationships. In this article, we present a detailed description of the nervous system of the eutardigrade Halobiotus crispae, using immunostainings, confocal laser scanning microscopy, and computer-aided three-dimensional reconstructions supported by transmission electron microscopy. We report details regarding the structure of the brain as well as the ganglia of the ventral nerve cord. In contrast to the newest investigation, we find transverse commissures in the ventral ganglia, and our data suggest that the brain is partitioned into at least three lobes. Additionally, we can confirm the existence of a subpharyngeal ganglion previously called subesophagal ganglion. According to our results, the original suggestion of a brain comprised of at least three parts cannot be rejected, and the data presented supports a sister group relationship of Tardigrada to 1) Arthropoda or 2) Onychophora or 3) Arthropoda + Onychophora.


Cloning, molecular characterization, and expression analysis of Copine 8.
Copines are ubiquitously expressed, phospholipid-binding proteins that have been conserved through evolution. In this paper, we report the cloning and molecular characterization of a new member of the Copine family, Copine 8. This gene has been isolated and characterized using a combination of bioinformatic and experimental approaches. Using an algorithm to cluster ESTs (expressed sequence tags) that are available through the public "GoldenPath" database, Copine 8 was initially identified as a gene predominantly expressed in prostate and testis. Cloning and molecular analysis revealed that this gene is expressed in low-levels in most tissues examined. Two different isoforms of this gene have been isolated. Strongest expression of Copine 8 mRNA is seen in the prostate, heart, and brain. Taken together, this data suggest that Copine 8 may have an important role to play in prostate regulation and development.


Moxetumomab pasudotox for hairy cell leukemia: preclinical development to FDA approval.
Moxetumomab pasudotox (MP) is an immunotoxin that recently received US Food and Drug Administration (FDA) approval for the treatment of hairy cell leukemia (HCL) that has failed at least 2 prior lines of therapy, including a purine analog. MP is a recombinant immunotoxin that consists of an anti-CD22 immunoglobulin variable domain genetically joined to Pseudomonas exotoxin (PE38). Unlike most antibody-drug conjugates, which use a chemical linker, recombinant DNA techniques are used to produce MP. MP and its predecessor, BL22, were initially developed to treat non-Hodgkin lymphoma, acute lymphoblastic leukemia, and HCL. However, MP was found to be particularly effective in HCL due to the high level of CD22 cell-surface expression. The recent pivotal phase 3 trial of MP in relapsed/refractory HCL demonstrated a durable complete remission rate of 30%, and 85% of complete responders achieved minimal residual disease negativity, which is associated with improved disease-free survival outcomes in HCL. In addition to an exceptional depth of response, MP appears to be less immunosuppressive than purine analogs. MP is generally well tolerated but has unique toxicities, including capillary leak syndrome and hemolytic uremic syndrome, which are poorly understood. This review will encompass the preclinical and clinical development of MP, with particular attention to its current indication in HCL.


[Unusual zones of osteitis detected during salvage tympanoplasty].
Three patients were noted to have unusual zones of osteitis during salvage myringoplasty. The first case involved the whole upper wall of the bony canal and was camouflaged by a weeping mucopolypoid carpet. In the second case there was a wide zone of osteitis of the posterosuperior angle of the canal and another smaller zone in the anteroinferior tympanic region. The osteitis in the third case had invaded the total mastoid cortex producing a vast plaque of superficial osteitis which could be removed without difficulty. Diffuse osteomatous reaction of the wall of the canal had resulted. In all three cases a salvage myringoplasty was possible after elimination of the osteitic lesions, although a glue ear persisted with a punctiform perforation in one patient, suggesting tubal dysfunction.


Recommendations for preventing transmission of human immunodeficiency virus and hepatitis B virus to patients during exposure-prone invasive procedures.
This document has been developed by the Centers for Disease Control (CDC) to update recommendations for prevention of transmission of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) in the health-care setting. Current data suggest that the risk for such transmission from a health-care worker (HCW) to a patient during an invasive procedure is small; a precise assessment of the risk is not yet available. This document contains recommendations to provide guidance for prevention of HIV and HBV transmission during those invasive procedures that are considered exposure-prone.


Moderate exercise at energy balance does not affect 24-h leucine oxidation or nitrogen retention in healthy men.
Short-term metabolic experiments have revealed that physical exercise increases the oxidation of leucine, which has been interpreted to indicate an increased requirement for dietary protein in physically active subjects. Because it may be inaccurate to extrapolate measurements of amino acid oxidation made over a few hours to the entire day, we have carried out a continuous 24-h intravenous [1-13C]leucine/[15N]urea tracer study in eight healthy adult men. Their diet supplied 1 g protein.kg-1.day-1, and exercise (mean maximal O2 consumption 46%) was for 90 min during the 12-h fast and 12-h fed periods of the day. Subjects were adapted to the diet and exercise regimen for 6 days. Then, on day 7, they were dressed in the University of Uppsala energy metabolic unit's direct calorimeter suit, were connected to an open-hood indirect calorimeter, and received the tracers. Exercise increased leucine oxidation by approximately 50 and 30% over preexercise rates for fast and fed periods, respectively. This increase amounted to approximately 4-7% of daily leucine oxidation. Subjects remained in body leucine equilibrium (balance -4.6 +/- 10.5 mg.kg-1.day-1; -3.6 +/- 8.3% of intake; P = not significant from zero balance). Therefore, moderate exercise did not cause a significant deterioration in leucine homeostasis at a protein intake of 1 g.kg-1.day-1. These findings underscore the importance of carrying out precise, continuous, 24-h measurements of whole body leucine kinetics; this model should be of value in studies concerning the quantitative interactions among physical exercise, energy/protein metabolism, and diet in humans.


The economic cost of sleep disorders.
To determine the economic cost of sleep disorders in Australia and relate these to likely costs in similar economies. Analysis of direct and indirect costs for 2004 of sleep disorders and the fractions of other health impacts attributable to sleep disorders, using data derived from national databases (including the Australian Institute of Health and Welfare and the Australian Bureau of Statistics). Direct health costs of sleep disorders (principally, obstructive sleep apnea, insomnia, and periodic limb movement disorder) and of associated conditions; indirect financial costs of associated work-related accidents, motor vehicle accidents, and other productivity losses; and nonfinancial costs of burden of disease. These were expressed in US dollars (dollar). The overall cost of sleep disorders in Australia in 2004 (population: 20.1 million) was dollar 7494 million. This comprised direct health costs of dollar 146 million for sleep disorders and dollar 313 million for associated conditions, dollar 1956 million for work-related injuries associated with sleep disorders (net of health costs), dollar 808 million for private motor vehicle accidents (net of health costs), dollar 1201 million for other productivity losses, dollar 100 million for the real costs associated with raising alternative taxation revenue, and dollar 2970 million for the net cost of suffering. The direct and indirect costs of sleep disorders are high. The total financial costs (independent of the cost of suffering) of dollar 4524 million represents 0.8% of Australian gross domestic product. The cost of suffering of dollar 2970 million is 1.4% of the total burden of disease in Australia.


Cognitive and brain correlates of acquired number-colour synaesthetic-like associations.
Synaesthesia is a condition in which one sensory dimension triggers another sensation. The exact contribution of genetic and environmental factors in synaesthesia is not yet fully understood. Most synaesthesia phenotypes involve associations in which the synaesthetic inducer constitutes some form of linguistic/conceptual information acquired during the course of development (e.g., digits, letters, and names of months). To study the role of learning in synaesthesia, we induced synaesthesia by training and examined the behavioural and brain correlates of number-colour associations. We took advantage of the well-known behavioural and neural signature of numbers and used number symbols as inducers. Short (2 weeks) and long (4 weeks) training protocols were conducted with two different groups. Task-related BOLD response was acquired while participants performed Stroop tasks requiring naming colours while ignoring the stimuli (i.e., number symbols, dots, words). If the arbitrary association involving number-colour is automatic, the irrelevant dimension (i.e., numbers) would interfere with the colour response. In addition, if number-colour associations are transferred to linguistic and non-symbolic representations, the passive viewing of stimuli (i.e., words and dots) would disrupt colour naming. Behavioural findings showed automatic associations as both training protocols elicited reliable congruency effects for all stimulus dimensions. Congruency effects following both training protocols produced reliable brain activations in various cortical sites involved in number and in cognitive control. The behavioural and brain patterns reported here support the role of learning in the brain correlates of developmental synaesthesia and provide the first evidence that automatic associations involving different magnitude dimensions can be acquired.


Health professionals' knowledge of driving restrictions following stroke and TIA: experience from a hyperacute stroke centre.
Assessment of fitness to drive (FTD) is important after stroke or transient ischaemic attack (TIA) to ensure that neither patients nor public are at risk. This is particularly important in patients with TIAs or minor stroke as many are discharged directly from emergency departments by a range of health professionals. We assessed stroke-related FTD knowledge among physicians' and allied health professionals' (AHPs) treating patients with stroke at a hyperacute stroke centre. Knowledge of FTD restrictions following a stroke or TIA for domestic and commercial use was assessed in 195 physicians and 45 AHPs using a multiple-choice questionnaire between January and December 2009. The effect of discipline, seniority, previous instruction in FTD restrictions and experience in stroke medicine on FTD was assessed. The correct driving restriction following stroke with domestic and commercial license was known to 29% and 73% of physicians, respectively. For AHPs, these figures were 36% and 20%. For TIA with domestic and commercial license, this was 37% and 43% for physicians, and 44% and 11% for AHPs. 25% of physicians and 11% of AHPs believed that no driving restrictions applied after a TIA. The correct office for reporting FTD was known to 180 (92%) doctors and 31 (69%) AHPs (p=0.0001); 160 (82%) physicians and 27 (60%) AHPs correctly identified that reporting was the patients' responsibility (p=0.001). FTD knowledge correlated with post in stroke (OR 3.2 (95% CI 1.6 to 6.2, p=0.001)) but not with seniority or previous FTD education. Health professionals providing stroke care showed limited knowledge of FTD regulations after minor stroke or TIA. Imparting accurate information on driving restrictions is an important but neglected part of stroke management.


[Drug damage to the liver: role of reactive metabolites and pharmacokinetics].
Metabolism of drugs by the drug-metabolizing enzyme system usually results in the formation of less toxic substances that are readily excreted. A major advance in toxicology, however, has been the observation that the same enzyme system can also activate innocuous drugs into reactive and highly toxic metabolites. Depending on their chemical nature, these metabolites either covalently bind to cellular macromolecules, give rise to toxic oxygen species, or react with membrane lipids to form lipid peroxides. Glutathione, vitamin E and possibly other antioxidants play an important role in protecting the cell from these toxic species. Alteration of a cellular protein by a chemically reactive metabolite may lead to the formation of an antigen and result in an allergic reaction with not only hepatic, but also systemic, manifestations. The formation of toxic metabolites has been postulated in the hepatotoxicity of acetaminophen, isoniazid, halothane, erythromycin and valproic acid. With other drugs, altered pharmacokinetics in the poor metabolizer phenotype and elderly patients may predispose to toxic reactions.


Dynein structure and function.
The structure of dynein isolated from several sources follows the pattern first observed with Tetrahymena 22S dynein, which has three globular heads attached by three flexible strands to a root-like base. Recent biochemical data indicate that there is one ATPase site on each dynein head and that all three heads interact with microtubules in an ATP-sensitive manner. Accordingly, images of dynein in situ can be interpreted in terms of a model for crossbridge action where the roots of the bouquet anchor the dynein to the A-tubule and all three heads reach out to interact with the B-tubule in an ATP-dependent reaction to produce a force for sliding.


Evaluation models and Brazilian health reform: a qualitative-participatory approach.
Throughout the last years, there has been a growing interest in ongoing assessment proposals in Latin America, which are more far-reaching and not traditional. The aim of this study was to analyze the potential of qualitative-participatory evaluation in view of the challenge of strengthening health reforms in the region, particularly those considered progressive, such as the Brazilian case. There is the need to assess health reforms in a rigorous and permanent way, especially the incongruity when using normative models to evaluate health systems based on principles of universality, comprehensiveness, humanization and democratic management. In addition to the demand for assessment instruments and strategies, the Brazilian health reform requires the adoption of evaluation proposals and practices that are founded on other paradigms, distinct from the hegemonic one, in the sphere of health assessment. It is recommended that emerging evaluative models be used, such as those with a qualitative-participatory approach.


Supplemental perioperative steroids for surgical patients with adrenal insufficiency.
Adrenal crisis is a life threatening condition which can be induced by stress during surgery in patients with adrenal insufficiency. This may be prevented by perioperative administration of high doses of steroids. There is disagreement on whether supplemental perioperative steroids are required and, when administered, on the amount and frequency of doses. The review was originally published in 2009 and was updated in 2012. To assess whether it is necessary to administer supplemental perioperative steroids in adult patients on maintenance doses of glucocorticoids because of adrenal insufficiency. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 2); MEDLINE (1966 to February 2012); EMBASE (1980 to February 2012); LILACS (1982 to May 2012); and the databases of ongoing trials. We handsearched the Journal of Clinical Endocrinology and Metabolism (1982 to 2008), Clinical Endocrinology (1972 to 2008), Surgery (1948 to 1994), Annals of Surgery (1948 to 1994), and Anaesthesia (1948 to 2001). The original search was performed in January 2009. We included randomized controlled trials that compared the use of supplemental perioperative steroids to placebo in adult patients on maintenance doses of steroids and who required surgery. Two review authors independently assessed trial quality and extracted data. Study authors were contacted for missing information. We used mean differences and standard deviations to summarize the data for each group. Two trials involving 37 patients were included. These studies reported that supplemental perioperative steroids were not required during surgery for patients with adrenal insufficiency. Neither study reported any adverse effects or complications in the intervention and control groups. Both studies were graded as having a high risk of bias. Owing to the small number of patients, the results may not be representative. Based on current available evidence, we are unable to support or refute the use of supplemental perioperative steroids for patients with adrenal insufficiency during surgery.


Basic regulatory principles of Escherichia coli's electron transport chain for varying oxygen conditions.
For adaptation between anaerobic, micro-aerobic and aerobic conditions Escherichia coli's metabolism and in particular its electron transport chain (ETC) is highly regulated. Although it is known that the global transcriptional regulators FNR and ArcA are involved in oxygen response it is unclear how they interplay in the regulation of ETC enzymes under micro-aerobic chemostat conditions. Also, there are diverse results which and how quinones (oxidised/reduced, ubiquinone/other quinones) are controlling the ArcBA two-component system. In the following a mathematical model of the E. coli ETC linked to basic modules for substrate uptake, fermentation product excretion and biomass formation is introduced. The kinetic modelling focusses on regulatory principles of the ETC for varying oxygen conditions in glucose-limited continuous cultures. The model is based on the balance of electron donation (glucose) and acceptance (oxygen or other acceptors). Also, it is able to account for different chemostat conditions due to changed substrate concentrations and dilution rates. The parameter identification process is divided into an estimation and a validation step based on previously published and new experimental data. The model shows that experimentally observed, qualitatively different behaviour of the ubiquinone redox state and the ArcA activity profile in the micro-aerobic range for different experimental conditions can emerge from a single network structure. The network structure features a strong feed-forward effect from the FNR regulatory system to the ArcBA regulatory system via a common control of the dehydrogenases of the ETC. The model supports the hypothesis that ubiquinone but not ubiquinol plays a key role in determining the activity of ArcBA in a glucose-limited chemostat at micro-aerobic conditions.


Emergency Front-of-Neck Airway Rescue Via the Cricothyroid Membrane: A High-Resolution Computed Tomography Study of Airway Anatomy in Adults.
Emergency front-of-neck airway rescue is recommended in a can't intubate, can't oxygenate clinical scenario. Cannula cricothyroidotomy has been reported as having a high failure rate. Our primary aim was to estimate the angle of the trachea in relation to the horizontal axis in a simulated emergency front-of-neck airway rescue position. Our secondary aims were to estimate the optimal cannula angle of approach and evaluate the anatomical relationship of the cricothyroid membrane (CTM) to adjacent structures. We also assessed whether the CTM lies above or below the neck midpoint, a point equidistant from the suprasternal notch (SSN), and the chin surface landmarks. All measurements were compared between the male and female subjects. Subjects having elective computed tomography of their thorax were consented to have extension of the computed tomography to include their neck. A preliminary radiation dose and risk assessment deemed the additional radiation to be of very low risk (level IIa). Subjects were positioned supinely on the computed tomography table. Standard neck extension was achieved by placing a pillow under the scapulae and a rolled towel under the neck to simulate emergency front-of-neck airway rescue positioning. Fifty-two subjects were included in this study: 31 men and 21 women. The mean angle of the trachea in relation to the horizontal axis was 25.5° (95% confidence interval [CI], 21.8-29.1) in men and 14.0° (95% CI, 11.5-16.5) in women. The mean minimum angles required for hypothetical cannula cricothyroidotomy for men and women were 55.2° (95% CI, 51.8-58.7) and 50.5° (95% CI, 45.4-55.6), respectively. The CTM was located lower in the neck in men compared to women. The CTM was located below the neck midpoint in 30 of 30 (100%) male subjects and 11 of 20 (55%) female subjects (P < .001). The trachea angulates posteriorly in a simulated emergency front-of-neck airway rescue position in supine subjects and to a greater degree in men compared to women (P < .001). The minimum angle required for hypothetical cannula cricothyroidotomy was >45° in the majority (75%) of subjects studied. A steeper cannula angle of approach may be more reliable and warrants further clinical study. If airway anatomy is indistinct and performing a vertical scalpel cricothyroidotomy, consideration should be given to performing this incision lower in the neck in men compared to women.


Active mammalian replication origins are associated with a high-density cluster of mCpG dinucleotides.
ori-beta is a well-characterized origin of bidirectional replication (OBR) located approximately 17 kb downstream of the dihydrofolate reductase gene in hamster cell chromosomes. The approximately 2-kb region of ori-beta that exhibits greatest replication initiation activity also contains 12 potential methylation sites in the form of CpG dinucleotides. To ascertain whether DNA methylation might play a role at mammalian replication origins, the methylation status of these sites was examined with bisulfite to chemically distinguish cytosine (C) from 5-methylcytosine (mC). All of the CpGs were methylated, and nine of them were located within 356 bp flanking the minimal OBR, creating a high-density cluster of mCpGs that was approximately 10 times greater than average for human DNA. However, the previously reported densely methylated island in which all cytosines were methylated regardless of their dinucleotide composition was not detected and appeared to be an experimental artifact. A second OBR, located at the 5' end of the RPS14 gene, exhibited a strikingly similar methylation pattern, and the organization of CpG dinucleotides at other mammalian origins revealed the potential for high-density CpG methylation. Moreover, analysis of bromodeoxyuridine-labeled nascent DNA confirmed that active replication origins were methylated. These results suggest that a high-density cluster of mCpG dinucleotides may play a role in either the establishment or the regulation of mammalian replication origins.


Multisite organic-inorganic hybrid catalysts for the direct sustainable synthesis of GABAergic drugs.
Multisite organic-inorganic hybrid catalysts have been prepared and applied in a new general, practical, and sustainable synthetic procedure toward industrially relevant GABA derivatives. The domino sequence is composed of seven chemical transformations which are performed in two one-pot reactions. The method produces both enantiomeric forms of the product in high enantiopurity as well as the racemate in good yields after a single column purification step. This protocol highlights major process intensification, catalyst recyclability, and low waste generation.


Transferable quinolone resistance in Vibrio cholerae.
Ciprofloxacin was introduced for treatment of patients with cholera in Bangladesh because of resistance to other agents, but its utility has been compromised by the decreasing ciprofloxacin susceptibility of Vibrio cholerae over time. We correlated levels of susceptibility and temporal patterns with the occurrence of mutation in gyrA, which encodes a subunit of DNA gyrase, followed by mutation in parC, which encodes a subunit of DNA topoisomerase IV. We found that ciprofloxacin activity was more recently further compromised in strains containing qnrVC3, which encodes a pentapeptide repeat protein of the Qnr subfamily, members of which protect topoisomerases from quinolone action. We show that qnrVC3 confers transferable low-level quinolone resistance and is present within a member of the SXT integrating conjugative element family found commonly on the chromosomes of multidrug-resistant strains of V. cholerae and on the chromosomes of Escherichia coli transconjugants constructed in the laboratory. Thus, progressive increases in quinolone resistance in V. cholerae are linked to cumulative mutations in quinolone targets and most recently to a qnr gene on a mobile multidrug resistance element, resulting in further challenges for the antimicrobial therapy of cholera.


Temperature dependence of laser-induced fluorescence of nitric oxide in laminar premixed atmospheric-pressure flames.
The temperature dependence of laser-induced NO A (2)?(+)-X (2)? fluorescence in the hot gases of natural gas-air flames, seeded with known quantities of NO, has been determined experimentally by means of a difference method. The flame temperature at three fixed equivalence ratios was changed when the mixture velocity was varied through a water-cooled, flat-flame burner and was measured by coherent anti-Stokes Raman spectroscopy. When the possible reburning of part of the seeded NO is allowed for, the results in the range 1700-2150 K are best described by the temperature dependence obtained from a model in which quenching corrections are neglected, as in the case of a saturated two-level system, when millijoule pulse energies are used. Measurements of the fluorescence intensity at constant seed concentration as a function of equivalence ratio between 0.75 and 1.3 also indicate that quenching corrections are unnecessary under these excitation conditions. Using the measured intensities of the seeded flame as a calibration factor, we determined the absolute NO concentrations as functions of the equivalence ratio at 1 cm above the burner. The results indicate that, with the calibration method presented here, a relative accuracy of 5% should be obtainable.


Evaluation of CSF-Chlamydia pneumoniae, CSF-tau, and CSF-Abeta42 in Alzheimer's disease and vascular dementia.
The potential role of microbiological factors such as Chlamydia pneumoniae (ChP) in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease (AD) and vascular dementia (VD), has been suggested, but the correctness of this hypothesis still needs to be tested. In this study the appearance of ChP in the cerebrospinal fluid (CSF) of 57 AD and 21 VD patients and in 47 controls (CG) as well as the influence of ChP on the levels of tau protein and Abeta42 were investigated. The frequency of ChP occurrence in the AD patient group (43.9%) was significantly higher (p < 0.001) than in the control group (10.6%). In the case of VD patients, 9.5% of this group was positive for ChP. The presence of ChP DNA in the CSF of patients with AD significantly increases the occurrence of this disease (odds ratio = 7.21). Cerebrospinal fluid Abeta42 levels were significantly lower in patients with AD than in the CG (p < 0.001). Cerebrospinal tau protein was significantly higher in AD vs. CG (p = 0.007). However, no relationships between the presence of the bacterium in CSF and the level of either tau or Abeta42 protein were observed. In conclusion, we may suspect that testing for the presence of ChP in CSF, along with the tau and Abeta42 markers, may be used in the clinic diagnosis of AD.


Functional flexibility of the FimH adhesin: insights from a random mutant library.
Type 1 fimbriae are surface organelles of Escherichia coli which mediate D-mannose-sensitive binding to different host surfaces. This binding is conferred by the minor fimbrial component FimH. Naturally occurring variants of the FimH protein have been selected in nature for their ability to recognize specific receptor targets. In particular, variants that bind strongly to terminally exposed monomannose residues have been associated with a pathogenicity-adaptive phenotype that enhances E. coli colonization of extraintestinal locations such as the urinary bladder. In this study we have used random mutagenesis to specifically identify nonselective mutations in the FimH adhesin which modify its binding phenotype. Isogenic E. coli clones expressing FimH variants were tested for their ability to bind yeast cells and model glycoproteins that contain oligosaccharide moieties rich in either terminal monomannose, oligomannose, or nonmannose residues. Both the monomannose- and the oligomannose-binding capacity of type 1 fimbriae could be altered by minor amino acid changes in the FimH protein. The monomannose-binding phenotype was particularly sensitive to changes, with extensive differences in binding being observed in comparison to wild-type FimH levels. Different structural alterations were able to cause similar functional changes in FimH, suggesting a high degree of flexibility to target recognition by this adhesin. Alteration of residue P49 of the mature FimH protein, which occurs within the recently elucidated carbohydrate-binding pocket of FimH, completely abolished its function. Amino acid changes that increased the binding capacity of FimH were located outside receptor-interacting residues, indicating that functional changes relevant to pathogenicity are likely to be due to conformational changes of the adhesin.


Coaxial interleaved stimulation of the thalamus and subthalamus for treatment of Holmes tremor.
Holmes tremor is often treated with multiple deep brain stimulation (DBS) electrodes. The authors describe a novel technique to suppress the tremors by effectively utilizing a single electrode. A 16-year-old boy presented with severe right arm tremor following a midbrain injury. A DBS electrode was implanted into the ventral oralis nucleus of the thalamus (VO) and the subthalamic region. While individual stimulation of each target was ineffective, an interleaved dual stimulation of both targets has been effective for 6 years. Coaxial interleaved stimulation of the VO and the subthalamic region is useful for treating Holmes tremor. The video can be found here: https://youtu.be/tSwGh3vy68c .


Surface waves on a soft viscoelastic layer produced by an oscillating microbubble.
Ultrasound-driven bubbles can cause significant deformation of soft viscoelastic layers, for instance in surface cleaning and biomedical applications. The effect of the viscoelastic properties of a boundary on the bubble-boundary interaction has been explored only qualitatively, and remains poorly understood. We investigate the dynamic deformation of a viscoelastic layer induced by the volumetric oscillations of an ultrasound-driven microbubble. High-speed video microscopy is used to observe the deformation produced by a bubble oscillating at 17-20 kHz in contact with the surface of a hydrogel. The localised oscillating pressure applied by the bubble generates surface elastic (Rayleigh) waves on the gel, characterised by elliptical particle trajectories. The tilt angle of the elliptical trajectories varies with increasing distance from the bubble. Unexpectedly, the direction of rotation of the surface elements on the elliptical trajectories shifts from prograde to retrograde at a distance from the bubble that depends on the viscoelastic properties of the gel. To explain these behaviours, we develop a simple three-dimensional model for the deformation of a viscoelastic solid by a localised oscillating force. By using as input for the model the values of the shear modulus obtained from the propagation velocity of the Rayleigh waves, we find good qualitative agreement with the experimental observations.


Prognostic value of estrogen receptor and Ki-67 index after neoadjuvant chemotherapy in locally advanced breast cancer expressing high levels of proliferation at diagnosis.
Breast cancers expressing high levels of Ki-67, a nuclear marker of cell proliferation, are associated with worse outcome. Recent data from neoadjuvant studies indicate that a single measurement of the nuclear proliferation marker Ki-67 in breast carcinoma during neoadjuvant therapy is strongly predictive of long-term outcome. Secondly, recent literature data indicate that prognostic evaluation with Ki-67 may be better after pre-surgical therapy. A retrospective study from a prospectively maintained clinical database to compare the predictive and prognostic significance of biological markers, assessed before and after neoadjuvant chemotherapy, in locally advanced breast cancer, was performed. The following parameters were considered before and after chemotherapy for their relationship with treatment response and disease-free survival in 64 patients with locally advanced breast cancer: clinical stage, clinical and pathological lymph node involvement, Ki-67, estrogen receptor (ER), progesterone receptor (Pgr), Her2, tumor grade, clinical response, type of surgery performed, and number of chemotherapy cycles administered. The expression of Ki-67 was assessed using immunohistochemistry in pre-therapy tru-cut and post-therapy surgical excision specimens after neoadjuvant chemotherapy; only patients with breast tumors expressing high baseline Ki-67 (≥ 15%) were included in the analysis. In addition, the correlation between pre-chemotherapy biological markers and clinical and pathological response was reported. Post-chemotherapy Ki-67 proliferation index decrease, pre-chemotherapy ER expression and post-chemotherapy ER expression were the only significant prognostic factors adversely influencing disease-free survival in univariate analysis. Her2 overexpression was the only factor to impact on the clinical response. Post-treatment Ki-67 and ER status were predictors of outcome for patients with locally advanced breast cancer and a high pre-chemotherapy proliferation index.


A mirror-image tetramolecular DNA quadruplex.
L-DNA, the mirror image of natural DNA forms structures of opposite chirality. We demonstrate here that a short guanine rich L-DNA strand forms a tetramolecular quadruplex with the same properties as a D-DNA strand of identical sequence, besides an inverted circular dichroism spectra. L- and D-strands self exclude when mixed together, showing that the controlled parallel self-assembly of different G-rich strands can be obtained through L-DNA use.


Nitrate removal with low N2O emission by application of sulfur denitrification in actual agricultural field.
Sulfur denitrification was applied to the agricultural field and the characteristics of the treatment were evaluated from the viewpoints of nitrate removal efficiency and nitrous oxide (N2O) emission. Two actual sites where sulfur denitrification was performed were surveyed. One is a valley bottom field, where groundwater contaminated with nitrate is coming up as spring water. The nitrate concentration in influent was about 45 mgN/L. The other was wastewater from a plastic greenhouse. The nitrate concentration in inflow water was about 200 mgN/L. Nitrate was almost removed by the containers packed with sulfur (S0)-CaCO3 blocks in both sites. Increase of sulfate indicated that nitrate was removed by sulfur denitrification. This was also estimated stoichiometrically from the relationships between the removed nitrate and produced sulfate. The N2O was supersaturated in water at most sampling points and the highest concentration of dissolved N2O reached 900 microgN/L in Saitama in March. It seemed that insufficient nitrate removal caused accumulation of intermediates during denitrification, such as nitrite and N2O, in this month. However, the emission ratio of N2O to the removed nitrate during these processes was kept low, ranging from 0.01 to 0.19%, at both two sites throughout all surveys.


[The influence of the GABA-B receptor antagonists 2-hydoxysaclofen and faclofen on the sedative effect of fenibut and baclofen].
Pretreatment of NIH-Swiss mice with HYS (8 mg/kg) is shown to reduce the inhibiting effect (namely, the reduction of the locomotion rate and the number of horizontal movements) of PHE (80 mg/kg) and do not affect the action of an equipotent dose (4 mg/kg) of BAC. BAC induced shortening of the locomotion period is reduced by HYS. HYS appeared to be inactive with respect to inhibiting effect of PHE. PHE and BAC shortening of the distance covered was insensitive to HYS administration. HYS reduces decrease in the rate and duration of rearings induced by PHE. PHA (8 mg/kg) do not change the sedative effect of PHE and BAC on locomotion, attenuated the PHE-induced inhibition of rearings and increase the effect of BAC. It is suggested that GABA-B receptors affect the inhibitory action of PHE rather strong than that of BAC and differ in the inhibition of horizontal and vertical components of the locomotor activity of mice.


Practice, progress and future directions for physical therapies in Huntingtons disease.
Physical therapies and exercise may have potential as a disease modifying agent in Huntington's disease (HD) and in recent years, there have been several small scale feasibility studies that have shown benefit as a result of physical interventions. When evaluating complex physical interventions, a phased approach using mixed methodology designs that report specific intervention components, adherence, acceptability, adverse events and defined intervention protocols is important for replication and planning of future trials and to ensure potential for implementation in clinical practice. A narrative review of the available literature related to physical activity, physical therapy and exercise in people with HD was performed using a population, intervention, comparison and outcome (PICO) approach. Eight studies met specific inclusion criteria and were reviewed in terms of their systematic conduct and reporting standards. All of the studies (n = 8) provided details of intervention including location and duration. The majority of interventions included balance training activities in combination with other complex activities of daily living that required therapist supervision. Two of the interventions were home based, the remainder were facility or hospital based. None of the studies reported adverse events whilst only 3/8 reported adherence rates which were ranging from 60-80%. In general, limited detail was provided on the specific individual components of the interventions. This review of primary publications and conference proceedings, suggests that researchers working in the field need to focus on clearer reporting of intervention protocols so as to generate a clearer understanding of the impact of exercise and physical therapies on the symptoms of HD, as well as any potential synergistic role alongside the impending disease-modifying interventions.