Second-order coherence properties of amplified spontaneous emission.
Properties of light sources based on amplified spontaneous emission (ASE) are similar to the properties of lasers in many regards. However, even though ASE has been widely studied, its photon statistics have not been settled. There are no reliable theoretical estimates or unambiguous experimental data for the second-order coherence function of photons that characterizes the coherence properties of a light source. Our computer simulation clearly establishes that, independently of pump power, the light produced by ASE is similar to that of a thermal source. This result lays bare the fundamental difference between ASE radiation and laser radiation.


Synthesis and Biological activity of kappa opioid receptor agonists. Part 2: preparation of 3-aryl-2-pyridone analogues generated by solution- and solid-phase parallel synthesis methods.
New analogues of the previously described 3-aryl pyridone KOR agonists have been synthesised by parallel synthetic methods, both in solution- and with solid-phase chemistry, making use of the well known and versatile Mitsunobu, Suzuki and Buchwald reactions. Opioid receptor binding data for the compounds produced is reported.


Structure-activity relationship (SAR) studies of quinoxalines as novel HCV NS5B RNA-dependent RNA polymerase inhibitors.
From chemical compound library screening using an HCV NS5B RNA-dependent RNA polymerase enzymatic assay, we identified a substituted quinoxaline hit with an IC(50) of 5.5 microM. A series of substituted quinoxaline amide derivatives were synthesized based on the hit's pharmacophore, and a good structure-activity relationship was observed. Computer modeling analysis was employed to help comprehend the SAR.


Individual functions of the HAK and TRK potassium transporters of Schwanniomyces occidentalis.
We have cloned the gene encoding the TRK transporter of the soil yeast Schwanniomyces occidentalis and obtained the HAK1 trk1 delta and the hak1 delta TRK1 mutant strains. Analyses of the transport capacities of these mutants have shown that (i) the HAK1 and the TRK1 potassium transporters are the only transporters operating at low and medium K+ concentrations (< 1 mM); (ii) the HAK1 transporter is functional at low pH but fails at high pH; and (iii) the TRK1 transporter functions at neutral and high pH and fails at low pH. At neutral pH, both transporters are functional, but HAK1 is not expressed, except at very low K+ concentrations (< 50 microM) where HAK1 is very effective. TRK1 is also involved in the control of the membrane potential.


Is eczema really on the increase worldwide?
It is unclear whether eczema prevalence is truly increasing worldwide. We sought to investigate worldwide secular trends in childhood eczema. Children (n = 302,159) aged 13 to 14 years in 105 centers from 55 countries and children aged 6 to 7 years (n = 187,943) in 64 centers from 35 countries were surveyed from the same study centers taking part in Phase One and Three of the International Study of Asthma and Allergies in Childhood by using identical validated and translated questionnaires. Eczema was defined as an itchy, relapsing, flexural skin rash in the last 12 months, and it was termed severe eczema when it was associated with 1 or more disturbed nights per week. Annual prevalence changes in relation to average prevalence across Phase One and Three were generally small and differed in direction according to the age of the participants and world region. For children 13 to 14 years old, eczema symptom prevalence decreased in some previously high-prevalence centers from the developed world, such as the United Kingdom and New Zealand, whereas centers with previously high prevalence rates from developing countries continued to increase. In the children 6 to 7 years old, most centers showed an increase in current eczema symptoms. Similar patterns to these were present for severe eczema at both ages. The epidemic of eczema seems to be leveling or decreasing in some countries with previously high prevalence rates. The picture elsewhere is mixed, with many formerly low-prevalence developing countries experiencing substantial increases, especially in the younger age group.


Suppression of transverse ablative Rayleigh-Taylor-like instability in the hole-boring radiation pressure acceleration by using elliptically polarized laser pulses.
It is shown that the transverse Rayleigh-Taylor-like (RT) instability in the hole-boring radiation pressure acceleration can be suppressed by using an elliptically polarized (EP) laser. A moderate J×B heating of the EP laser will thermalize the local electrons, which leads to the transverse diffusion of ions, suppressing the short wavelength perturbations of RT instability. A proper condition of polarization ratio is obtained analytically for the given laser intensity and plasma density. The idea is confirmed by two-dimensional particle-in-cell simulations, showing that the ion beam driven by the EP laser is more concentrated and intense compared with that of the circularly polarized laser.


Impact of Imatinib on the Fertility of Male Patients with Chronic Myelogenous Leukaemia in the Chronic Phase.
Imatinib is a first-line tyrosine kinase inhibitor for treating chronic myelogenous leukaemia (CML) and has greatly improved the prognosis of this disease. An increasing number of CML patients of reproductive age are diagnosed each year, and the impact of imatinib on fertility is a major concern. Providing useful advice to these patients regarding the choice of their therapeutic treatment is very important. This study examined the impact of imatinib on the fertility of male patients with CML in the chronic phase. We performed a study of 48 adult male CML patients in the chronic phase (CML-CP), 50 healthy control subjects, and 10 male patients with infertility. Imatinib levels in semen and plasma were measured using high-performance liquid chromatography/mass spectrometry. We examined the effects of imatinib on sperm parameters and the male reproductive system using a computer-assisted sperm assay and ultrasound, respectively. We analysed sex hormone levels in the sera of CML-CP patients using an enzyme-linked immunosorbent assay. Imatinib levels in semen were comparable to plasma levels in CML-CP patients. CML-CP patients treated with imatinib exhibited reduced sperm density, counts, survival rates, and activity. Ultrasound demonstrated that the shape and size of the testis and epididymis in CML-CP patients undergoing imatinib treatment were normal. However, 19 of these patients exhibited a hydrocele in their tunica vaginalis, with a large dark area of effusion (0.7-2.9 cm in width). Sex hormone levels in the sera of the CML-CP patients were normal. These results suggest that imatinib crosses the blood-testis barrier and reduces sperm density, sperm count, survival rates, and activity in CML-CP patients. However, imatinib did not affect the structure of reproductive organs or sex hormone levels.


Capsicum oleoresin: development of an in-soil repellent for pocket gophers.
A pre- and post-monitoring study was conducted of the potential use of capsicum oleoresin as an in-soil repellent for northern pocket gophers (Thomomys talpoides). Pocket gophers were captured in irrigated alfalfa (Medicago sativa L), affixed with radio transmitters, and monitored daily for location. Six plots (4.87 x 4.87 m) each were randomly assigned to capsicum oleoresin and soybean oil treatments; these were set up based upon the centers of initial core areas of gophers. Mean (+/-SD) volumes of capsicum oleoresin and water and soybean oil and water mixtures (10 + 90 by volume) dispensed onto plots equaled 178.5 (+/-4.7) and 175.7 (+/-14.0) liters, respectively. Movements (m) of the radio-transmitted gophers from plot centers were computed for four daily readings (i.e., 0801-1000, 1101-1300, 1501-1700 and 1801-2000 h). Spectrophotometric analysis of soil samples from capsicum oleoresin plots validated the presence of capsicum on plots and the absence of capsicum on placebo- and off-plot locations. Analysis of variance for movement distances of gophers yielded a Date main effect [F(11, 103) = 2.08, P < or = 0.03] and a Date x Reading (time) interaction [F(32, 299) = 3.21, P < or = 0.01]. Results showed that gophers were located farther from plot centers for the 0801-1000 and 1501-1700 h telemetry readings for < or =3 days post-chemical application-a probable 'disturbance' effect rather than a chemical-induced avoidance. In a prior laboratory study, capsicum oleoresin and soil treatments of 1.5% w/w capsicum caused nearly a 50% decrease in soil contact time by gophers relative to placebo-exposed control animals. This implies that procedural variables warrant revision before abandoning this approach. The potential for soil insertion of repellents as a technique for expelling pocket gophers from territories and some methodological changes for future research of the technique are discussed.


Permeability of the porcine iris stroma.
Current literature has not considered or provided any data on the permeability of the iris stroma. In this study, we aimed to determine the hydraulic permeability of porcine irides from the isolated stroma. Fifteen enucleated porcine eyes were acquired from the local abattoir. The iris pigment epithelium was scraped off using a pair of forceps and the dilator muscles were pinched off using a pair of colibri toothed forceps. We designed an experimental setup, based on Darcy's law, and consisting of a custom 3D-printed pressure column using acrylonitrile butadiene styrene (ABS) plastic. PBS solution was passed through the iris stroma in a 180° arc shape, with a column height of approximately 204 mm (2000 Pa). Measurements of iris stromal thickness were conducted using optical coherence tomography (OCT). To measure flow rate, we measured the mass (volume) of PBS solution using a mass balance in approximately 1 min. Histology was performed using hematoxylin and eosin (H&E) and anti-smooth muscle antibody (anti-α-SMA) for validation. The permeability experiments demonstrated that the iris stroma is a biphasic tissue that allows fluid flow. Our image processing results determined the area of flow to be 7.55 mm2 and the tissue thickness to be between 180 and 430 μm. The hydraulic permeability of the porcine stroma, calculated using Darcy's law, was 5.13 ± 2.39 × 10-5 mm2/Pa•s. Histological and immunochemical studies confirmed that the tissues used for this permeability study were solely iris stroma. Additionally, anti-α-SMA staining revealed staining specific for stromal blood vessels, with the notable absence of dilator and sphincter muscle staining. Our study combined experimental microscopic data with the theory of biphasic materials to investigate the hydraulic permeability of the iris stroma. This work will serve as a basis on which to validate future biomechanical studies of human irides with which may ultimately aid disease diagnosis and inform the design of novel treatments.


Antihypertensive effects of CI-907 (indolapril): a novel nonsulfhydryl angiotensin converting enzyme inhibitor.
CI-907 is a new orally active nonsulfhydryl angiotensin converting enzyme (ACE) inhibitor. Monoester (prodrug) and diacid forms produced concentration related ACE inhibition in guinea-pig serum (IC50 for monoester, 1.7 X 10(-7) M and for diacid, 2.6 X 10(-9) M). In isolated rabbit aortic rings and in rat and dog autonomic studies, CI-907 is highly specific in suppressing the contractile or pressor responses to angiotensin I. In two-kidney, one-clip Goldblatt hypertensive rats, single daily doses (0.03-30 mg/kg p.o.) produced dose-dependent decreases in blood pressure; 3 mg/kg lowered blood pressure to normotensive levels. In the spontaneously hypertensive rat, subacute administration of CI-907 (30 mg/kg/day for 5 days) produced the same decrease in blood pressure as that obtained in the renal hypertensive rat. In diuretic-pretreated renal hypertensive dogs, 10 mg/kg normalized blood pressure. For equivalent drops in blood pressure, heart rate increases were less in CI-907 than in enalapril-treated renal hypertensive dogs. No side effects were observed with CI-907 in any of the conscious animals. The antihypertensive response to CI-907 (0.03-1.0 mg/kg p.o.) was found to correlate with inhibition of vascular tissue ACE, but not plasma or brain ACE in two-kidney, one-clip renal hypertensive rats. These studies indicate that CI-907 is a potent antihypertensive agent with a heart rate profile different from enalapril.


[Pediatric epidural catheterization in Japan: a postal survey of current status in university hospitals].
Despite widespread use of epidural catheter for post-operative pain management in adults, its prevalence of use for pediatric patients in Japan has not been clarified. Postal survey had been conducted of the anesthesia departments of university hospitals (105 institutions) throughout the country. Information was requested on hospital policy of indication and technique of pediatric epidural catheterization. Methods of pain management for typical pediatric surgical patients were also investigated. The response rate was 68.6%. Of these respondents, 36 institutions (50%) use epidural catheter for pediatric post-operative pain treatment. However, the indication and/or policy of epidural catheterization were significantly different among hospitals. The most common reason for avoiding pediatric epidural catheter placement was fear of nerve injury during epidural puncture in unconscious patients. Pain management strategies for post-operative children were also divergent. There was little consensus regarding pediatric epidural analgesia and post-operative pain management among anesthesiologists in Japanese university hospitals.


Natural cellulose fiber derived hollow-tubular-oriented polydopamine: In-situ formation of Ag nanoparticles for reduction of 4-nitrophenol.
A facile method was reported to achieve hollow-tubular-oriented polydopamine (HTO-PDA) layer using natural kapok fiber (KF) as the bio-template without any pretreatments by altering hydrophobic fiber into hydrophilic one. Subsequently, the HTO-PDA can be utilized for direct in-situ deposition of Ag nanoparticles (NPs). The structures of pristine fiber and HTO-PDA, as well as the resulting Ag NPs attached HTO-PDA (Ag@HTO-PDA) were well characterized by means of scanning electron microscopy (SEM) coupled energy dispersion spectrum (EDS), x-ray diffraction (XRD), transmission electron microscopy (TEM), thermogravimetric analysis (TGA) and Fourier transform infrared (FTIR) spectroscopy. Due to the presence of relatively uniform Ag NPs attached onto PDA layer, Ag@KF-HTO-PDA shows stable catalytic ability towards the reduction of 4-nitrophenol into its amino derivative. Further, this method was used for facile fabrication of Calotropis gigantea fiber derived, surface-functionalized material. The experimental data demonstrated also its excellent catalytic efficiency towards 4-nitrophenol reduction.


7. Whiplash-associated disorders.
Whiplash-associated disorders are comprised of a range of symptoms of which neck complaints and headaches are the most significant spine related. In the acute and sub-acute stage of the disorder, conservative treatment for minimally 6 months is recommended, active mobilization is slightly better than passive treatment. Thereafter, interventional treatment may be considered. The available evidence for injection of Botulinum toxin A (2 B-) and intra-articular corticosteroid injections (2 C-) supports a negative recommendation. Radiofrequency treatment of the ramus medialis (medial branch) of the ramus dorsalis is recommended (2 B+).


Changing definitions of women's health: implications for health care and policy.
To present an overview of how and why normative conceptions of women's health are changing and to discuss some implications of definitional shifts in the context of the changing U.S. health care system. The paper describes the historical development of views of women's health and health care, contrasts the biomedical and biopsychosocial perspectives on women's health, and presents some evidence of challenges and opportunities for change in health care and policy. While women's health has generally been equated with reproductive functions, expanded definitions focus on health through the life span and in the context of women's multiple roles and diverse social circumstances. This expanded view highlights the limitations of health services and policy based on narrower conceptions and program mandates and the need for strategies for integrated, continuous care. There is evidence of change in women's health care, including in Title V programs. New understandings of women's health are particularly relevant to maternal and child health programs, which are positioned to provide model approaches for improving women's health care.


Purification and properties of glycerol:NADP+ 2-oxidoreductase from Schizosaccharomyces pombe.
Glycerol:NADP+ 2-oxidoreductase (EC 1.1.1.156) was isolated from Schizosaccharomyces pombe, purified and characterized. It had an Mr of 57,000, and SDS-PAGE revealed two polypeptides, of Mr 25,000 and 30,000. Its coenzyme requirement was satisfied exclusively by NADP. The pH optimum for glycerol oxidation was 9.5, for dihydroxyacetone reduction 6.0. Rates of oxidation with some structurally related diols were three- to six-fold lower than for glycerol, while glyceraldehyde and other carbonyl compounds showed negligible rates of reduction. Neither monovalent nor divalent cations activated the enzyme. Apparent Km and Vmax values were determined. The enzyme is similar to glycerol dehydrogenases isolated from Mucor javanicus and from Dunaliella parva but differs considerably from the glycerol:NAD+ 2-oxidoreductase of S. pombe.


Multidimensional reference regions for IGF-I, IGFBP-2 and IGFBP-3 concentrations in serum of healthy adults.
The insulin-like growth factor (IGF) system exerts many effects on the growth and differentiation of both normal and malignant cells. The serum concentrations of insulin-like growth factor I (S-IGF-I), insulin-like growth factor-binding protein 2 (S-IGFBP-2) and insulin-like growth factor-binding protein 3 (S-IGFBP-3) and their inter-relations may differ in certain disease states from those seen in healthy individuals. To estimate age-, gender- and body mass index (BMI)-specific univariate, bivariate and trivariate 95% reference regions for these components in healthy adults and present indices that will facilitate interpretation of patient observations in relation to these reference regions. Blood samples were taken in the morning from 427 healthy, non-fasting German blood donors of both genders (age range, 18-79 years; BMI range, 16-44 kg/m(2)). Reference regions were developed with multivariate regression methods. Regression analyses showed that S-IGF-I and S-IGFBP-3 levels decrease with increasing age, whereas S-IGFBP-2 concentrations increase with age (P<0.0001). Females had significantly higher S-IGFBP-3 levels than males (P<0.0001) and similar S-IGF-I and S-IGFBP-2 concentrations. Increasing BMI was associated with decreasing S-IGFBP-2 (P<0.0001), but was not significantly associated with the concentrations of the other two analytes. Controlling for age, gender and BMI, S-IGF-I and S-IGFBP-3 were positively correlated (r=0.58), whereas S-IGF-I and S-IGFBP-2, and S-IGFBP-2 and S-IGFBP-3 were negatively correlated (r=-0.11 and r=-0.18, respectively). Based on the regression models, which were controlled for age, gender and BMI, two- and three-dimensional 95% reference regions with associated patient indices were described for each pair of analytes and for the trio of analytes, respectively. The multivariate reference regions developed in this study should be useful in identifying patients with an abnormal IGF-IGFBP axis. It is suggested that introducing multidimensional reference regions and the described patient indices into clinical practice may aid monitoring of the safety of GH therapy. These patient indices may also be useful in the assessment of cancer risk.


bac genes for recombinant bacilysin and anticapsin production in Bacillus host strains.
The genes encoding the biosynthesis of the dipeptide bacilysin and its antibiotic constituent anticapsin were isolated from several strains of Bacillus subtilis as well as B. amyloliquefaciens and B. pumilus. The ywfBCDEF genes of B. subtilis 168 were shown to carry the biosynthetic core functions and were renamed bacABCDE. Mutation of the bacD gene or transformation of the bacABC genes into a B. subtilis Delta (ywfA-bacABCDE) deletion mutant led to the accumulation of anticapsin, which was fourfold higher after transformation of the bacABC genes into a bacD mutant. The genes bacD and bacE proved to encode the functions of amino acid ligation and self-protection to bacilysin, respectively. Amplification of the bacABCDE gene cluster in a bacAB gene-deficient host strain of B. amyloliquefaciens resulted in a tenfold bacilysin overproduction. Some host strains required distinct glucosamine and yeast extract supplements in order to prevent suicidal effects of the recombinant antibiotic production. The bac genes from different Bacillus species revealed the same arrangement and 72.6-88.6% of sequence identity.


The ethics of tobacco advertising and advertising bans.
In this chapter, I will examine the main ethical parameters of the arguments pertaining to the alleged 'right' to advertise tobacco products and those maintaining that it should be banned. In particular, I will explore the ethics of the adoption of 'partial' bans on tobacco advertising, since there are now few countries which do not restrict tobacco advertising in some way.


Transdermal macromolecular delivery: real-time visualization of iontophoretic and chemically enhanced transport using two-photon excitation microscopy.
To investigate the transdermal delivery of a model macromolecule by passive and iontophoretic means following pretreatment with C12-penetration enhancers and to visualise transport across human stratum corneum (SC) in real time. Transport studies of dextran, labelled with fluorescent Cascade Blue (D-CB: M(R) = 3 kDa) across human stratum corneum, were conducted during passive and iontophoretic modes of delivery following pretreatment with either dodecyltrimethylammonium bromide (DTAB), sodium dodecyl sulphate (SDS) or Azone. Size-exclusion chromatography was used to assess maintenance of dextran structural integrity throughout experimental lifetime. Two-photon excitation microscopy was employed to visualise real-time dextran transport during current application. The positively charged C12-enhancer DTAB elevated passive D-CB steady-state flux (J(ss)) and was the only enhancer to do so above control during iontophoresis. The negatively charged SDS had the least effect during both stages. On-line macromolecular transport was visualised, indicating both inter- and intra-cellular pathways across SC during current application. No transport was visible across untreated SC during passive transport. Use of a positively charged enhancer may improve J(ss) of anionic macromolecular penetrants during passive and iontophoretic delivery. On-line visualisation of iontophoresis across SC was possible and can provide mechanistic insight into SC transport pathways.


Cryosurgical modification of retrograde atrioventricular conduction. Implications for the surgical treatment of atrioventricular nodal reentry tachycardia.
Paroxysmal supraventricular tachycardia resulting from atrioventricular nodal reentry is a common arrhythmia that usually responds to medical therapy. When atrioventricular nodal reentry tachycardia is refractory to medical therapy, cryoablation or endocardial catheter ablation of the His bundle has been employed to protect the ventricles from the tachycardia. However, these techniques necessitate implantation of a permanent ventricular pacemaker. A cryosurgical procedure that ablates the anatomic-electrophysiologic substrate for atrioventricular nodal reentry tachycardia while preserving antegrade atrioventricular conduction has been described. The purpose of the present study was to determine the effects of this procedure on retrograde atrioventricular conduction and on the ventricular echo phenomenon in particular. Thirty adult mongrel dogs underwent either the cryosurgical procedure (n = 20) or a sham operation (n = 10). The animals were studied either immediately postoperatively (acute cryosurgery group and control group, n = 10 for each group) or 14 weeks postoperatively (chronic cryosurgery group, n = 10). Decremental ventricular pacing and programmed premature ventricular pacing protocols were used to determine the retrograde atrioventricular nodal conduction time, Wenckebach point, atrioventricular nodal refractory periods, and ventricular echo reflection time. No electrophysiologic alterations were noted in the sham-operated group. In the acute cryosurgery group, the retrograde Wenckebach point, atrioventricular nodal conduction time, functional refractory period of the atrioventricular node, effective refractory period of the atrioventricular node, and ventricular echo reflection time were all significantly prolonged. In the chronic cryosurgery group, no significant change in ventriculoatrial conduction was noted, but the ventricular echo phenomenon was eliminated in all but one animal. These data further document that this cryosurgical procedure is capable of ablating the anatomic-electrophysiologic substrate necessary for atrioventricular nodal reentry tachycardia while preserving atrioventricular conduction.


Implicit and explicit attitudes towards sport among young elite athletes with high versus low burnout symptoms.
The development of cynical attitudes towards elite sport is a core symptom of athlete burnout and has been associated with dropout from elite sport. To date, this phenomenon has mainly been studied by investigating explicit attitudes towards sport, whereas athletes' automatic evaluations (i.e. implicit attitudes) that have been shown to influence behavior as well were not considered. This study aimed to compare explicit and implicit attitudes towards sport of young elite athletes with high (N = 24) versus low (N = 26) burnout symptoms. Using self-reported measures, general and athlete burnout symptoms were assessed. Additionally, a single-target implicit association test was administered to examine participants' automatic evaluation of sport. Statistical analysis revealed greater emotional/physical exhaustion and sport devaluation in athletes reporting high compared to low burnout symptoms. Implicit attitudes towards sport did not significantly differ between the groups. Furthermore, no significant correlations were observed between different athlete burnout symptoms and implicit attitudes. Athletes with high burnout symptoms show a tendency to explicitly detach themselves from sport, thus fostering sport devaluation as a core symptom of athlete burnout. However, this process does not seem to be reflected in their implicit attitudes towards sport.


Delayed presentation of traumatic splenic arterio-venous fistula.
We report a patient who presented with dyspnoea and was found on examination to have a machinery murmur in the left upper quadrant of the abdomen. The patient had sustained blunt abdominal trauma one year prior to presentation. A diagnosis of splenic arteriovenous fistula was made. The diagnosis and management of delayed presentation of traumatic splenic arteriovenous fistula are discussed.


Glycation of Matrix Proteins in the Artery Inhibits Migration of Smooth Muscle Cells from the Media to the Intima.
Formation and growth of atherosclerotic plaques have serious clinical consequences. One mechanism that occurs during atherogenesis is migration of smooth muscle cells from the middle layer of the artery to the intima, where they proliferate and are transformed into foam cells. This degenerative process is accompanied by glycation, by which proteins are modified and change the biomechanical and biochemical properties. The aim of the study was to determine whether glycation of collagen and elastin building the walls of blood vessels alters the adhesion and rate of myocyte migration. In vitro experiments included migration assays and immunocytochemical staining with anti α-actin, β-catenin anti-collagen type IV antibodies. It turns out that there is a tendency to decrease the number of cells that had migrated through the barrier consisting of glycated proteins as compared to the control. Adversely, the morphology of the cells cultured in the presence of glycated substrates is changed. The lower intensity of β-catenin staining indicates lower adhesiveness of such cells. It is proposed that glycation inhibits migration of smooth muscle cells from the media to the intima, which represents part of the anti-atherogenic mechanism.


[Three vertebral reduction and fixation for revision of lumbar spondylolisthesis].
To analyze the surgical failure of lumbar spondylolisthesis and investigate the clinical effect of three vertebral reduction and fixation in revision of lumbar spondylolisthesis. The clinical data of 19 patients underwent revision to lumbar spondylolisthesis was retrospectively analyzed between January 2009 and December 2012. There were 12 males and 7 females, aged from 36 to 68 years old with an average of 51.5 years. Reduction loss of olisthy segment had in 6 cases, internal fixation loosening or breakage had in 5 cases, slippage aggravating had in 8 cases. Clinical symptoms including lower back pain, unilateral or bilateral lower extremity pain and numbness, etc. Revision surgery was performed with three vertebral pedicle screw internal fixation and posterior decompression, reduction, and posterolateral bone graft between vertebral body. For the first time after surgery pedicle screw loosening or fracture of vertebral body, to switch thick or long pedicle screws implanted into again, or with bone cement perfusion and implanted with pedicle. The condition of intervertebral fusion and clinical effect were respectively assessed by X-ray films and JOA score. All patients were followed up from 10 to 30 months with an average of 18 months. X-ray showed all bone graft obtained fusion and fusion time was from 5.5 to 7 months after revision. No pedicle screws loosening and breakage were found and no reduction loss vertebral body. JOA score were statistically analyzed between preoperative and postoperative at 6 months, in 3 cases with degree I, the score respectively was 13.33 ± 1.53 and 26.33 ± 0.58; in 7 cases with degree II, the score respectively was 12.85 ± 2.19 and 26.29 ± 2.21; in 9 cases with degree III, the score respectively was 12.21 ± 2.73 and 26.44 ± 1.81; there was statistical significance between preoperative and postoperative at 6 months, the improvement rate of JOA was (78.06 ± 3.90)%. For the patients with lumbar spondylolisthesis, the reason of primary surgical failure mainly concerned with internal fixation loosening and breakage, and bone graft no-fusion. Revision surgery using three vertebral pedicle screw internal fixation, can get rigid fixation, complete decompression, bone graft fusion, combined with the guidance of the postoperative functional exercise for patients, can obtain satisfactory therapeutic effects.


Pitting and bubbling artefacts in surface replicas made with silicone elastomers.
Pitting or bubbling on the surface of epoxy resin replicas is a frequently encountered artefact associated with the use of silicone rubber impression materials. Several variants of this type of artefact are illustrated. It is suggested that bubbles or pits form at the mould:epoxy interface during curing of the epoxy, and that they are caused by gas escaping from the mould material itself. Duration of silicone rubber polymerization, base-catalyst ratios, and surface porosity of the object may all influence the occurrence of mould degassing.


The multifunctional polypeptide chains of rabbit-mammary fatty-acid synthase. Stoichiometry of active sites and active-site mapping using limited proteolysis.
Several methods have been used to label active centres on the multifunctional polypeptide chains of rabbit mammary fatty acid synthase. Experiments using [14C]acetyl-CoA or [14C]malonyl-CoA have shown that there is a single non-thiol site which binds either acetyl or malonyl groups, present at a stoichiometry of two per enzyme dimer, and representing an intermediate in the acyl transferase reaction. This adds further support to the view that the two subunits are identical and that each polypeptide chain contains up to seven active centres. However, two novel and independent methods for the quantification of the pantetheine thiol demonstrate that this prosthetic group can be present in sub-stoichiometric amounts. By studying intermediates during limited elastase digestion of fatty acid synthase labelled in different active centres, we have been able to map the positions of four active centres within the polypeptide chain. The thioesterase domain is present in a terminal location on both polypeptide chains as previously reported. The acyl carrier domain (pantetheine thiol) is located in a region of molecular weight 9000 immediately adjacent to the thioesterase domain. The acyl transferase (acyl-O-ester site) and the 3-oxoacylsynthase thiol are located in a region of molecular weight 110000 at the opposite end of the polypeptide chain to the thioesterase domain. The relationship between the disposition of the activities on the multifunctional polypeptide chains of yeast and mammalian fatty acid synthase is discussed.


Sensitivity and cost considerations for the detection and eradication of marine pests in ports.
Port surveys are being conducted in Australia, New Zealand and around the world to confirm the presence or absence of particular marine pests. The most critical aspect of these surveys is their sensitivity-the probability that they will correctly identify a species as present if indeed it is present. This is not, however, adequately addressed in the relevant national and international standards. Simple calculations show that the sensitivity of port survey methods is closely related to their encounter rate-the average number of target individuals expected to be detected by the method. The encounter rate (which reflects any difference in relative pest density), divided by the cost of the method, provides one way to compare the cost-effectiveness of different survey methods. The most cost-effective survey method is site- and species-specific but, in general, will involve sampling from the habitat with the highest expected population of target individuals. A case study of Perna viridis in Trinity Inlet, Cairns, demonstrates that plankton trawls processed with gene probes provide the same level of sensitivity for a fraction of the cost associated with the next best available method-snorkel transects in bad visibility (secchi depth=0.72 m). Visibility and the adult/larvae ratio, however, are critical to these arguments. If visibility were good (secchi depth=10 m), the two approaches would be comparable. Diver deployed quadrats were at least three orders of magnitude less cost-effective in this case study. It is very important that environmental managers and scientists perform sensitivity calculations before embarking on port surveys to ensure the highest level of sensitivity is achieved for any given budget.


Freeform illumination design model for multiple light sources simultaneously.
In this paper, we have proposed an innovative model of freeform illumination design, which differs from the current model that covers almost all of the existing freeform illumination systems. In our model, a freeform illumination system is designed for multiple light sources simultaneously, rather than just for one certain source like the current model. All the sources have the same size, shape, intensity distribution, and other photometric characteristics, but are located at different positions or directions. Each source can individually achieve an illumination pattern on the target plane. All the patterns are expected to have the same size, shape, and illuminance distribution, but the position of each pattern has a linear relationship with the position or direction of the corresponding source. Two new (to our knowledge) illumination functions can be realized in our model, as the light sources are non-single and movable. The first one is the continuous scanning of the illumination pattern on the target plane, and the second one achieves a flexible, diverse, and controllable array of illumination patterns on the target plane. As an example, a coaxial freeform illumination system has been designed under the framework of this model, in which multiple collimated light sources are introduced simultaneously. The design method and process of the system are presented. The system is further promoted, and the two new illumination functions are explained in detail based on the design example.


Acute phase response impairs host defense against Pseudomonas aeruginosa pneumonia in mice.
Pseudomonas aeruginosa is a common pathogen in hospital-acquired pneumonia. Especially trauma and postsurgical patients display a profound acute phase protein response and are susceptible to acquiring pneumonia. The objective was to study the influence of the acute phase response induced by sterile tissue injury on pulmonary host defense. Laboratory investigation. Academic medical center. Female C57Bl/6 wild-type mice, 8-10 wks old. Mice were injected subcutaneously with either turpentine or sterile saline (control) in both hind limbs 1 day before intranasal infection with P. aeruginosa. The turpentine-induced acute phase response was associated with 100% lethality after induction of pneumonia, whereas control mice all survived the Pseudomonas infection. In addition, turpentine-injected mice demonstrated much higher bacterial loads in their lungs and an increased dissemination of the infection. The acute phase reaction attenuated lung inflammation during pneumonia, as reflected by histopathology, reduced pulmonary levels of proinflammatory cytokines, and a strongly diminished recruitment of neutrophils to the site of infection. Blood neutrophils harvested from turpentine injected mice displayed a reduced capacity to up-regulate their CD11b/CD18 expression upon stimulation with Pseudomonas ex vivo and during Pseudomonas pneumonia in vivo. Administration of a blocking anti-CD11b antibody to turpentine-injected and control mice almost completely abrogated the difference in bacterial outgrowth, whereas inhibition of the sympathetic nervous system did not affect the impaired pulmonary host defense in mice with an acute phase response. These data suggest that a systemic acute phase response might impair host defense against P. aeruginosa pneumonia, possibly in part by inhibition of CD11b/CD18-dependent neutrophil recruitment.


[An improved quantitative method for evaluation of ischemic injury and neuroprotection in mouse brain slices].
To establish a simpler and more accurate method for evaluating in vitro ischemic injury and neuroprotective effects of drugs through improving experimental instrument and quantitative index in mouse brain slices. An incubation instrument was developed and its application tested. 2,3,5-triphenyltetrazolium chloride (TTC) was used as a substrate to biosynthesize formazan standard in mouse brain slices, and formazan was isolated, purified and identified. Ischemic injury of mouse brain slices was induced by oxygen/glucose deprivation (OGD), the produced formazan from TTC in the cortex and striatum was measured at 490 nm spectrophotometrically. Edaravone and ONO-1078 were added into the incubation medium to observe their neuroprotective effects. The incubation instrument worked well for incubating brain slices and obtaining stable results efficiently. Standard formazan was biosynthesized and purified with a purity of 99.3%, and showed a linear range of 0.05 - 1 mg/ml in absorbance at 490 nm (r=0.9997). OGD decreased formazan production in the cortex and striatum in a duration-dependent manner. Edaravone (0.01 to 1 micromol/L) recovered OGD-induced decrease of formazan production, but ONO-1078 showed no effect. The incubation instrument and quantitative measurement of formazan developed in this study are efficient,accurate and simple for evaluating ischemic injury and neuroprotection,which can be used in screening of neuroprotective drugs in vitro.


Downregulation of microRNA‑660 inhibits cell proliferation and invasion in osteosarcoma by directly targeting forkhead box O1.
The abnormal expression of microRNAs (miRNAs/miRs) has been observed in osteosarcoma (OS), and these differently expressed miRNAs contribute to the occurrence and development of OS by regulating various biological behaviours. Therefore, a comprehensive understanding of the detailed roles of aberrantly expressed miRNAs in OS progression may be favourable to the identification of promising therapeutic strategies for the treatment of patients with this malignancy. The present study demonstrated that miR‑660‑5p (miR‑660) expression was significantly upregulated in OS tissues and cell lines compared with that in normal adjacent tissues and normal human osteoblast hFOB1.19, respectively. miR‑660 downregulation led to a significant decrease in the proliferation and invasion of OS cells. Forkhead box O1 (FOXO1) was predicted as a potential target of miR‑660. The subsequent luciferase reporter assay indicated that miR‑660 directly binds to the 3'‑untranslated region of FOXO1. Furthermore, miR‑660 inhibition increased the FOXO1 expression in OS cells at mRNA and protein levels. Moreover, FOXO1 was downregulated in OS tissues and this downregulation was negatively correlated with miR‑660 levels. Besides, rescue experiments demonstrated that FOXO1 knockdown abolished the effects of miR‑660 knockdown on OS cell proliferation and invasion. These results suggest that miR‑660 may serve oncogenic roles in OS by directly targeting FOXO1. Targeting miR‑660 may be an effective candidate for the treatment of patients with OS.


Direct and Catalytic Amide Synthesis from Ketones via Transoximation and Beckmann Rearrangement under Mild Conditions.
The Brønsted acid-catalyzed synthesis of secondary amides from ketones under mild conditions is described via transoximation and Beckmann rearrangement using O-protected oximes as more stable equivalents of explosive O-protected hydroxylamines. This methodology could be applied to highly rearrangement-selective amide synthesis from α-branched alkyl aryl ketones and performed on a 1-g scale. The presence of water is essential for this reaction, and its role was clarified by isotope-labeling experiments.


An anesthetic approach to amputation and pain syndromes.
Primary anesthetic intervention is a very effective modality in the prevention of phantom limb pain. The first phase is reduction of the preamputation pain by epidural or intrathecal infusion with local anesthetic and opioid. The catheter can be used for the operative phase, along with an intraneural catheter placement, if necessary. The epidural/intrathecal infusion can continue for 2 to 3 days and eventually be converted to a pharmacologic regimen. This can include opioids for surgical pain, along with a tricyclic antidepressant and an alpha-2 adrenergic agonist. If phantom sensation or phantom limb pain develops, gabapentin (Neurontin) is an effective agent for neuropathic pain. Surgical ablative therapy consists of cordotomy, rhizotomy, dorsal root entry zone lesion, or thalamotomy. Other modalities include dorsal column stimulation to facilitate inhibitory descending pathways. An intrathecal delivery system can be placed to infuse clonidine, local anesthetic, and opioid. For pain management, implantable intrathecal delivery systems may become an important tool for the future management of postamputation pain syndrome.


First trimester urinary placental growth factor and development of pre-eclampsia.
To compare urinary placental growth factor (PlGF) concentration at 11(+0) to 13(+6) weeks of gestation in women who subsequently develop pre-eclampsia with normotensive controls. Nested case-control study within a prospective study for first trimester prediction of pre-eclampsia. Routine antenatal visit in a teaching hospital. Fifty-two women who developed pre-eclampsia and 52 controls matched for gestational age and sample storage time. Urinary PlGF concentration and PlGF to creatinine ratio were measured in women who developed pre-eclampsia and their matched controls. Comparisons between groups were performed using Student's t test. Development of pre-eclampsia. In the pre-eclampsia group, the median urinary PlGF concentration (20.6 pg/ml, interquartile range [IQR] 9.1-32.0 pg/ml) and median urinary PlGF to creatinine ratio (1.6 pg/mg, IQR 1.2-2.5 pg/mg) were not significantly different from the control group (11.8 pg/ml, IQR 5.5-29.8 pg/ml, P=0.1 and 1.7 pg/mg, IQR 1.2-2.3 pg/mg, P=0.3, respectively). There were no significant differences between women with early-onset pre-eclampsia requiring delivery before 34 weeks (n=13) and those with late-onset pre-eclampsia (n=39) and between women with pre-eclampsia and fetal growth restriction (FGR) (n=25) and those with pre-eclampsia and no FGR (n=27) in either median PlGF concentration or median urinary PlGF to creatinine ratio. The development of pre-eclampsia is not preceded by altered urinary PlGF concentration in the first trimester of pregnancy.


Age- and sex-related differences in the presentation of paediatric migraine: A retrospective cohort study.
Introduction Although migraine is a common headache complaint in children and adolescents there remains a significant gap in understanding the unique aspects of the disease in these age groups and their evolution with development. The aim of this retrospective cohort study was to identify migraine features that are influenced by age and sex. Methods The headache characteristics of 359 paediatric patients with a clinical diagnosis of migraine from a tertiary paediatric headache clinic were assessed. Patients retrospectively reported headache characteristics during a structured intake interview and clinical exam. Headache characteristics, description and associated symptoms were compared between children (age ≤ 12 years) and adolescents (age > 12 years), and between male and female migraineurs. Results Several migraine features differed significantly with age and/or sex, including: (i) a marked change from a 1:1 sex ratio in children to a 2:1 predominance of girls in adolescents; (ii) a higher frequency of headache attacks per month in adolescents and female migraineurs; (iii) a higher proportion of adolescents endorsed a 'throbbing' pain quality; (iv) a higher proportion of children reporting nausea and vomiting; and (v) a higher proportion of adolescents, particularly female migraineurs, had a diagnosis of a co-morbid anxiety. Conclusion The presentation of migraine, both in terms of its headache characteristics and associated symptoms, appear to vary as a function of age and sex. Given that migraine symptoms have a neural basis, it is not surprising that during the key period of neurodevelopment from childhood to adolescence this may impact their presentation.


Simulation-based training to teach nurses skills in falls assessment and prevention.
A simulation-based training course was designed to support the development of nurses' skills in falls assessment and prevention. National guidance on falls risk assessment and prevention was used to develop the course content. The course enabled participants to practise real-life scenarios in a safe environment, reflect on their performance and receive feedback from their peers. The post-course evaluations showed positive feedback with all the nurses reporting benefit from this style of learning. They all thought their participation would have a significant effect on their clinical practice and aid their ability to care for patients who had fallen. On an organisational level, the trust has seen an 11% reduction in the number of falls since the training was introduced in 2016.


Stimulatory effects of growth hormone and thyroxine on the concentration of gangliosides in the Snell dwarf cerebrum.
The concentration of gangliosides in the Snell dwarf mouse cerebrum was monitored from postnatal day 5 to day 40. In the dwarf cerebrum, the concentration of total gangliosides increased up to postnatal day 20 and then stopped, whereas in the control cerebrum, it continued to increase up to postnatal day 40. At postnatal day 40, the ganglioside level in the dwarf cerebrum was 70% of that in the control cerebrum. Among the ganglioside species, the concentrations of GM4, GM2, GM1, GD1a, GD3, GD1b, GT1b, and GQ1b were significantly lower in the dwarf cerebrum than in the controls at postnatal day 40. The reduced concentrations of ganglioside species GM2, GD1a, GD3, GD1b, and GQ1b were completely restored by administration of bovine growth hormone (GH) during the first 20 days of postnatal life. The reduced concentration of the GM1 and GM4 species were most efficiently restored by administration of bovine GH plus thyroxine (T4) during the second 20 days of postnatal life. These results indicate that the lower ganglioside concentrations in the dwarf cerebrum can be elevated by hormone therapy and that there exist distinct GH and T4 actions on the enzymes participating in ganglioside metabolism.


The proenkephalin gene (PENK) and opioid dependence.
We tested the hypothesis that the alleles at the (CA)n repeat of the proenkephalin gene (PENK) might be associated with opioid addiction in 31 non-Hispanic Caucasian subjects with opioid dependence (heroin), 89 ethnically matched subjects with substance dependence other than opioid dependence and 132 controls. Among the subjects with opioid dependence, 66% carried the > or = 81 bp allele compared with 40% of subjects with other types of substance abuse (chi2 = 11.31, p < 0.004) and 49% of controls (chi2 = 6.0, p < 0.015). These results are consistent with a role of the PENK gene in opioid dependence.


Insights into the activation mechanism of the visual receptor rhodopsin.
Recent advances in the structural biology of GPCRs (G-protein-coupled receptors) have provided insights into their structure and function. Comparisons of the visual and ligand-activated receptors highlight the unique elements of rhodopsin that allow it to function as a highly sensitive dim-light photoreceptor in vertebrates, as well as the common elements that it shares with the large class A GPCR family. However, despite progress, a number of questions remain unanswered about how these receptors are activated.


Comparative bioavailability of aspirin and paracetamol following single dose administration of soluble and plain tablets.
In this study, the bioavailability of aspirin and paracetamol was compared in plain and soluble combination formulations in fasting, healthy volunteers. Blood samples were taken and Cmax, Tmax and AUC measured at various times following administration of single doses of the two formulations in 12 subjects. The rapidity of uptake of aspirin following administration of a soluble formulation suggests significant absorption from the stomach. There was no significant difference in the pharmacokinetic parameters of paracetamol derived from a soluble or plain formulation. A comparison of the uptake of aspirin from the soluble aspirin formulation with paracetamol from either plain or soluble tablets showed that aspirin entered the plasma and achieved peak levels significantly more quickly. However, the half life of paracetamol was significantly longer than that of aspirin. These findings suggest that onset of analgesia should be more rapid following dosing with soluble aspirin, a conclusion supported by comparative efficacy studies conducted with differing formulations of aspirin.


Valuing whole complex lives: Young adults' experiences of recovery-related principles in mental healthcare in the United States.
One in five young adults (aged 18-25 years) in the United States experiences a past year mental disorder, commonly including depression or anxiety. Yet, 1.5 million each year do not receive needed mental health services and are unlikely, in general, to seek formal mental healthcare. We aimed to inform the development of a novel programme for young adult mental health by first eliciting their positive and negative prior experiences with mental health providers. Four focus groups with 19 young adults (aged 19-26 years) recruited from the community and with moderate to severe depression and/or anxiety were conducted in 2018 in a western US state. Participants' prior experiences with services/providers were elicited along six pre-defined recovery-related concepts: feeling listened to and validated, inclusivity, full information and consent, hope and optimism, connectedness, and change. Focus groups were audio-recorded, transcribed verbatim and uploaded into NVivo version 12 software. Two independent coders used deductive thematic analysis to identify patterned responses. Feeling listened to and validated appeared as a cornerstone of other recovery concepts. Participants discussed past negative experiences with psychiatrists and regret for being put on medications in their teenage years without information or options. Hope and optimism were low because of a general focus by professionals to address immediate symptom-based issues, rather than on improving their overall lives. Service providers' focus on medication-taking, and other one-size-fits-all tools, was interpreted as lacking a sincere desire to help. Young adults were particularly sensitive to inauthentic interactions and superficial strategies, which left them craving care that incorporated their whole lives, acknowledged biopsychosocial interconnections and prioritised improving their lives over 'feeling better' in a given moment. Mental health providers should consider developing programmes that shift focus away from an exclusively medical understanding of distress and towards holistic, educational or relational approaches that value body, mind, self-exploration and authentic connection.


[Missed malignant melanoma: legal considerations].
Malignant melanoma may be missed both clinically and histopathologically. The appearance of metastases after local excision of a skin lesion which was not recognized as melanoma indicates a diagnostic error. In a lawsuit three things have to be proven: that the doctor has behaved negligently, that the patient has been damaged and that there is a causal relation between the two. After local excision of a lesion that subsequently proves to be a metastasized melanoma, no damage ('loss of chance') occurs because neither local surgery nor adjuvant therapy influences disease-free survival. These particularities are of importance in legal judgments.


Ratoon rice generated from primed parent plants exhibit enhanced herbivore resistance.
Rice ratooning is practiced in many rice-growing countries for achieving increased rice production with limited labour input. Here, we report that attack by insect herbivores, or treatment with a defense signaling compound in parent plants, can prime anti-herbivore defense responses in subsequent ratoon plants. We compared the defense responses of rice ratoons generated from parent plants that had been either infested by Cnaphalocrocis medinalis (rice leaffolder, LF) caterpillars or treated with methyl jasmonate (MeJA) during vegetative growth, with ratoons generated from control parent plants. Ratoon plants generated from parents receiving prior LF infestation or MeJA treatment exhibited higher jasmonic acid (JA) levels, as well as elevated levels of transcripts of defense-related genes associated with JA signaling. In addition, elevated activities of peroxidase, polyphenol oxidase and trypsin protease inhibitor were observed, as well as enhanced resistance towards subsequent LF infestation. Pre-priming of ratoon defense responses was significantly reduced in plants where expression of OsAOS (allene oxide synthase, involved in JA biosynthesis) or OsCOI1 (CORONATINE INSENSITIVE1, involved in JA perception) was inhibited by RNA interference. Our results indicate that herbivore exposure or MeJA treatment in rice parent plants enhances anti-herbivore resistance in subsequently generated ratoons through priming of JA-mediated defenses.


Alcoholic ketoacidosis: a case report.
A 43-year-old alcoholic presented in coma with ketoacidosis, after three days of nausea and feeling generally unwell, which had been preceded by a prolonged three-week period of heavy alcohol consumption with poor dietary intake. The acidosis responded rapidly to intravenous dextrose. This is the first Scottish report of a case of alcoholic ketoacidosis.


Rapid determination of apixaban concentration in human plasma by liquid chromatography/tandem mass spectrometry: application to pharmacokinetic study.
We described the development and full validation of a rapid, high throughput sensible and accurate LC method using tandem mass spectrometry detection for determining apixaban concentration with [(¹³C, ²H₇]-apixaban as internal standard in human plasma. Plasma pretreatment involved a one-step protein precipitation with methanol. The separation was performed by reverse-phase chromatography on a Luna MercuryMS C18 column (20 mm × 4 mm × 3 μm) column. The multiple reaction monitoring transitions used for quantification were m/z 460.20→443.27 and 460.20→198.99 for apixaban, 468.22→451.30 for [(¹³C, ²H₇]-apixaban in the electrospray positive ionization mode. The method was linear over the concentration range of 5-500 μg/L. The intra- and inter-day precision values were below 14% and accuracy was from 90.0 to 105.8% at all quality control levels. Sample analysis time was less than 10 min including sample preparation. The present method was successfully applied to a pharmacokinetic study following oral administration of apixaban.


[Effect of water stress in partial root zone on response of photosynthesis of Aconitum barbatum].
To study the effect of different water stress mode on photosynthesis characteristics of Aconitum barbaturnm, aimed at providing the theoretical basis for cultivating this kind of plant for the arid area. The transplanted seedlings of A. barbatum were processed with fixed partial root zone drying(TI) ,alternate partial root zone drying(T2) and both partial root zone irrigation (T3) for three cycles,and relative parameters were measured. The net photosynthetic rate (Pn) in the treatment of T2 gradually increased and was higher than that in the treatment of T3 about 6.53%, mainly effected by non-stomatal factors. The water use efficiency (WUE) was higher than that in the treatments of T3 about 25.21%, while the transpiration rate (Tr) and the stomatal conductance was lower than those in the treatment of T1 and T3 separately. The maximum net photosynthesis rate (Pmax),the apparent quantum yield (AQY) and the dark respiration rate (Rd) were higher than those in comparison condition slightly. The alternate partial root zone drying is worth promoting vigorously, and it shall be a rational way to cultivate the A. barbatum under woodland.


Encircled: large-scale purification of replication origins from Mammalian chromosomes.
A novel cloning strategy for sequences comprising mammalian replication origins, described by Mesner et al. (2006) in a recent issue of Molecular Cell, utilizes an origin trapping assay in which replication bubbles are selectively retained in agarose due to their circular nature.


Further characterisation of the inotropic effect of a bufodienolide glycoside--an endogenous ouabain like compound.
A ouabain like compound obtained from toad skin and plasma and identified to be a steroidal bufodienolide glycoside was found to displace ouabain from its binding site and to inhibit Na+-K+ ATPase, and have positive inotropic effects on cardiac muscle. The ionic and rate dependence of this positive inotropy was studied in the frog atrium. The effect was dependent on extracellular potassium, sodium, and calcium concentrations and on the rate of stimulation, which is similar to the properties of cardiac glycosides. Occasionally, the compound gave transient or even negative inotropic responses, as do the glycosides. The action potential configuration was also affected by the compound in the same complex pattern as is that of cardiac glycosides. It is concluded that the endogenous bufodienolide compound has the same physiological effects as cardiac glycosides. Since the same compound is present in toad plasma it may serve as an intrinsic humoral regulator of cardiac contractility. This study is the first detailed characterisation of the cardioactive properties of this compound.


Irreversible suppression of growth hormone-dependent cytochrome P450 2C11 in adult rats neonatally treated with monosodium glutamate.
Neonatal exposure to monosodium glutamate (MSG) permanently blocks growth hormone (GH) secretion, which results in the development of a well-defined syndrome characterized by stunted body growth, obesity and impaired drug metabolism. We have found that restoration of the normal masculine circulating profile of GH (i.e., six daily pulses) by use of an external pumping apparatus is ineffective in restoring the normal expression of hepatic cytochrome P450 2C11, a major GH-dependent drug and steroid metabolizing enzyme that is eliminated by MSG treatment. Moreover, administering GH at two, four or seven plasma pulses per day with amplitudes ranging from physiologic to 7 times normal were similarly ineffective in restoring the expression (at both an activity and mRNA level) of the cytochrome. Additionally, multicytochrome P450-dependent hexobarbital hydroxylase was also unresponsive to GH administration in the MSG-treated rats. Because GH replacement was unable to correct the enzyme defects, our results suggest that the developmental abnormalities produced by neonatal MSG are not simply a result of a GH deficiency per se, but are due to an irreversible insensitivity of the target cell to GH.


Central representation of phantom limb phenomenon in amputees studied with single photon emission computerized tomography.
To explore the possible mechanisms of phantom limb discomfort after amputation, three amputees with phantom limb pain were studied. This study examined the change of regional cerebral blood flow using technetium-99m hexamethylpropyleneamine oxime-single photon emission computerized tomography, which was arranged at the time of severe phantom limb discomfort and after the discomfort subsided or was completely relieved. Nine representative transverse slices parallel to the orbitomeatal line were selected for quantification. The cortical ribbon (2-cm thickness) was equally subdivided into 12 symmetrical pairs of sector regions of interest in each slice. The irregularly shaped regions of interest were drawn manually around the right thalamus and basal ganglion and then mirrored to the left thalamus and basal ganglion. The contralateral to ipsilateral ratio of regional cerebral blood flow for each area was calculated. The intensity of phantom limb pain was evaluated on a 0 to 10 visual analog scale. In Cases 1 and 2, the contralateral to ipsilateral regional cerebral blood flow ratios of multiple areas of the frontal, temporal, or parietal lobes were increased at the time of more severe phantom limb pain, and the ratios were normalized or even decreased when the phantom limb pain subsided. In Case 3, increased contralateral to ipsilateral regional cerebral blood flow ratios were also found over the frontal, temporal, and parietal lobe. However, most of the increased regional cerebral blood flow ratios of regions of interest in the first study persisted in the follow-up study. Also, the regional cerebral blood flow ratios of greater number of regions of interest of the same gyrus and new gyrus were increased. There was no significant right-left difference of regional cerebral blood flow over bilateral thalami and basal ganglia in all three cases. The results suggested that phantom limb pain might be associated with cortical activation involving the frontal, temporal, or parietal cortex, and it may imply the possibility of the existence of an ascending polysynaptic pathway that conveys the uncomfortable phantom limb sensation to the cerebral cortex. These findings may also indicate that reorganization of the cortical blood flow occurs in amputees. However, it is still difficult to conclude that the changes in regional cerebral blood flow were attributable directly to pain. With no comparison group of amputees and because of the small number of cases, it is hard to generalize about cerebrocortical involvement in phantom pain, and it is possible that the findings represent a normal phenomenon seen after 'amputation. Another possibility is that the findings represent increased arousal caused by pain rather than an intrinsic pain pathway. Further study is worthwhile.


A randomized phase II trial of oral topotecan versus docetaxel in the second-line treatment of non-small-cell lung cancer.
This randomized phase II trial evaluated the efficacy and toxicity of oral topotecan compared with intravenous docetaxel in the second-line treatment of patients with non-small-cell lung cancer (NSCLC). Eighty patients were randomized to receive topotecan (2 mg per day or 2.5 mg per day fixed dose for 5 of 7 days for 2 weeks) or docetaxel (75 mg/m2) every 21 days. Thirty-nine patients received 138 cycles of topotecan. The overall response rate (RR; ORR) was 8%, median time to progression (TTP) was 1.6 months, median survival was 8.4 months, and the 1- and 2-year survival rates were 36% and 13%, respectively, for patients receiving topotecan. Forty-one patients were randomized, but only 38 patients were actually treated with 136 cycles of docetaxel. The ORR was 8% (7% intent to treat RR), median TTP was 1.4 months, median survival was 7.6 months, and the 1- and 2-year survival rates were 29% and 13%, respectively, for patients receiving docetaxel. Oral topotecan appears to be active and well tolerated when administered as a fixed dose daily for 5 of every 7 days for 2 weeks every 21 days and might provide another treatment alternative for patients with advanced-stage NSCLC.


The blood-brain barrier efflux transporters as a detoxifying system for the brain.
The role played by efflux transport systems across the blood-brain barrier (BBB) in the disposition of xenobiotics in the brain is described. Several drugs and organic anions are transported across the BBB via P-glycoprotein and other carrier-mediated efflux transport systems. Studies using in vitro cultured brain capillary endothelial cells, kinetic analysis, and mdr1a gene knock-out mice have shown that P-glycoprotein, located on the BBB, restricts the entry of vincristine and quinidine to the brain. Brain microdialysis studies have demonstrated that the brain interstitial fluid (ISF) concentrations of quinolone antibiotics are significantly lower than their corresponding unbound serum concentrations. A distributed model analysis supports the finding that efflux transport systems on the BBB restrict distribution of 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxyinosine (DDI), and quinolone antibiotics. A brain efflux index (BEI) method has been developed to provide direct evidence of an efflux transport system for carrying substrates from the cerebrum to the circulating blood across the BBB. The BEI method revealed the existence of carrier-mediated efflux organic anion transport systems for compounds such as p-aminohippuric acid, AZT, DDI, taurocholic acid, BQ-123, and estron sulfate. Moreover, cerebral neurotransmitters such as gamma-aminobutyric acid, L-glutamic acid, and L-aspartic acid are transported from brain to the circulating blood in the intact form via a carrier-mediated efflux transport system. The BBB not only restricts nonspecific permeation from the circulating blood to the brain, but also functions as an active efflux transport system for xenobiotics. Accordingly, the BBB plays a very important role by pumping xenobiotics and some endogenous compounds out of the brain, acting as a central nervous system (CNS)-specific detoxifying system supporting and maintaining normal cerebral function.


[Effects of morbidity mortality conferences. Experience of the Aurore perinatal network from 2005 to 2007].
To assess the impact of morbidity mortality conferences on medical care in case of perinatal death and to point out situations with high risk of inappropriate care. We have prospectively listed in the Aurore perinatal network all the perinatal deaths and their related causes using a controlled declarative system between January 2005 and December 2007. A multidisciplinary committee retrospectively analysed during morbidity mortality conferences the quality of care and subsequently classified the management as appropriate, inappropriate or doubtful. We analysed 687 perinatal deaths. The suboptimal care rates varied between 12 and 13% during the study (nonsignificant). Intrauterine growth restriction (IUGR) was the first cause of stillbirth (25 to 30%). IUGR was not suspected prenatally in more than 50% of the cases. IUGRs were significantly associated with higher rates of inappropriate management when compared to the other aetiologies of stillbirth (20 to 28% vs 7 to 11% respectively, p < or = 0.05). Despite the morbidity mortality conferences, the rate of inappropriate care stayed stable. Identification and management of IUGR fetuses have to be improved to decrease the suboptimal care rate in the Aurore perinatal network.


Knockdown of IRE1ɑ suppresses metastatic potential of colon cancer cells through inhibiting FN1-Src/FAK-GTPases signaling.
The inositol-requiring enzyme 1α (IRE1α) is an endoplasmic reticulum (ER)-resident transmembrane protein and senses cellular unfolded/misfolded proteins. Upon activation, IRE1α removes a 26-bp nucleotide from the mRNA encoding X-box binding protein (XBP) 1 to generate a spliced active form of this transcription factor (XBP1s). Though IRE1α is implicated in development of cancer, the role and underlying mechanism remain unclear. Here, we demonstrate that IRE1α regulates colon cancer cell metastasis through regulating the expression of fibronectin-1 (FN1). We found that knockdown of IRE1α inhibited colon cancer cell migration and invasion in vitro and metastasis in vivo. Knockdown of IRE1α decreased the formation of XBP1s and attenuated the expression of FN1, leading to inhibition of phosphorylation of Src and FAK and inactivation the downstream effector GTPases including RhoA, Rac1 and CDC42. Addition of exogenous FN1 reversed Src/FAK phosphorylation and cell migration inhibited by IRE1α knockdown. We found that XBP1s bound FN1 promoter and acted as a transcription factor to initiate FN1 expression. Our results suggest that IRE1α modulates metastatic potential of colon cancer cells through regulating the expression of FN1.


Histometric study of healing of periodontal tissues in rats after surgical injury. I. Design of a standardized surgical procedure.
A standardized surgical procedure in rats is described which allowed a histometric registration of the repair of cementum, periondontal ligaments and bone, and which eliminated the possibility of interference of pocket epithelium during the healing process. Using an extraoral incision, the lateral surface of the mandible was exposed, and a cavity was cut through the vestibular bone plate, the periodontal ligaments and into the root surface, using a specially designed handpiece and bur. This procedure was performed in 20 male Wistar rats, 9 weeks old. The observation period was 12 weeks. The systematic error, precision and interanimal variation were examined for histometric registrations of the repair of cementum, periodontal ligaments and bone. The precision of the histometric procedures was in this study found to be 5% or less for most of the different structures measured, and the estimated combined systematic errors probably less than 5% for cementum repair. The coefficient of variation in cementum repair among different rats was 24%. This variance has two components, the combined influence of systematic errors and precision of histologic and histometric procedures and the other the biological variance due to inter-animal differences. The precision and systematic errors probably do not account for more than one third of this variance, the remaining two thirds being inter-animal differences. These differences could not be completely controlled in this study in spite of the use of a controlled genetic strain of rats bred in litters of the same size under SPF conditions.


Suppressed serum and urine levels of indoxyl sulfate by oral sorbent in experimental uremic rats.
In uremic patients, the serum concentration of indoxyl sulfate is markedly increased. To determine if oral sorbent (AST-120) suppresses the endogenous synthesis of indoxyl sulfate, it was administered to experimental uremic rats, and the serum concentration and urinary excretion of indoxyl sulfate were quantified by high-performance liquid chromatography. Oral sorbent decreased both the serum concentration and urinary excretion of indoxyl sulfate, suggesting that there was suppression of the endogenous synthesis of indoxyl sulfate by the oral sorbent. Oral sorbent did not decrease the serum concentration and urinary excretion of hippuric acid, but it did alleviate the deterioration of renal function in the experimental uremic rats.


Spatially regulated SpEts4 transcription factor activity along the sea urchin embryo animal-vegetal axis.
Because the transcription of the SpHE gene is regulated cell-autonomously and asymmetrically along the maternally determined animal-vegetal axis of the very early sea urchin embryo, its regulators provide an excellent entry point for investigating the mechanism(s) that establishes this initial polarity. Previous studies support a model in which spatial regulation of SpHE transcription relies on multiple nonvegetal positive transcription factor activities (Wei, Z., Angerer, L. M. and Angerer, R. C. (1997) Dev. Biol. 187, 71-78) and a yeast one-hybrid screen has identified one, SpEts4, which binds with high specificity to a cis element in the SpHE regulatory region and confers positive activation of SpHE promoter transgenes (Wei, Z., Angerer, R. C. and Angerer, L. M. (1999) Mol. Cell. Biol. 19, 1271-1278). Here we demonstrate that SpEts4 can bind to the regulatory region of the endogenous SpHE gene because a dominant repressor, created by fusing SpEts4 DNA binding and Drosophila engrailed repression domains, suppresses its transcription. The pattern of expression of the SpEts4 gene is consistent with a role in regulating SpHE transcription in the nonvegetal region of the embryo during late cleavage/early blastula stages. Although maternal transcripts are uniformly distributed in the egg and early cleaving embryo, they rapidly turn over and are replaced by zygotic transcripts that accumulate in a pattern congruent with SpHE transcription. In addition, in vivo functional tests show that the SpEts4 cis element confers nonvegetal transcription of a beta-galactosidase reporter gene containing the SpHE basal promoter, and provide strong evidence that the activity of this transcription factor is an integral component of the nonvegetal transcriptional regulatory apparatus, which is proximal to, or part of, the mechanism that establishes the animal-vegetal axis of the sea urchin embryo.


Monoclonal antibodies against transitional cell carcinoma for detection of malignant urothelial cells in bladder washing.
The diagnosis of transitional cell carcinoma by cytological examination of exfoliated urinary cells is important in the early detection and followup of patients with this disease. Proper interpretation requires a skilled pathologist. Accuracy also is influenced by collection methods and nonmalignant pathological conditions of the bladder. An immunocytochemical technique using monoclonal antibodies G4 and E7 successfully identified tumor-associated antigens on the surface of transitional carcinoma cells obtained by bladder washings. The method, which uses immunoperoxidase staining, was compared to conventional Papanicolaou staining of bladder washings from 75 patients with and without transitional cell carcinoma. Patients were divided into 4 groups: group 1 (nontumor control)--15 patients with no pathological condition of the bladder or nonmalignant urological diseases, group 2 (nontransitional cell carcinoma)--19 patients with other urological malignancies, group 3-18 patients with active transitional cell carcinoma and group 4-23 patients with a history of transitional cell carcinoma but no evidence of tumor at the time of the washing. The incidence of positive staining in these groups was 0, 5, 78 and 0 per cent, respectively. The diagnostic value of immunoperoxidase staining was similar to that of Papanicolaou staining in the control group and in patients with high grade transitional cell carcinoma, and provided specific morphological criteria not possible by conventional cytology studies. Interpretation of immunoperoxidase staining was difficult in washings with a large number of inflammatory cells if endogenous peroxidase activity was not blocked properly. The application of the immunoperoxidase staining method for diagnosis of low grade tumor is under further investigation.


[Correlation between biochemical markers and coronary angiography in patients with non-ST elevation acute coronary syndromes].
Investigate the correlation between biochemical markers (TNI, CRP and fibrinogen) and anatomical coronary angiographic findings in patients with non-ST elevation acute coronary syndromes (NSTE-ACS). One blood sample was obtained to test for markers, and coronary angiography was performed within the first 72 hours after hospitalization. Univariate analysis was used to search for correlations between the 3 markers and the angiographic findings in the group of patients with an identified ischemia-related artery (IRA), and multivariate analysis was performed to investigate the correlation between these markers and the presence of unstable atherosclerotic lesions solely in the group with a coronary obstruction > 50%. Prospective study conducted with 84 patients, 65.5% of whom were men. In the IRA-identified group, blood levels of the three markers were higher than in the groups with no IRA-identified or with normal coronary arteries. The analysis used to evaluate the IRA-identified group showed significant correlations between TIMI flow and TN-I (p = 0.006), unstable atherosclerotic lesions and TN-I and fibrinogen (p = 0.02 and p = 0.01, respectively), and multivessel disease and CRP (p = 0.0005). The multivariate analysis showed that CRP, fibrinogen and TN-I were independent predictors of unstable atherosclerotic lesions (p = 0.002; p = 0.003 and p = 0.007, respectively). In NSTE-ACS patients, TN-I, CRP and fibrinogen blood levels within the first 10 hours after hospitalization correlated with coronary angiographic findings.


Synthesis and biological activity of some novel trifluoromethyl-substituted 1,2,4-triazole and bis(1,2,4-triazole) Mannich bases containing piperazine rings.
A series of trifluoromethyl-substituted 1,2,4-triazole Mannich base 6 and bis(1,2,4-triazole) Mannich base 7 containing pyrimidinylpiperazine rings via the Mannich reaction were synthesized and characterized by infrared (IR), (1)H nuclear magnetic resonance (NMR), and elemental analysis. The fungicidal tests indicated that most of compounds 6 and 7 possessed excellent fungicidal activity. Among 19 novel compounds, some showed superiority over commercial fungicides Dimethomorph, Thiophanate-methyl, Iprodione, and Zhongshengmycin. Some compounds also exhibited favorable herbicidal activity in the preliminary studies. On the basis of the comparative molecular field analysis (CoMFA), five novel compounds were subsequently synthesized, their activities were estimated fairly accurately, and compounds 6-A1 and 7-A2 displayed good fungicidal activity against Pseudoperonospora cubensis (96.9 and 84.9%) as 6h and 7c, respectively.


Radiobiology of vestibular schwannomas: mechanisms of radioresistance and potential targets for therapeutic sensitization.
Vestibular schwannomas (VS) are benign tumors arising from the Schwann cells of cranial nerve VIII. Historically the prevailing therapy for patients with VS has been microsurgical resection. More recently, stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy have gained acceptance as effective alternatives. Although the side effect profile and rates of tumor control appear to be favorable for SRS, there is a subset of radioresistant tumors that continue to progress despite properly administered radiation treatment. In this review, the authors summarize what is known about the mechanism of radioresistance in VS at the clinical and molecular level. An improved understanding of the radiobiological behavior of VS may help guide appropriate patient selection for SRS and potentially aid in the design of novel therapies to treat radioresistant tumors.


Micro-Raman spectroscopy study of colloidal crystal films of polystyrene-gold composites.
Monolayers and multilayers of polystyrene (PS)-gold composite films prepared by two different deposition methods have been investigated by atomic force microscopy (AFM), scanning electron microscopy (SEM), X-ray diffraction (XRD), and confocal Raman microspectroscopy. The intensity of the 1001 cm(-1) ring breathing mode of PS is used to evaluate the degree of ordering of monolayers and multilayers within a colloidal crystal. The depth profiling capability of confocal Raman microscopy is used to probe the regions inside the fractures in multilayered films. The intensity profile of the 1001 cm(-1) peak revealed the presence of fractures of different shapes with some PS microspheres at the bottom of the fracture. A strong increase in the Raman intensity (by 10(3) times) has been observed when probing the regions where Au nanoparticles are concentrated in aggregates of different shapes. This enhancement is attributed to the surface plasmons generated by the periodic structure of the gold nanoparticles.


Improved preservation of ultrastructural morphology in human spermatozoa using betaine in the primary fixative.
Improved preservation of the ultrastructural morphology of human spermatozoa was obtained by filtration onto a Millipore filter (0.45 micron pore size) followed by fixation for 1 h in a fixative containing 3% glutaraldehyde, 1% formaldehyde and 21 mM betaine in Hepes or cacodylate buffer. Betaine raised fixative osmolality only slightly but markedly improved the ultrastructural appearance of the spermatozoa; it is known to function as an osmoprotectant in other situations, and may protect the cells from osmotic damage during the initial stages of fixation. The method is suitable for oligozoospermic samples as they are concentrated when the seminal plasma passes through the filter. Utilizing fixation after swim-up, it is suitable also for highly viscous semen. The fixative gave equally good preservation of sperm heads and tails and can be stored prior to use. The Millipore filter did not dissolve until placed in acetone prior to embedding, simplifying the exchange of solutions during processing. Improved preservation of rat epididymal ultrastructure was obtained by addition of betaine to the fixative of Ito & Karnovsky (1968), using immersion fixation.


Oestrogen-mediated hormonal imbalance precipitates erectile dysfunction.
Declining testosterone (T) in an aging male offsets the equilibrium between androgen and oestrogen (oestradiol, E(2)) with a resultant increase in E(2)-T ratio. Similar functional hormone imbalance is existent in clinical states of hypogonadism and is likely to arise from exposure of males to environmental oestrogens. The pathophysiological significance of this derangement on erectile function, hitherto unknown, was estimated in sexually mature male rats following acute and chronic treatment with oestrogen. A total of 60 male Sprague-Dawley rats (200-250 g) were divided into control and two treatment groups, administered 0.01 and 0.1 mg of oestradiol through oral gavage daily for 1 week (n=30, acute study) and 12 weeks (n=30, long-term study), respectively. Sexual activity in the presence of hormonally primed female rats and intracavernous pressure (ICP) response to electrical stimulation estimated treatment-induced changes, which were correlated with hormone levels and penile morphology at 12 weeks. Following two to five-fold elevation in serum E(2) levels (and simultaneous reduction in testosterone), there was a significant prolongation of mount, intromission, ejaculation latencies and some decrease in frequencies. The ICP response to nerve stimulation was also impaired in all the treated groups. Histologically, trichrome staining highlighted the cavernosal connective tissue hyperplasia in the long-term study groups. Results of this investigation indicate that oestradiol causes pathophysiological changes in erectile function. These observations provide an indirect evidence for the possible sexual health hazards in man upon inadvertent exposure to environmental oestrogens, ageing and derangement of E(2)-T ratio.


Early embryonic development in the spider Achaearanea tepidariorum: Microinjection verifies that cellularization is complete before the blastoderm stage.
The spider Achaearanea tepidariorum is emerging as a non-insect model for studying developmental biology. However, the availability of microinjection into early embryos of this spider has not been reported. We defined the early embryonic stages in A. tepidariorum and applied microinjection to its embryos. During the preblastoderm 16- and 32-nucleus stages, the energids were moving toward the egg periphery. When fluorochrome-conjugated dextran was microinjected into the peripheral region of 16-nucleus stage embryos, it was often incorporated into a single energid and inherited in the progeny without leaking out to surrounding energids. This suggested that 16-nucleus stage embryos consisted of compartments, each containing a single energid. These compartments were considered to be separate cells. Fluorochrome-conjugated dextran could be introduced into single cells of 16- to 128-nucleus stage embryos, allowing us to track cell fate and movement. Injection with mRNA encoding a nuclear localization signal/green fluorescent protein fusion construct demonstrated exogenous expression of the protein in live spider embryos. We propose that use of microinjection will facilitate studies of spider development. Furthermore, these data imply that in contrast to the Drosophila syncytial blastoderm embryo, the cell-based structure of the Achaearanea blastoderm embryo restricts diffusion of cytoplasmic gene products.


Prevention of life-threatening ventricular tachyarrhythmia by a novel and pure class-III agent, nifekalant hydrochloride.
Nifekalant hydrochloride (NIF) is a novel intravenous class-III antiarrhythmic agent with a pirimidinedione structure that purely blocks the K+ channel without inhibiting beta-adrenergic receptors. The authors investigated the efficacy of NIF for refractory ventricular tachycardia/fibrillation (VT/VF). They studied 30 patients treated with an intravenous infusion of NIF [ 26 men, 4 women; age: 63 +/- 17 (mean +/- SD) years] at a dose of 0.19 +/- 0.14 mg/kg body weight per hour. Sixteen were patients with acute coronary syndrome (ACS), and 14 were patients with chronic structural heart disease (Chr-HD). Amiodarone and sotalol had already been administered to 9 patients with Chr-HD before the administration of NIF. The QT and T peak-end (Tp-e) intervals were measured and corrected by Bazett's method (QTc, cTp-e). The left ventricular ejection fraction was depressed (28 +/- 9%). NIF was effective for preventing VT/VF without proarrhythmia and hemodynamic deterioration in 21 patients (70%; 12 with ACS; 9 with Chr-HD), but ineffective in 4 patients (all with Chr-HD). The QTc prolongation in the responders was more pronounced than in the nonresponders (25% +/- 15% versus 5% +/- 7% increase; P < 0.05). Proarrhythmic torsade de pointes (TdP) developed transiently in the remaining 5 patients in whom the cTp-e was markedly increased compared with that in the responders (93% +/- 49% versus 37% +/- 41% increase; P < 0.05). In conclusion, these findings indicate that the intravenous administration of NIF is useful in the emergent treatment of inhibiting drug-refractory VT/VF, although proarrhythmic TdP owing to an enhancement of transmural dispersion of repolarization needs to be taken into account.


Beta cell replacement for the treatment of diabetes.
The replacement of insulin-producing beta cells by islet transplantation can efficiently reverse diabetes. The recent improvements in clinical results were made possible by transplanting higher islet masses and through the introduction of new immunosuppressive protocols that avoid diabetogenicity. The need for alternatives to continuous immunosuppression, and an unlimited source of glucose-sensitive, insulin-secreting tissue, is emerging. In this review we discuss the various key steps in islet transplantation and offer perspectives for future developments in the replacement of insulin-producing beta cells for the treatment of type I diabetes.


Hearing impairment and socioeconomic factors: a population-based survey of an urban locality in southern Brazil.
To provide the first population-based data on deafness and hearing impairment in Brazil. In 2003, a cross-sectional household survey was conducted of 2,427 persons 4 years old and over. The study population was composed of 1,040 systematically chosen households in 40 randomly selected census tracts (dwelling clusters) in the city of Canoas, which is in the state of Rio Grande do Sul, in southern Brazil. Hearing function was evaluated in all subjects by both pure-tone audiometry and physical examination, using the World Health Organization Ear and Hearing Disorders Survey Protocol and definitions of hearing levels. The socioeconomic data that were gathered included the amount of schooling of all individuals tested and the income of the head of the household. It was found that 26.1% of the population studied showed some level of hearing impairment, and 6.8% (95% confidence interval (CI) = 5.5%-8.1%) were classified in the disabling hearing impairment group. The prevalence of moderate hearing loss was 5.4% (95% CI = 4.4%-6.4%); for severe hearing loss, 1.2% (95% CI = 0.7%-1.7%); and for profound hearing loss, 0.2% (95% CI = 0.03%-0.33%). The groups at higher risk for hearing loss were men (odds ratio (OR) = 1.54; 95% CI = 1.06-2.23); participants 60 years of age and over (OR = 12.55; 95% CI = 8.38-18.79); those with fewer years of formal schooling (OR = 3.92; 95% CI = 2.14-7.16); and those with lower income (OR = 1.56; 95% CI = 1.06-2.27). These results support advocacy by health policy planners and care providers for the prevention of deafness and hearing impairment. The findings could help build awareness in the community, in universities, and in government agencies of the health care needs that hearing problems create.


Laser-shock compression of magnesium oxide in the warm-dense-matter regime.
Magnesium oxide has been experimentally and computationally investigated in the warm-dense solid and liquid ranges from 200 GPa to 1 TPa along the principal Hugoniot. The linear approximation between shock velocity and particle velocity is validated up to a shock velocity of 15 km/s from the experimental data, this suggesting that the MgO B1 structure is stable up to the corresponding shock pressure of ∼350 GPa. Moreover, our Hugoniot data, combined with ab initio simulations, show two crossovers between MgO Hugoniot and the extrapolation of the linear approximation line, occurring at a shock pressures of approximately 350 and 650 GPa, with shock temperatures of 8000 and 14,000 K, respectively. These crossover regions are consistent with the solid-solid (B1-B2) and the solid-liquid (B2-melt) phase boundaries predicted by the ab initio calculations.


Molecular components of physiological stress responses in Escherichia coli.
In order to survive under and adapt to different conditions Escherichia coli has evolved elaborate systems that are able to sense and respond to environmental stimuli. Very often, different stresses act on a bacterium simultaneously and a variety of stresses have similar effects on cellular molecules and processes. Therefore, the various stress response systems have to interact (cross talk) with each other. A complex network of global regulatory systems with a multitude of molecular components ensures a coordinated and effective answer. Such regulatory components include DNA, mRNAs, sRNAs, proteins, such as DNA-and RNA binding proteins, alternative sigma factors and two-component systems, as well as small molecular weight molecules, as for example (p)ppGpp. These regulatory systems govern the expression of a plethora of further effectors that aim at maintaining stability of the cellular equilibrium under the various conditions. Using five of the most important stress response systems, we will discuss the roles and mechanisms of such regulatory and effector molecules in more detail. The heat shock response, controlled by the sigma factor sigma32, and the envelope stress response, controlled by the sigma factor sigmaE and the Cpx two-component system, both result in an increased expression of chaperones and proteases in response to misfolded proteins. The cold shock response governs expression of RNA chaperones and ribosomal factors, ensuring accurate translation at low temperatures. The general stress response depends on the sigma factor sigmaS, which controls the expression of more than 50 genes conferring resistance to many different stresses. The (p)ppGpp-dependent stringent response reduces the cellular protein synthesis capacity and controls further global responses upon nutritional downshift. A lot has been learned in recent years about the mechanisms of action of single components. However, the main challenge for the future is to achieve an understanding of the interactions of these components under different physiological conditions.


Value of peri-procedural B-type natriuretic peptide levels in predicting cardiac events after elective percutaneous coronary intervention.
B-type natriuretic peptide (BNP) has diagnostic and prognostic value in a wide variety of cardiac disorders including heart failure and acute coronary syndromes. We aimed to evaluate the prognostic value of baseline and post-procedural BNP levels in predicting major adverse cardiac events (MACE) in stable coronary artery disease (CAD) patients undergoing elective percutaneous coronary intervention (PCI). Blood samples for BNP were obtained before, 1 hour and 24 hours after PCI of stable CAD patients who underwent elective PCI for de novo lesions in native coronary arteries. Patients were followed for 12 months for the occurrence of major adverse cardiac events (MACE) including cardiac death, myocardial infarction, hospitalization with angina or repeat revascularization. Among the 95 patients with one-year follow-up data 22 had MACE. Baseline clinical and procedural characteristics of patients with and without MACE were similar. Only EF was significantly lower (P < 0.001) and complex lesion type was significantly more common in patients with MACE (P = 0.012). All measured plasma BNP levels were significantly higher in patients with MACE compared to those free of MACE (baseline P < 0.001, 1st hour P = 0.001 and 24th hour P < 0.001). Multiple logistic regression analysis identified the EF (P = 0.026) and 24th hour BNP (P = 0.002) as independent predictors of MACE. If baseline or post-PCI 1st hour BNP levels were put into analysis instead of post-PCI 24th hour BNP the predictive value of BNP lost its significance (both P > 0.05). Post-PCI 24th hour BNP is an independent predictor of MACE during 12 months of follow-up after elective successful PCI.


Collective motions in glucosamine-6-phosphate synthase: influence of ligand binding and role in ammonia channelling and opening of the fructose-6-phosphate binding site.
The large protein motions of the bacterial enzyme glucosamine-6-phosphate synthase have been addressed using full atom normal modes analysis for the empty, the glucose-6-phosphate and the glucose-6-phosphate+glutamate bound proteins. The approach that was used involving energy minimizations along the normal modes coordinates identified functional motions of the protein, some of which were characterized earlier by X-ray diffraction studies. This method made it possible for the first time to highlight significant energy differences according to whether none, only one or both of the active sites of the protein were occupied. Our data favoured a specific motion of the glutamine binding domain following the fixation of fructose-6-phosphate and suggested a rigidified structure with both sites occupied. Here, we show that most of the collective large amplitude motions of glucosamine-6-phosphate synthase that are modulated by ligand binding are crucial for the enzyme catalytic cycle, as they strongly modify the geometry of both the ammonia channel and the C-tail, demonstrating their role in ammonia transfer and ligand binding.


[Does ultraclean air in the operating room provide greater safety?].
The Dutch quality control plan for climatisation of the operating room (OR), which was published in 2005, describes the management and maintenance of the air conditioning system. This management plan proposes a standard for air quality in class 1 ORs. This has been adopted by the Dutch Orthopaedic Society, but not by other surgical societies. The British study which underlies the proposed norm for air quality in class 1 ORs, a study on the infection preventive effect of ultraclean air, dates from 1982 and is inadequately controlled for prophylactic use of antibiotics. Antibiotic prophylaxis in itself already reduces the number of surgical site infections.-More recent studies fail to show an infection preventive effect of ultraclean air in the OR. The Dutch Working Party for Infection Prevention (WIP) ought to take the initiative, together with the medical Scientific Societies and the Society of Infection Prevention and Control in the health care setting (VHIG), to establish enforceable norms for microbiological air quality and to set criteria as to which types of operations are allowed to be performed in which class of OR.