IR and NMR properties of ionic liquids: do they tell us the same thing?
We used a combination of theoretical and experimental methods to derive the spectroscopic properties of imidazolium-based ionic liquids. Vibrational frequencies, NMR chemical shifts, and quadrupole coupling constants react in comparable manner to changes in the chemical environment. This suggests that both the IR and the NMR spectroscopic properties reflect a similar type of electronic perturbation caused by hydrogen bonding. These relationships of the spectroscopic properties provide detailed information about structural complexes and may thus serve as good indicators of ion-pair formation. They also help to decide which spectroscopic tool is the most sensitive for investigating molecular interactions. The measurement of only one spectroscopic property allows the prediction of other properties that cannot be so easily measured. In some cases, this is the only way to obtain reliable coupling constants for deriving molecular correlation times from macroscopic NMR relaxation times, thus opening a new path for studying structure-dynamics relations in ionic liquids.


A professional development model for medical laboratory scientists working in the Core Laboratory.
The Division of Pathology and Laboratory Medicine at The University of Texas MD Anderson Cancer Center has implemented a professional development model designed to further the education, expertise, and experiences of medical laboratory scientists in the core laboratory. The professional development model (PDM) has four competency levels: Discovery, Application, Maturation and Expert. All levels require the medical laboratory scientist to learn new skill sets, complete task and projects, and meet continuing education and certification requirements. Each level encourages personal development, recognizes increased competencies, and sets high standards for all services provided. Upon completion of a level within a given timeframe, the medical laboratory scientist receives a salary adjustment based on the competency level completed.


Production and preclinical assessment of camelid immunoglobulins against Echis sochureki venom from desert of Rajasthan, India.
Snakebite is a significant cause of death and disability in subsistent farming populations of rural India. Antivenom is the most effective treatment of envenoming and is manufactured from IgG of venom-immunised horses. Because of complex fiscal reasons, the production, testing and delivery of antivenoms designed to treat envenoming by the most medically-important snakes in the region has been questioned time to time. In this study, we report successful immunisation of dromedaries (Camelus dromedarius) against the venom of Indian saw-scaled Viper- Echis carinatus sochureki. This study assessed the specificity and potential of camels immunised with venom of medically most important snake of Western India, the saw-scaled viper (Echis c. sochureki). Using WHO standard pre-clinical in vivo tests the neutralisation of the venom responsible for the lethal, haemorrhagic, coagulant and local necrotizing activities were measured, since these are the most significant effects that characterize envenoming by this species. The anti-venom was found significantly effective in the neutralisation of all these effects tested and thus, revealed further an immunological perspective, that camel IgG anti-venom (monospecific) would be as efficacious as specific equine anti-venoms or even of better choice in treating snake specific envenoming.


Exposure to epichlorohydrin and central nervous system neoplasms at a resin and dye manufacturing plant.
This study evaluated the relationship between central nervous system neoplasms (CNSN) and exposure to epichlorohydrin (ECH) among 11 CNSN cases and 44 controls who were members of a cohort of chemical workers. Information on area of employment and potential exposure to ECH was obtained from plant personnel and medical records and from interviews with long-term employees. An elevated odds ratio (OR) for CNSN was observed for subjects who worked in the epoxy resin process line (OR = infinity, 95% confidence interval [CI] = 1.2-infinity), and in the production of anthraquinone intermediate dyes (OR = infinity, 95% CI = 1.7-infinity) and azo dyes (OR = 3.6, 95% CI = 0.6-41). Routine potential exposure to ECH was associated with CNSN (OR = 4.2, 95% CI = 0.7-26). Dose-response relationships were found with duration and with cumulative routine potential exposure to ECH (p = .11 and .08, respectively). Acute exposure to ECH requiring treatment at the plant infirmary also was associated with subsequent CNSN (OR = infinity, 95% CI = 1.5-infinity).


Modulating charge-transfer interactions in topologically different porphyrin-C60 dyads.
Control over the interchromophore separation, their angular relationship, and the spatial overlap of their electronic clouds in several ZnP-C(60) dyads (ZnP=zinc porphyrin) is used to modulate the rates of intramolecular electron transfer. For the first time, a detailed analysis of the charge transfer absorption and emission spectra, time-dependent spectroscopic measurements, and molecular dynamics simulations prove quantitatively that the same two moieties can produce widely different electron-transfer regimes. This investigation also shows that the combination of ZnP and C(60) consistently produces charge recombination in the inverted Marcus region, with reorganization energies that are remarkably low, regardless of the solvent polarity. The time constants of electron transfer range from the mus to the ps regime, the electronic couplings from a few tens to several hundreds of cm(-1), and the reorganization energies remain below 0.54 eV and can be as low as 0.16 eV.


Spherulin and coccidioidin: cross-reactions in dermal sensitivity to histoplasmin and paracoccidioidin.
Until recently coccidioidin has been the only antigenic preparation available for detecting delayed dermal sensitivity induced by an experience with Coccidioides immitis. It is prepared from autolysates of the mycelial phase (saprophytic) of the fungus. A more sensitive reagent, spherulin, was developed in 1969 from the spherule phase (parasitic) of the organism. Use of spherulin showed that coccidioidin failed to detect approximately 30% of individuals specifically sensitive to C. immitis. However the potential of spherulin to detect cross-sensitivity induced by Histoplasma capsulatum was unknown. This information was considered to be germane because of the capacity of coccidioidin to detect a histoplasmal experience. Accordingly, both reagents as well as paracoccidioidin were compared simultaneously in 365 Columbian soldiers from areas endemic for histoplasmosis but not for coccidioidomycosis. At standard strength both preparations detected nonspecific responses in 0.8% to 3% of the histoplasmin negative and positive subgroups, respectively. At 10-times standard strength both preparations cross-detected histoplasmin sensitivity comparably; 5.1% to 7.1% of histoplasmin-positive subjects reacted with the coccidioidal antigens. No pattern of cross-reactivity was observed between paracoccidioidin sensitivity and sensitivity to the coccidioidal antigens.


The SNARE Machinery in Mast Cell Secretion.
Mast cells are known as inflammatory cells which exert their functions in allergic and anaphylactic reactions by secretion of numerous inflammatory mediators. During an allergic response, the high-affinity IgE receptor, FcεRI, becomes cross-linked by receptor-bound IgE and antigen resulting in immediate release of pre-synthesized mediators - stored in granules - as well as in de novo synthesis of various mediators like cytokines and chemokines. Soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptors (SNARE) proteins were found to play a central role in regulating membrane fusion events during exocytosis. In addition, several accessory regulators like Munc13, Munc18, Rab GTPases, secretory carrier membrane proteins, complexins, or synaptotagmins were found to be involved in membrane fusion. In this review we summarize our current knowledge about the SNARE machinery and its mechanism of action in mast cell secretion.


Potential role of dietary flavonoids in reducing microvascular endothelium vulnerability to oxidative and inflammatory insults ( small star, filled).
Although antioxidant systems help control the level of reactive oxygen species they may be overwhelmed during periods of oxidative stress. Evidence suggests that oxidative stress components as well as inflammatory mediators may be involved in the pathogenesis of vascular disorders, where localized markers of oxidative damage have been found. In this regard we investigated the putative antioxidant and anti-inflammatory effects of blueberry and cranberry anthocyanins and hydroxycinnamic acids against H(2)O(2) and TNFalpha induced damage to human microvascular endothelial cells. Polyphenols from both berries were able to localize into endothelial cells subsequently reducing endothelial cells vulnerability to increased oxidative stress at both the membrane and cytosol level. Furthermore, berry polyphenols also reduced TNFalpha induced up-regulation of various inflammatory mediators (IL-8, MCP-1 and ICAM-1) involved in the recruitment of leukocytes to sites of damage or inflammation along the endothelium. In conclusion, polyphenols isolated from both blueberry and cranberry were able to afford protection to endothelial cells against stressor induced up-regulation of oxidative and inflammatory insults. This may have beneficial actions against the initiation and development of vascular diseases and be a contributing factor in the reduction of age-related deficits in neurological impairments previously reported by us.


Effects of stirring and sparging on cultured hybridoma cells.
The response of hybridoma cells to fluid shear caused by stirring and sparging has been investigated in a 2-L turbine-agitated bioreactor. Viable cell count, lactate dehydrogenase (LDH) release, and antibody secretion were measured over the course of batch culture experiments under varied conditions of stirring and gas sparging. The effectiveness of Pluronic F68 as a protective agent in sparged cultures was also studied. Growth was found to be unaffected by stirring of the culture under surface aerated conditions, but gas sparging had a significant detrimental effect on growth and antibody production. The effect of sparging was reduced when cultures were supplemented with Pluronic at a level of 0.4% (w/v). Experimental data were analyzed through formulation of models for LDH release and antibody production. Rates of cell lysis could be estimated by correlating extracellular LDH levels through the model for LDH release. The lysis rate estimated for sparged conditions was sufficiently large to approximately account for the observed decrease in the specific growth rate of the culture. The presence of Pluronic apparently interfered with the LDH release mechanism, so precise estimation of lysis rates under these conditions was not possible. Sparging was found not to have a detrimental effect on antibody production in cultures without Pluronic added. Specific antibody production rates in cultures supplemented with Pluronic were about 25% higher than in sparged cultures without Pluronic added.


Inheritance of polymorphic markers generated by DNA amplification fingerprinting and their use as genetic markers in soybean.
DNA amplification fingerprinting (DAF) using a high primer-to-template ratio and single, very short arbitrary primers, was used to generate amplified fragment length polymorphic markers (AFLP) in soybean (Glycine max (L.) Merr.). The inheritance of AFLPs was studied using a cross between the ancestral Glycine soja PI468.397 and Glycine max (L.) Merr. line nts382, F1 and F2 progeny. The amplification reaction was carried out with soybean genomic DNA and 8 base long oligonucleotide primers. Silver-stained 5% polyacrylamide gels containing 7 M urea detected from 11 to 28 DAF products with primers of varying GC content (ranging from 50 to 100% GC). Depending on their intensity, AFLPs were classified into three classes. DAF profiles were reproducible for different DNA extractions and gels. Forty AFLPs were detected by 26 primers when comparing G. soja and G. max. Most AFLPs were inherited as dominant Mendelian markers in F1 and F2 populations. However, abnormal inheritance occurred with about 25% of polymorphisms. One marker was inherited as a maternal marker, presumably originating from organelle DNA while another showed apparent paternal inheritance. To confirm the nuclear origin and utility of dominant Mendelian markers, three DAF polymorphisms were mapped using a F11 mapping population of recombinant inbred lines from soybean cultivars Minsoy x Noir 1. The study showed that DAF-generated polymorphic markers occur frequently and reliably, that they are inherited as Mendelian dominant loci and that they can be used in genome mapping.


Increased peripheral of brain-derived neurotrophic factor levels in phenylketonuric patients treated with l-carnitine.
Phenylketonuria (PKU) is the most common inherited metabolic disorders caused by severe deficiency or absence of phenylalanine hydroxylase activity that converts phenylalanine (Phe) to tyrosine. PKU patients were treated with a Phe restricted diet supplemented with a special formula containing l-carnitine (L-car), well-known antioxidant compound. The lack of treatment can cause neurological and cognitive impairment, as severe mental retardation, neuronal cell loss and synaptic density reduction. Although Phe has been widely demonstrated to be involved in PKU neurotoxicity, the mechanisms responsible for the CNS injury are still not fully known. In this work, we evaluated markers of neurodegeneration, namely BDNF (brain-derived neurotrophic factor), PAI-1 total (Plasminogen activator inhibitor-1 total), Cathepsin D, PDGF AB/BB (platelet-derived growth factor), and NCAM (neuronal adhesion molecule) in plasma of PKU patients at early and late diagnosis and under treatment. We found decreased Phe levels and increased L-car concentrations in PKU patients treated with L-car compared to the other groups, indicating that the proposed treatment was effective. Furthermore, we found increased BDNF levels in the patients under treatment compared to patients at early diagnosis, and a positive correlation between BDNF and L-car and a negative correlation between BDNF and Phe. Our results may indicate that in PKU patients treated with L-car there is an attempt to adjust neuronal plasticity and recover the damage suffered, reflecting a compensatory response to brain injury.


A deleted retroviral insertion at the ev21-K complex locus in Indonesian chickens.
Very poor feather development has been observed in chickens of the Nunukan strain, originating from Indonesia. The wing of the newly hatched chick does not show any primary or covert feathers; this phenotype will be referred to as very-late feathering (VLF). As adults, chickens are feathered but tail feathers are short and fragile. An experimental population was set up at the National Institute of Agronomic Research (INRA), Jouy-en-Josas, from one Nunukan male and four Nunukan females. Preliminary observations did not support the hypothesis of a sex-linked dominant mode of inheritance for the VLF phenotype. A restriction fragment length polymorphism (RFLP) study using five restriction enzymes and two probes, RAV-2 and endogenous virus (ev) ev21-int specific for the endogenous viral locus ALVE21, showed the presence of the expected 3' junction fragments for the ev21 occupied site but failed to reveal the expected 5' junction fragments for ev21 in Nunukan chickens. The unoccupied site corresponded to the ev21 unoccupied repeat (UR) of type a (URa). A deletion in the 5' region of the provirus and of the insertion site was indicated by the RFLP analysis and confirmed by a PCR study. Primers were designed in order to amplify a 5' junction fragment specific to the modified ev21 found in the Nunukan chickens. The sequence of this amplified product showed that the deletion started 652 bp upstream of the insertion site of ev21 and ended within the pol gene of the viral genome. This deletion represents a new allele, OSD, at the ev21 insertion site (locus ALVE21), that appears insufficient to produce a complete virus. Current data do not show a clear causal relationship between OSD and the VLF phenotype. The presence of OSD may be required but is not in itself sufficient to obtain the VLF phenotype. The genetic relationships between OSD and the altered feathering phenotype of Nunukan chickens will be investigated further in families segregating for the VLF phenotype, using the locus-specific PCR test developed as part of this study.


Radiological studies on the upper digestive tract in Tanzanians at Mwanza.
Among 462 barium meals performed in rural Tanzanians in 1973-1974 121 pathological lesions were diagnosed. The principal were peptic ulcer in 59 patients, duodenitis in 20, serious gastritis in 10, carcinoma of the stomach in nine and of the oesophagus in seven. Peptic ulcer was most prevalent in young adults. The frequency of duodenitis was associated with invasion by parasitic worms. The social factors in the prevalence of peptic ulcer are discussed. Gastroptosis was a very common finding in patients with stomach complaints.


Intentions to use a novel Zika vaccine: the effects of misbeliefs about the MMR vaccine and perceptions about Zika.
People's intentions to use vaccines are influenced by their beliefs about both the specific vaccine and the disease it prevents. In the absence of firm beliefs about Zika virus (ZIKV), individuals may base their intentions to vaccinate against it on beliefs about other vaccines, and specifically the misbelief that MMR causes autism. A survey of 3337 Americans, using a random-digit-dialing sample of landline telephone households and cell-phones. Intentions to use a Zika vaccine were influenced by beliefs about Zika, science in general, and MMR. Intentions were positively influenced by perceived severity of and vulnerability to Zika, as well as belief in science's efficacy. However, intentions were negatively influenced by the belief that MMR causes autism in children. The misbelief about MMR and autism may reduce people's intentions to use a new Zika vaccine. However, perceptions of severity of and vulnerability to Zika may increase intentions. Implications for science educators and public health officials are discussed.


Cooperative CO2 adsorption mechanism in a perfluorinated CeIV-based metal organic framework.
Adsorbents able to uptake large amounts of gases within a narrow range of pressure, i.e., phase-change adsorbents, are emerging as highly interesting systems to achieve excellent gas separation performances with little energy input for regeneration. A recently discovered phase-change metal-organic framework (MOF) adsorbent is F4_MIL-140A(Ce), based on CeIV and tetrafluoroterephthalate. This MOF displays a non-hysteretic step-shaped CO2 adsorption isotherm, reaching saturation in conditions of temperature and pressure compatible with real life application in post-combustion carbon capture, biogas upgrading and acetylene purification. Such peculiar behaviour is responsible for the exceptional CO2/N2 selectivity and reverse CO2/C2H2 selectivity of F4_MIL-140A(Ce). Here, we combine data obtained from a wide pool of characterisation techniques - namely gas sorption analysis, in situ infrared spectroscopy, in situ powder X-ray diffraction, in situ X-ray absorption spectroscopy, multinuclear solid state nuclear magnetic resonance spectroscopy and adsorption microcalorimetry - with periodic density functional theory simulations to provide evidence for the existence of a unique cooperative CO2 adsorption mechanism in F4_MIL-140A(Ce). Such mechanism involves the concerted rotation of perfluorinated aromatic rings when a threshold partial pressure of CO2 is reached, opening the gate towards an adsorption site where CO2 interacts with both open metal sites and the fluorine atoms of the linker.


Direct Catalytic Asymmetric Mannich Reaction with Dithiomalonates as Excellent Mannich Donors: Organocatalytic Synthesis of (R)-Sitagliptin.
In this study, dithiomalonates (DTMs) were demonstrated to be exceptionally efficient Mannich donors in terms of reactivity and stereoselectivity in cinchona-based-squaramide-catalyzed enantioselective Mannich reactions of diverse imines or α-amidosulfones as imine surrogates. Owing to the superior reactivity of DTMs as compared to conventional malonates, the catalyst loading could be reduced to 0.1 mol % without the erosion of enantioselectivity (up to 99 % ee). Furthermore, by the use of a DTM, even some highly challenging primary alkyl α-amidosulfones were smoothly converted into the desired adducts with excellent enantioselectivity (up to 97 % ee), whereas the use of a malonate or monothiomalonate resulted in no reaction under identical conditions. The synthetic utility of the chiral Mannich adducts obtained from primary alkyl substrates was highlighted by the organocatalytic, coupling-reagent-free synthesis of the antidiabetic drug (-)-(R)-sitagliptin.


Pharmacodynamics and pharmacokinetics of digoxin in the presence of lithium.
Previous biochemical and clinical data suggest there may be an interaction between digoxin and lithium. The pharmacodynamics and pharmacokinetics of an intravenous infusion of digoxin were studied in six male subjects before and after 2 weeks treatment with lithium carbonate. The effects of lithium on sodium pump activity, intracellular electrolytes and extracellular electrolytes were studied. No significant interaction between digoxin and lithium was found. No significant effects of lithium on sodium pump activity or electrolyte concentrations were found.


Interferon immunosuppression: mediation by a suppressor factor.
Suppression of the in vitro antibody response to sheep erythrocytes by mouse fibroblast interferon occurred by induction of suppressor cell activity in spleen cells. The suppressor cells produced a soluble factor which mediated the immunosuppression. The suppressor factor did not inhibit virus replication; thus, interferon probably regulates the B-cell response by a mechanism that is different from its antiviral effect.


Total Knee Arthroplasty in Severe Unstable Knee: Case-Report and Literature Review.
Multiplanar or global laxity in arthritic knee is rare, most of this patients have neuromuscular disorder (post poliomyelitis, spinal dystrophy) or history of knee trauma. Ligament insufficiency and severe bone loss is significant in this patient. The estimated prevalence for the concurrence of charcot marie-tooth (CMT) with myasthenia gravis (MG) suggests an extremely rare event. We have presented a 54-year-old female patient with CMT and MG complaining of progressive pain, swelling, and crepitation of the knee joints who had been undergone total knee arthroplasty (TKA) with rotating hinge prosthesis. She had an acute myasthenia crisis soon after operation with prolonged intubation and intensive care unit admission. Radiographies and physical examination revealed bilateral severe unstable arthritic knee joints and left knee posterior dislocation. Short-term postoperative follow-up revealed improved knee function and resolution of all symptoms in the operated side.


Correlation of perfusion- and diffusion-weighted MRI with NIHSS score in acute (<6.5 hour) ischemic stroke.
Diffusion-weighted (DWI) and perfusion-weighted (PWI) MRI are powerful new techniques for the assessment of acute cerebral ischemia. However, quantitative data comparing the severity of clinical neurologic deficit with the results of DWI or PWI in the earliest phases of stroke are scarce. Such information is vital if MRI is potentially to be used as an objective adjunctive measure of stroke severity and outcome. The authors compared initial DWI and PWI lesion volumes with subsequent 24-hour neurologic deficit as determined by National Institutes of Health Stroke Scale (NIHSS) score in acute stroke patients. Initial DWI and PWI volumes were also compared with T2W MRI lesion volume at 1 week to assess the accuracy of these MRI techniques for the detection of acute cerebral ischemia. Patients with stroke underwent MRI scanning within 6.5 hours of symptom onset. Lesion volumes on DWI and PWI were measured and compared with 24-hour NIHSS score. Initial DWI and PWI volumes were also compared with T2W lesion size at 1 week. There was a high correlation between 24-hour NIHSS score and lesion volume as determined by PWI (r = 0.96, p < 0.001) or DWI (r = 0.67, p = 0.03). A similar high correlation was seen between T2W stroke size at 7 days and initial DWI and PWI lesion size (r = 0.99, p < 0.00001). Both DWI and PWI are highly correlated with severity of neurologic deficit by 24-hour NIHSS score. These findings may have substantial implications for the use of MRI scanning in the assessment and management of acute stroke patients.


Computational analyses of mechanism of action (MoA): data, methods and integration.
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potential side-effects. Bioinformatic approaches, advances in machine learning techniques and the increasing deposition of high-throughput data in public databases have significantly contributed to recent advances in the field, but it is not straightforward to decide which data and methods are most suitable to use in a given case. In this review, we focus on these methods and data and their applications in generating MoA hypotheses for subsequent experimental validation. We discuss compound-specific data such as -omics, cell morphology and bioactivity data, as well as commonly used supplementary prior knowledge such as network and pathway data, and provide information on databases where this data can be accessed. In terms of methodologies, we discuss both well-established methods (connectivity mapping, pathway enrichment) as well as more developing methods (neural networks and multi-omics integration). Finally, we review case studies where the MoA of a compound was successfully suggested from computational analysis by incorporating multiple data modalities and/or methodologies. Our aim for this review is to provide researchers with insights into the benefits and drawbacks of both the data and methods in terms of level of understanding, biases and interpretation - and to highlight future avenues of investigation which we foresee will improve the field of MoA elucidation, including greater public access to -omics data and methodologies which are capable of data integration.


Bronchopleural fistula treatment with use of a bronchial stent-graft occluder.
The purpose of this report is to describe our experience in the successful treatment of two patients with postpneumonectomy bronchopleural fistula (BPF). With use of computed tomography reformatting, the stent-graft occluders were tailored to precisely fit the fistula site and remnant bronchus stump. These were placed under fluoroscopic guidance via a preexisting chest tube tract in one case and via an open thoracostomy window site in the other. The BPFs were successfully occluded without complications, and the stent-graft occluders remained stable in position for 1 year and 6 months of follow-up, respectively.


Intentional binding of two effects.
An action that produced an effect is perceived later in time compared to an action that did not produce an effect. Likewise, the effect of an action is perceived earlier in time compared to a stimulus that was not produced by an action. Despite numerous studies on this phenomenon-referred to as Intentional Binding effect (IB)-the underlying mechanisms are still not fully understood. Typically, IB is investigated in settings where the action produces just one single effect, whereas in everyday action contexts, it rather causes a sequence of effects before leading to the desired outcome. Therefore, we investigated IB of two consecutive effects. We observed substantially more IB of a first effect tone compared to a second tone. This pattern was observed for second tones that were temporally predictable (Exp. 1) or not (Exp. 2 and 3). Interestingly, the second tone yielded stronger IB when it was less delayed (Exp. 4). Thus, also an event occurring later in an unfolding action-effect sequence can be bound to its causing action, but it might be less bound to the action than a first effect. Instead of the fact that it is the second of two consecutive effects, this, however, rather seems to be influenced by the longer delay of a second and, therefore, later occurring effect.


Assessment of mitral regurgitation in dogs: comparison of results of echocardiography with magnetic resonance imaging.
Echocardiography is used routinely to assess mitral regurgitation severity, but echocardiographic measures of mitral regurgitation in dogs have not been compared with other quantitative methods. The study aim was to compare echocardiographic measures of mitral regurgitation with cardiac magnetic resonance imaging-derived mitral regurgitant fraction in small-breed dogs. Dogs with myxomatous mitral valve disease scheduled for magnetic resonance imaging assessment of neurological disease were recruited. Correlations were tested between cardiac magnetic resonance imaging-derived mitral regurgitant fraction and the following echocardiographic measures: vena contracta/aortic diameter, transmitral E-wave velocity, amplitude of mitral prolapse/aortic diameter, diastolic left ventricular diameter:aortic diameter, left atrium:aortic diameter, mitral regurgitation jet area ratio and regurgitant fraction calculated using the proximal isovelocity surface area method. Measurement of cardiac magnetic resonance imaging-derived mitral regurgitant fraction was attempted in 21 dogs. Twelve consecutive, complete studies were obtained and 10 dogs were included in the final analysis: vena contracta/aortic diameter (r = 0 · 89, p = 0 · 001) and E-wave velocity (r = 0 · 86, p = 0 · 001) had the strongest correlations with cardiac magnetic resonance imaging-derived mitral regurgitant fraction. E velocity had superior repeatability and could be measured in all dogs. The presence of multiple jets precluded vena contracta/aortic diameter measurement in one dog. Measurement of cardiac magnetic resonance imaging-derived mitral regurgitant fraction is feasible but technically demanding. The echocardiographic measures that correlated most closely with cardiac magnetic resonance imaging-derived mitral regurgitant fraction were vena contracta/aortic diameter and E-wave velocity.


Muscle fibers and their synapses differentially adapt to aging and endurance training.
This project aimed to determine the adaptability of the neuromuscular system to the stimuli of exercise training, and aging. Young adult, and aged male rats were randomly assigned to either exercise training, or sedentary control groups. Exercise training featured an 8 week program of treadmill running. At the end of the intervention period, neuromuscular function was quantified with ex vivo stimulation procedures on isolated soleus muscles. Morphological adaptations were determined by quantifying myofiber profiles (fiber size and type) of soleus muscles. Ex vivo procedures confirmed that rested (fresh) young muscles were significantly (P < 0.05) stronger than aged ones. By the end of the 5 min stimulation protocol, however, young and aged muscles displayed similar levels of strength. Neuromuscular transmission efficacy as assessed by comparing force produced during indirect (neural) and direct (muscle) stimulation was unaffected by aging, or training, but under both conditions significantly declined over the stimulation protocol mimicking declines in strength. Myofiber size was unaffected by age, but training caused reductions in young, but not aged myofibers. Aged solei displayed a higher percentage of Type I fibers, along with a lower percentage of Type II fibers than young muscles. The greater strength of young muscles has a neural, rather than a muscular focal point. The loss of strength discerned over the 5 min stimulation protocol was linked to similar fatigue-related impairments in neuromuscular transmission. The two components of the neuromuscular system, i.e. nerves and muscles, do not respond in concert to the stimulus of either aging, or exercise training.


[Thrombolysis in acute myocardial infarct].
Thrombolysis for acute myocardial infarction is based on the discovery some 80 years ago that the total occlusion of a coronary artery is universally due to a thrombus. In the eighties, thrombolysis has become established as the therapy of choice for infarction, and its value has since been proved in large randomized studies. First, the ISIS-2 study showed the efficacy of streptokinase alone and in combination with aspirin in reducing mortality. The GISSI study corroborated these data. The ISIS-3 study and the GISSI-2 study (complemented by the International Study) failed to show a difference in efficacy between TPA and streptokinase. Anistreplase (APSAC) proved inferior to the other two drugs. The GUSTO study (over 40,000 patients) revealed a minor advantage of an accelerated regimen of TPA compared with the usual streptokinase dose. TPA was combined with intravenous heparin. According to the data gathered in American centers, about one life could be saved per 100 patients treated albeit at the considerably higher price of the TPA. European data suggest that it may only be one life saved per 200 treated patients. The main complication of thrombolysis is bleeding. The more efficient the thrombolytic treatment is, the higher the bleeding rate. Cerebral insults (particularly hemorrhages) are increased in patients with thrombolysis complemented by aspirin and heparin. However, these complications do not completely forfeit the beneficial effect of the two adjunctive medications on cardiac mortality. It has emerged that intravenous heparin is not essential in the first hour of TPA treatment but because important thereafter, whereas it may be essential in the first hour of streptokinase treatment but deleterious thereafter.(ABSTRACT TRUNCATED AT 250 WORDS)


Solid-state 115In and 31P NMR studies of triarylphosphine indium trihalide adducts.
Solid-state (115)In and (31)P NMR spectroscopy, relativistic density functional theory (DFT) calculations, and single-crystal X-ray diffraction were used to investigate a series of triarylphosphine indium(III) trihalide adducts, X(3)In(PR(3)) and X(3)In(PR(3))(2) (X = Cl, Br or I; PR(3) = triarylphosphine ligand). The electric field gradient tensors at indium as well as the indium and phosphorus magnetic shielding tensors and the direct and indirect (115)In-(31)P spin-spin coupling were characterized; for complexes possessing a C(3) symmetry axis, the anisotropy in the indirect spin-spin coupling, DeltaJ((115)In,(31)P), was also determined. The (115)In quadrupolar coupling constants, C(Q)((115)In), range from +/-1.25 +/- 0.10 to -166.0 +/- 2.0 MHz. For any given phosphine ligand, the indium nuclei are most shielded for X = I and least shielded for X = Cl, a trend also observed for other group-13 nuclei in M(III) complexes. This experimental trend, attributed to spin-orbit effects of the halogen ligands, is reproduced by the DFT calculations. The spans of the indium magnetic shielding tensors for these complexes, delta(11)-delta(33), range from 40 +/- 7 to 710 +/- 60 ppm; those determined for phosphorus range from 28 +/- 1.5 to 50 +/- 3 ppm. Values of (1)J((115)In,(31)P) range from 550 +/- 20 to 2500 +/- 20 Hz. For any given halide, the (1)J((115)In,(31)P) values generally increase with increasing basicity of the PR(3) ligand. Calculated values of (1)J((115)In,(31)P) and DeltaJ((115)In,(31)P) duplicate experimental trends and indicate that both the Fermi-contact and spin-dipolar Fermi-contact mechanisms make important contributions to the (1)J((115)In,(31)P) tensors.


Comparative optical genome analysis of two pangolin species: Manis pentadactyla and Manis javanica.
The pangolin is a Pholidota mammal with large keratin scales protecting its skin. Two pangolin species ( Manis pentadactyla and Manis javanica ) have been recorded as critically endangered on the International Union for Conservation of Nature Red List of Threatened Species. Optical mapping constructs high-resolution restriction maps from single DNA molecules for genome analysis at the megabase scale and to assist genome assembly. Here, we constructed restriction maps of M. pentadactyla and M. javanica using optical mapping to assist with genome assembly and analysis of these species. Genomic DNA was nicked with Nt.BspQI and then labeled using fluorescently labeled bases that were detected by the Irys optical mapping system. In total, 3,313,734 DNA molecules (517.847 Gb) for M. pentadactyla and 3,439,885 DNA molecules (504.743 Gb) for M. javanica were obtained, which corresponded to approximately 178X and 177X genome coverage, respectively. Qualified molecules (≥150 kb with a label density of >6 sites per 100 kb) were analyzed using the de novo assembly program embedded in the IrysView pipeline. We obtained two maps that were 2.91 Gb and 2.85 Gb in size with N50s of 1.88 Mb and 1.97 Mb, respectively. Optical mapping reveals large-scale structural information that is especially important for non-model genomes that lack a good reference. The approach has the potential to guide de novo assembly of genomes sequenced using next-generation sequencing. Our data provide a resource for Manidae genome analysis and references for de novo assembly. This note also provides new insights into Manidae evolutionary analysis at the genome structure level.


Pituitary-adrenal responses to human corticotropin-releasing hormone in critically ill patients.
To investigate the pattern of pituitary-adrenal responses to human corticotropin-releasing hormone (hCRH) in critically ill patients and to examine the relation between responses and clinical outcome. Prospective study in consecutive critically ill patients in a general intensive care unit in a teaching hospital. The study included 37 critically ill, mechanically ventilated patients with diverse underlying diagnoses (28 men, 9 women; median age 56 years). A morning blood sample was obtained to measure baseline cortisol, corticotropin (ACTH), and cytokines. Patients were then injected with 100 microg hCRH, and plasma cortisol and ACTH were measured over a period of 2 h. In the overall patient population baseline and peak cortisol concentrations following hCRH were 16+/-5 and 21+/-5 microg/dl, respectively, and median baseline and peak ACTH levels 23 and 65 pg/ml, respectively. Higher ACTH levels and longer release of cortisol were noted in nonsurvivors (n=18) than in survivors (n=19). Furthermore, nonsurvivors had higher concentrations of interleukin 8 (115 vs. 38 pg/ml) and interleukin 6 (200 vs. 128 pg/ml) than survivors. Critically ill patients demonstrate altered pituitary-adrenal axis responses to hCRH. This is particularly evident in the sickest patients with the highest degree of inflammatory profile who ultimately do not survive.


Role of isoprenylcysteine carboxyl methyltransferase in tumor necrosis factor-alpha stimulation of expression of vascular cell adhesion molecule-1 in endothelial cells.
We have previously shown that cytokine stimulation of the expression of vascular cell adhesion molecule-1 (VCAM-1), but not that of intercellular adhesion molecule-1 (ICAM-1), is redox sensitive in endothelial cells. Here, we investigated the role of isoprenylcysteine carboxyl methyltransferase (ICMTase), which methylates isoprenylated CAAX (where C indicates cysteine; A, aliphatic amino acids; and X, almost any other amino acid) proteins, including Rac1, a component of superoxide-generating NAD(P)H oxidase, in the expression of VCAM-1. Pretreatment of endothelial cells with N-acetyl-S-farnesyl-L-cysteine (AFC) or N-acetyl-S-geranylgeranyl-L-cysteine (AGGC), specific inhibitors of ICMTase, inhibited the tumor necrosis factor-alpha (TNF-alpha) stimulation of mRNA expression of VCAM-1 but not that of ICAM-1. Endothelial cells expressed constitutively active ICMTase, as suggested by the presence of methylated Rac1 and the methylation of AFC by the cells. TNF-alpha stimulation of the cells significantly increased the methylation of AFC and Rac1 in endothelial cells. That ICMTase was a component of the redox-sensitive signaling pathway was also suggested by the AFC inhibition of the generation of reactive oxygen species by TNF-alpha. Interestingly, the dominant-negative isoform of Rac1 was not selective but inhibited the TNF-alpha stimulation of the mRNA expression of VCAM-1 and ICAM-1. Thus, ICMTase is a critical component of the redox-sensitive VCAM-1-selective signaling pathway, and it appears to activate a discrete inflammatory signaling pathway, at least in part, through the methylation of Rac1.


Strain diversity and host specificity in a specialized gut symbiont of honeybees and bumblebees.
Host-restricted lineages of gut bacteria often include many closely related strains, but this fine-scale diversity is rarely investigated. The specialized gut symbiont Snodgrassella alvi has codiversified with honeybees (Apis mellifera) and bumblebees (Bombus) for millions of years. Snodgrassella alvi strains are nearly identical for 16S rRNA gene sequences but have distinct gene repertoires potentially affecting host biology and community interactions. We examined S. alvi strain diversity within and between hosts using deep sequencing both of a single-copy coding gene (minD) and of the V4 region of the 16S rRNA gene. We sampled workers from domestic and feral A. mellifera colonies and wild-caught Bombus representing 14 species. Conventional analyses of community profiles, based on the V4 region of the 16S rRNA gene, failed to expose most strain variation. In contrast, the minD analysis revealed extensive strain variation within and between host species and individuals. Snodgrassella alvi strain diversity is significantly higher in A. mellifera than in Bombus, supporting the hypothesis that colony founding by swarms of workers enables retention of more diversity than colony founding by a single queen. Most Bombus individuals (72%) are dominated by a single S. alvi strain, whereas most A. mellifera (86%) possess multiple strains. No S. alvi strains are shared between A. mellifera and Bombus, indicating some host specificity. Among Bombus-restricted strains, some are restricted to a single host species or subgenus, while others occur in multiple subgenera. Findings demonstrate that strains diversify both within and between host species and can be highly specific or relatively generalized in their host associations.


Monitoring renal transplants: an application of the multiprocess Kalman filter.
The multiprocess Kalman filter offers a powerful general framework for the modelling and analysis of noisy time series which are subject to abrupt changes in pattern. It has considerable potential application to many forms of biological series used in clinical monitoring. In particular, the approach can be used to provide on-line probabilities of whether changes have occurred, as well as to identify the type of change that is involved. In this paper, we extend and illustrate the methodology within the context of a particular case study. The general features of the problem, and the approach adopted, will be seen to have wide application.


Functional organization of the human amygdala in appetitive learning.
The amygdala is a small subcortical structure located bilaterally in medial temporal lobes. It is a key region for emotional processes and some forms of associative learning. In particular, the role of the amygdala in processing of negative emotions and aversive learning has been shown in numerous studies. However, involvement of this structure in processing of positive affect and appetitive learning is not fully understood. Previous experiments in animals are not consistent. While some authors implicate only the centromedial part of the amygdala in appetitive learning, the others suggest contribution of both centromedial and basolateral subregions. Although from the evolutionary perspective appetitive learning is equally important as aversive learning, research on the role of the human amygdala and its subregions in appetitive learning is undertaken relatively rarely and the results are not conclusive. Therefore, the aim of this review is twofold: to summarize the current knowledge in this field and to indicate and discuss the factors, which might affect the observed level of the amygdala activity during appetitive learning in humans.


CDDO-Me, a synthetic triterpenoid, inhibits expression of IL-6 and Stat3 phosphorylation in multi-drug resistant ovarian cancer cells.
Previous studies have identified interleukin 6 (IL-6) as an important cytokine with prognostic significance in ovarian cancer. Activation of the IL-6-Stat3 pathway contributes to tumor cell growth, survival and drug resistance in several cancers, including ovarian cancer. To explore potential therapeutic strategies for interrupting signaling through this pathway, we assessed the ability of CDDO-Me, a synthetic triterpenoid, to inhibit IL-6 secretion, Stat3 phosphorylation, Stat3 nuclear translocation and paclitaxel sensitivity in several cell line model systems. These studies demonstrated that CDDO-Me significantly inhibits IL-6 secretion in paclitaxel-resistant ovarian cancer cells and specifically suppresses IL-6- or oncostatin M-induced Stat3 nuclear translocation. Treatment with CDDO-Me significantly decreases the levels of Stat3, Jak2, and Src phosphorylation in ovarian and breast cancer cell lines with constitutively activated Stat3. This inhibition of the IL-6-Stat3 pathway correlated with suppression of the anti-apoptotic Stat3 target genes Bcl-X(L), survivin, and Mcl-1, and with apoptosis induction as measured by monitoring PARP and its cleavage product, as well as by quantitative measurement of the apoptosis-associated CK18Asp396. Furthermore, CDDO-Me increases the cytotoxic effects of paclitaxel in the paclitaxel-resistant ovarian cancer cell line OVCAR8(TR) (2 to 5-fold) and of cisplatin in the cisplatin-resistant ovarian cancer cell line A2780cp70 (2 to 4-fold). Our data confirm that CDDO-Me interrupts the signaling of multiple kinases involved in the IL-6-Stat3 and Src signaling pathways. Inhibition is likely achieved through multiple points within these pathways. In a model system of established acquired drug resistance, CCDO-Me is effective at partially reversing the drug-resistance phenotype.


Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group.
To evaluate response rate, event-free survival (EFS), and toxicity of two chemotherapeutic regimens for treatment of children younger than 36 months with malignant brain tumors and to estimate control intervals without irradiation in children with no residual tumor after initial surgery and induction chemotherapy and with delayed irradiation in patients with residual tumor or metastatic disease at diagnosis. Patients were randomly assigned to one of two regimens of induction chemotherapy (vincristine, cisplatin, cyclophosphamide, and etoposide v vincristine, carboplatin, ifosfamide, and etoposide). Maintenance chemotherapy began after induction in children without progressive disease. Children with no residual tumors after induction therapy and no metastatic disease at diagnosis were not to receive radiation therapy unless their tumors progressed. Two hundred ninety-nine infants were enrolled. Forty-two percent of patients responded to induction chemotherapy. At 5 years from study entry, the EFS rate was 27% +/- 3%, and the survival rate was 43% +/- 3%. There was no significant difference between the two arms in terms of response rate or EFS. For medulloblastoma, supratentorial primitive neuroectodermal tumor, ependymoma, and rhabdoid tumors, 5-year EFS rates were 32% +/- 5%, 17% +/- 6%, and 32% +/- 6%, and 14% +/- 7%, respectively. Fifty-eight percent of patients who were alive 5 years after study entry had not received radiation therapy. Intensified induction chemotherapy resulted in a high response rate of malignant brain tumors in infants. Survival was comparable to that of previous studies, and most patients who survived did not receive radiation therapy.


Initial catabolism of aromatic biogenic amines by Pseudomonas aeruginosa PAO: pathway description, mapping of mutations, and cloning of essential genes.
Pseudomonas aeruginosa PAO1 was able to utilize several aromatic biogenic amines as sole sources of carbon or nitrogen. These included the phenethylamines tyramine and dopamine and the phenethanolamines octopamine, synephrine, and norepinephrine. Initial catabolism of the phenethylamines was mediated by a membrane-bound tyramine dehydrogenase which produced 4-hydroxyphenylacetaldehyde (4HPAL) with tyramine as the substrate. The enzyme was induced by growth with both classes of amines. Initial catabolism of octopamine (except when present as the sole source of carbon and nitrogen) was mediated by a soluble enzyme with activity against the phenethanolamines but not against tyramine or dopamine. The product of the reaction with octopamine as substrate was also 4HPAL. Addition of NAD to reaction mixtures yielded 4-hydroxyphenylacetic acid and NADH. These activities, octopamine hydrolyase and 4-HPAL dehydrogenase (measured as a combined activity, OCAH-4HPALDH), were only induced by growth with phenethanolamines. However, the combined activities were not observed in extracts from cells grown with octopamine as the sole source of carbon and nitrogen, suggesting that an alternate pathway is used under this growth condition. Two independently isolated mutant strains were unable to utilize tyramine as a sole source of carbon or nitrogen. These mutants were also unable to utilize dopamine but grew at wild-type rates on the phenethanolamines. The mutations were mapped at about 70 min on the PAO1 chromosome with the chromosome-mobilizing plasmid R68.45, and both were linked to the catA1, mtu-9002, tyu-9009, and puuE mutations. DNA complementing both of the mutations was cloned on a single BamHI fragment approximately 13.8 kilobase pairs in length. Analysis of a subcloned fragment showed that the two mutations were in different genes.


A Compiled Update on Nutrition, Phytochemicals, Processing Effects, Analytical Testing and Health Effects of Chenopodium album: A Non-Conventional Edible Plant (NCEP).
Bathua (Chenopodium album) is a rich source of extensive-ranging nutrients, including bio-active carbohydrates, flavonoids and phenolics, minerals, and vitamins that translate to countless health benefits such as anticancer, antidiabetic, anti-inflammatory, antimicrobial, and antioxidant activity. Ascaridole, an important phytoconstituent present in aerial parts of the plant, contributes to its anthelmintic property. Even with vast historical use and significant health benefits, its renown has not spread, and utilization has significantly decreased in recent decades. Gradually, the plant has become known under the name of Non-conventional edible plant (NCEP). This compilation is prepared to bring out the plant under the spotlight for further research by foregrounding previous studies on the plant. Scientific research databases, including PubMed, Google Scholar, Scopus, SpringerLink, ScienceDirect, and Wiley Online, were used to fetch data on C. album. This review offers over up-to-date knowledge on nutritious values, phytochemical composition, volatile compounds, as well as health benefits of C. album. The ethnobotanical and ethnomedicinal uses of the plant in India and other parts of the world are deliberately discussed. Scrutinizing the reported literature on C. album reveals its powerful nutrient composition advantageous in the development of food products. The impact of various cooking and processing methods on the nutritional profile and bioavailability are discussed. The future perspectives with regards to the potential for food and nutraceutical products are critically addressed. This review proves the necessity of breakthrough research to investigate the pharmacology and safety of phytochemicals and nutraceutical development studies on the C. album.


Loss of RASSF2 Enhances Tumorigencity of Lung Cancer Cells and Confers Resistance to Chemotherapy.
RASSF2 is a novel pro-apoptotic effector of K-Ras that is frequently inactivated in a variety of primary tumors by promoter methylation. Inactivation of RASSF2 enhances K-Ras-mediated transformation and overexpression of RASSF2 suppresses tumor cell growth. In this study, we confirm that RASSF2 and K-Ras form an endogenous complex, validating that RASSF2 is a bona fide K-Ras effector. We adopted an RNAi approach to determine the effects of inactivation of RASSF2 on the transformed phenotype of lung cancer cells containing an oncogenic K-Ras. Loss of RASSF2 expression resulted in a more aggressive phenotype that was characterized by enhanced cell proliferation and invasion, decreased cell adhesion, the ability to grow in an anchorage-independent manner and cell morphological changes. This enhanced transformed phenotype of the cells correlated with increased levels of activated AKT, indicating that RASSF2 can modulate Ras signaling pathways. Loss of RASSF2 expression also confers resistance to taxol and cisplatin, two frontline therapeutics for the treatment of lung cancer. Thus we have shown that inactivation of RASSF2, a process that occurs frequently in primary tumors, enhances the transforming potential of activated K-Ras and our data suggests that RASSF2 may be a novel candidate for epigenetic-based therapy in lung cancer.


Secondhand smoke as an acute threat for the cardiovascular system: a change in paradigm.
The evidence that active smoking is a risk factor for cardiovascular disease (CVD) and the leading cause of preventable death is overwhelming. However, numerous epidemiological findings indicate that even passive exposure to cigarette smoke may exert detrimental effects on vascular homoeostasis. Recent experimental data provide a deeper insight into the pathophysiological mechanisms linking secondhand smoke (SHS) to CVD. Importantly, most of these effects appear to be characterized by a rapid onset. For example, the relatively low doses of toxins inhaled by passive smoking are sufficient to elicit acute endothelial dysfunction, and these effects may be related, at least in part, to the inactivation of nitric oxide. Moreover, passive smoking may directly impair the viability of endothelial cells and reduce the number and functional activity of circulating endothelial progenitor cells. In addition, platelets of non-smokers appear to be susceptible to pro-aggregatory changes with every passive smoke exposure. Overall, SHS induces oxidative stress and promotes vascular inflammation. Apart from vasoconstriction and thrombus formation, however, the myocardial oxygen balance is further impaired by SHS-induced adrenergic stimulation and autonomic dysfunction. These data strongly suggest that passive smoking is capable of precipitating acute manifestations of CVD (atherothrombosis) and may also have a negative impact on the outcome of patients who suffer acute coronary syndromes.


Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in hypertension due to primary aldosteronism: a case for exclusion.
Aldosterone antagonists are the mainstay of therapy in patients with hypertension due to primary aldosteronism. However, in our experience, these patients are sometimes placed on angiotensin-converting enzyme (ACE) inhibitors in accordance with guidelines applying to the general hypertensive population. We believe this practice is inappropriate because of the inability of ACE inhibitors to lower blood pressure in patients with low renin levels. Furthermore, pleiotropic effects of ACE inhibitors are unlikely to provide significant benefits in the absence of blood pressure reduction. Therefore, ACE inhibitors should be discouraged for the majority of patients with primary aldosteronism, even in the face of renal or cardiac disease.


Thiamine supplementation may be associated with improved prognosis in patients with sepsis.
Sepsis is a clinical syndrome characterised by a severe disorder of pathophysiology caused by infection of pathogenic micro-organisms. The addition of antioxidant micronutrient therapies such as thiamine to sepsis treatment remains controversial. This study explored the effect of thiamine on the prognosis of patients with sepsis. This study was a retrospective study involving patients with sepsis from the Medical Information Mart for Intensive Care IV. Patients were divided into two groups, the thiamine received group (TR) and the thiamine unreceived group (TUR), according to whether they were supplemented with thiamin via intravenous while in the intensive care unit (ICU). The primary outcome was ICU mortality. The association between thiamine and outcome was analysed using the Cox proportional hazards regression model, propensity score matching (PSM), generalised boosted model-based inverse probability of treatment weighting (IPTW) and doubly robust estimation. A total of 11 553 sepsis patients were enrolled in this study. After controlling for potential confounders using Cox regression models, the TR group had a statistically significantly lower ICU mortality risk than the TUR group. The hazard ratio of ICU mortality for the TR group was 0·80 (95 % CI 0·70, 0·93). We obtained the same results after using PSM, IPTW and doubly robust estimation. Supplementation with thiamine has a beneficial effect on the prognosis of patients with sepsis. More randomised controlled trials are needed to confirm the effectiveness of thiamine supplementation in the treatment of sepsis.


Effect of dietary nucleotide supplementation on growth and immune function in term infants: a randomized controlled trial.
To examine the effect of nucleotide (NT)-supplemented cow's milk-based formula on growth and biochemical indices of immune function in healthy infants. Randomized controlled trial (RCT) of formula-fed term infants allocated to control formula with an innate level of NT at 10 mg/l (n = 102), or formula fortified with NT at 33.5 mg/l (n = 98). A parallel group of 125 breastfed infants followed the same protocol as a reference. Growth was assessed at enrolment, 7 weeks, 4 months and 7 months of age. Natural killer cell activity, cytokine production and lymphocyte subpopulations were assessed at 7 weeks of age. Antibody responses to diphtheria toxoid, tetanus toxoid and Haemophilus influenzae type b (Hib) immunizations were measured at 7 months of age. NT supplementation did not influence the growth of formula fed infants or any markers of immunity measured at 7 weeks of age. Antibody responses to tetanus toxoid were higher in the NT-supplemented group (n = 68) compared with the control group (n = 70) at 7 months of age (median (5th, 95% percentile): 1.57(0.42, 3.43) vs 1.01(0.41, 4.66) IU/ml, P < 0.03). A difference between treatments was seen in response to diphtheria toxoid but this effect disappeared when adjusted for hepatitis B immunization at birth. There was no effect of treatment on antibody responses to Hib immunization. Supplementation of formulas with NT at 33.5 mg/l resulted in a modest improvement in antibody response consistent with RCTs that used higher levels of NT supplementation. Whether this translates to clinical benefits in well-nourished infants requires further study. Supported by a grant from Wyeth Nutrition. Dr Makrides was supported by an RD Wright Fellowship from the National Health and Medical Research Council of Australia and Dr Gibson was partially supported by the MS McLeod Research Trust and a Senior Research Fellowship from the National Health and Medical Research Council of Australia.


Use of traditional medicine in Lao PDR.
Exploring the attitudes and knowledge of household members and health staff in Lao PDR regarding the use of traditional medicine. Along with modern medicine, traditional medicine utilisation is officially supported in Laos, being part of the cultural heritage and considered useful for this low-income country in relation to the problems with access to modern pharmaceuticals. The study population comprised 600 households from one lowland (Pakse) and one mountainous (Paksong) district. In a stratified two-stage sampling procedure, household surveys were conducted and focus group discussions (FGD) were performed among health staff and villagers in the same districts. Seventy-seven per cent of the households stated the ever use of traditional medicine including herbal medicines, sauna, massage and acupuncture. The main reason given was perceived efficacy. Traditional medicine was used for both chronic and acute diseases. The FGD revealed the perceived need to have training courses for traditional medicine providers and to have a medicinal garden in the villages. Utilisation was similar in lowland and mountainous districts as well as in urban and rural areas. The study indicates that traditional medicine is widely used and perceived as effective by a fairly large proportion of Lao people. The findings may form a basis for health sector reforms that are congruent with perceived local needs, e.g. in establishing a strategic plan for the development of the traditional medicine sector in Lao PDR.


The 2008 annual report of the Regional Infant and Child Mortality Review Committee.
The 2008 annual report of the Regional Infant and Child Mortality Review Committee (RICMRC) is presented. This committee has as its mission the review of infant and child deaths so that information can be transformed into action to protect young lives. The 2008 review area includes South Dakota's Minnehaha, Turner, Lincoln, Moody, Lake, McCook, Union, Hansen, Miner and Brookings counties. Within our region in 2008, there were six infant deaths labeled as Sudden Unexpected Infant Deaths (SUID), of which two met the criteria for the Sudden Infant Death Syndrome (SIDS). The four non-SIDS SUID deaths all represented deaths where asphyxia from unsafe sleeping environments could not be excluded. In addition, there were two accidental deaths from asphyxia in unsafe sleeping enviroments. We need to continue to promote the "Back to Sleep" campaign message of not only placing infants to sleep on their backs, but also making sure infants are put down to sleep on safe, firm, sleeping surfaces and are appropriately dressed for the ambient temperature. Parents need to be aware of the potential hazards of bed-sharing with their infants. In both 2007 and 2008, four children died in motor vehicle crashes, none of which were alcohol-related. Three fire-related childhood deaths were associated with one house fire involving a nonfunctional smoke alarm and a sleeping arrangement without an easy egress from a fire. Since 1997, the RICMRC has sought to achieve its mission to "review infant and child deaths so that information can be transformed into action to protect young lives". For 2008, the committee reviewed 21 deaths from Minnehaha, Turner, Lincoln, Moody, Lake, McCook, Union, Hansen, Miner and Brookings counties that met the following criteria: Children under the age of 18 dying subsequent to hospital discharge following delivery. Children who either died in these counties from causes sustained in them, or residents who died elsewhere from causes sustained in the ten-county region.


HYPERREFLECTIVE FOCI AS AN INDEPENDENT VISUAL OUTCOME PREDICTOR IN MACULAR EDEMA DUE TO RETINAL VASCULAR DISEASES TREATED WITH INTRAVITREAL DEXAMETHASONE OR RANIBIZUMAB.
To evaluate the potential role of hyperreflective foci (HF) in predicting visual outcome in patients undergoing treatment for macular edema due to retinal vascular diseases. Data and images of 92 patients with macular edema due to diabetes mellitus or branch retinal vein occlusion, treated with either intravitreal dexamethasone implant or ranibizumab, were analyzed. All patients underwent best-corrected visual acuity measurement, slit-lamp examination, spectral domain optical coherence tomography at baseline and at all time points of the follow-up (Month 1, 2, 3, 6, and 9). Generalized least squares random effects linear or logistic regression analysis was used to investigate potential factors associated with the final best-corrected visual acuity and number of HF, respectively. Increasing age (P < 0.001), central retinal thickness (P < 0.001), number of HF (P = 0.028), presence of subretinal fluid (P < 0.001), intraretinal fluid (P < 0.001), intraretinal cysts (P < 0.001), and disruption of ellipsoid zone/external limiting membrane (P < 0.001) were significantly associated with poorer visual outcome. Factors associated with HF were increasing central retinal thickness (P = 0.003), presence of subretinal fluid (P = 0.049), intraretinal fluid (P = 0.002), cysts (P = 0.015), and disruption of ellipsoid zone (P = 0.047). No significant differences in change in best-corrected visual acuity, central retinal thickness, and HF were observed between the two treatment groups. Hyperreflective foci are associated with poorer visual outcome in patients with macular edema due to retinal vascular diseases. Similar reductions in HF are achieved by intravitreal steroid and anti-vascular endothelial growth factor agent.


Chemotherapy for multiple myeloma.
The effects of eight different drug combinations were evaluated in 256 patients with multiple myeloma. The response rate and time to remission were superior from regimens that added both vincristine and Adriamycin (doxorubicin) to an alkylating agent-prednisone combination. There was no improvement in response rate or survival time from two alternating drug combinations evaluated in an attempt to achieve more marked tumor reductions and to delay the emergence of resistant subclones. The addition of levamisole during remission maintenance did not improve survival time. Results supported the utility of unmaintained remission follow-up in selected patients with marked reductions in myeloma cell mass.


Mechanochemically assisted morphing of shape shifting polymers.
Morphing in creatures has inspired various synthetic polymer materials that are capable of shape shifting. The morphing of polymers generally relies on stimuli-active (typically heat and light active) units that fix the shape after a mechanical load-based shape programming. Herein, we report a strategy that uses a mechanochemically active 2,2'-bis(2-phenylindan-1,3-dione) (BPID) mechanophore as a switching unit for mechanochemical morphing. The mechanical load on the polymer triggers the dissociation of the BPID moiety into stable 2-phenylindan-1,3-dione (PID) radicals, whose subsequent spontaneous dimerization regenerates BPID and fixes the temporary shapes that can be effectively recovered to the permanent shapes by heating. A greater extent of BPID activation, through a higher BPID content or mechanical load, leads to higher mechanochemical shape fixity. By contrast, a relatively mechanochemically less active hexaarylbiimidazole (HABI) mechanophore shows a lower fixing efficiency when subjected to the same programing conditions. Another control system without a mechanophore shows a low fixing efficiency comparable to the HABI system. Additionally, the introduction of the BPID moiety also manifests remarkable mechanochromic behavior during the shape programing process, offering a visualizable indicator for the pre-evaluation of morphing efficiency. Unlike conventional mechanical mechanisms that simultaneously induce morphing, such as strain-induced plastic deformation or crystallization, our mechanochemical method allows for shape programming after the mechanical treatment. Our concept has potential for the design of mechanochemically programmable and mechanoresponsive shape shifting polymers.


Co-Trimoxazole-Induced DRESS Syndrome: A Case Report.
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS syndrome) is a severe adverse drug reaction. The drugs, which most commonly induce this condition, are anti-convulsants and sulfonamides. A 15-year-old Thai woman with no known underlying disease was prescribed co-trimoxazole, and two months after initiation, DRESS was diagnosed by RegiSCAR's score. Her clinical symptoms were fever laboratory abnormalities and maculopapular rash on her face, trunk and extremities. She was treated with antipyretics, antihistamines and steroid therapy, and her clinical and laboratory findings were restored to normal by the 10th day of treatment. Early diagnosis, discontinuation of the culprit drug, and management with steroids therapy can reduce the severity of DRESS syndrome.


Cardiac autonomic function in patients with diabetes improves with practice of comprehensive yogic breathing program.
The aim of this study was to observe the effect comprehensive yogic breathing (Sudarshan Kriya Yoga [SKY] and Pranayam) had on cardiac autonomic functions in patients with diabetes. This is a prospective randomized controlled intervention trial. Cardiac autonomic functions were assessed in 64 diabetics. Patients were randomized into two groups, one group receiving standard therapy for diabetes and the other group receiving standard therapy for diabetes and comprehensive yogic breathing program. Standard therapy included dietary advice, brisk walking for 45 min daily, and administration of oral antidiabetic drugs. Comprehensive yogic breathing program was introduced to the participants through a course of 12 h spread over 3 days. It was an interactive session in which SKY, a rhythmic cyclical breathing, preceded by Pranayam is taught under the guidance of a certified teacher. Cardiac autonomic function tests were done before and after 6 months of intervention. In the intervention group, after practicing the breathing techniques for 6 months, the improvement in sympathetic functions was statistically significant (P 0.04). The change in sympathetic functions in the standard therapy group was not significant (P 0.75). Parasympathetic functions did not show any significant change in either group. When both parasympathetic and sympathetic cardiac autonomic functions were considered, there was a trend toward improvement in patients following comprehensive yogic breathing program (P 0.06). In the standard therapy group, no change in cardiac autonomic functions was noted (P 0.99). Cardiac autonomic functions improved in patients with diabetes on standard treatment who followed the comprehensive yogic breathing program compared to patients who were on standard therapy alone.


Glycogen distribution in mouse hippocampus.
The hippocampus is a limbic structure involved in the consolidation of episodic memory. In the recent decade, glycogenolysis in the rodent hippocampus has been shown critical for synaptic plasticity and memory formation. Astrocytes are the primary cells that store glycogen which is subject to degradation in hypoglycemic conditions. Focused microwave application to the brain halts metabolic activities, and therefore preserves brain glycogen. Immunohistochemistry against glycogen on focused microwave-assisted brain samples is suitable for both macroscopic and microscopic investigation of glycogen distribution. Glycogen immunohistochemistry in the hippocampus showed a characteristic punctate signal pattern that depended on hippocampal layers. In particular, the hilus is the most glycogen-rich subregion of the hippocampus. Moreover, large glycogen puncta (>0.5 µm in diameter) observed in neuropil areas are organized in a patchy pattern consisting of puncta-rich and -poor astrocytes. These observations are discussed with respect to distinct hippocampal neural activity states observed in live animals.


Implementing best practice in hospital multidisciplinary nutritional care: an example of using the knowledge-to-action process for a research program.
Prospective use of knowledge translation and implementation science frameworks can increase the likelihood of meaningful improvements in health care practices. An example of this creation and application of knowledge is the series of studies conducted by and with the Canadian Malnutrition Task Force (CMTF). Following a cohort study and synthesis of evidence regarding best practice for identification, treatment, and prevention of malnutrition in hospitals, CMTF created an evidence-informed, consensus-based pathway for nutritional care in hospitals. The purpose of this paper is to detail the steps taken in this research program, through four studies, as an example of the knowledge-to-action (KTA) process. The KTA process includes knowledge creation and action cycles. The steps of the action cycle within this program of research are iterative, and up to this point have been informed by three studies, with a fourth underway. The first study identified the magnitude of the malnutrition problem upon admission to hospital and how it is undetected and undertreated (study 1). Knowledge creation resulted in an evidence-based pathway established to address care gaps (study 2) and the development of monitoring tools (study 3). The study was then adapted to local context: focus groups validated face validate the evidence-based pathway; during the final phase, study site implementation teams will continue to adapt the pathway (studies 2 and 4). Barriers to implementation were also assessed; focus groups and interviews were conducted to inform the pathway implementation (studies 1, 2, and 4). In the next step, specific interventions were selected, tailored, and implemented. In the final study in this research program, plan-do-study-act cycles will be used to make changes and to implement the pathway (study 4). To monitor knowledge use and to evaluate outcomes, audits, staff surveys, patient outcomes, etc will be used to record process evaluations (studies 3 and 4). Finally, a sustainability plan will be incorporated into the final study of the program (study 4) to sustain knowledge use. Use of frameworks can increase the likelihood of meaningful and sustainable improvements in health care practice. The example of this program of research demonstrates how existing evidence has been used to identify, create, and adapt knowledge, and how multidisciplinary teams have been used to effect changes in the hospital setting. Effective implementation is essential in nutritional health care, and this multidisciplinary program of research provides an example of how the KTA process can facilitate implementation and promote sustainability.


Treatment of congestive heart failure: present and future.
The treatment of patients with congestive heart failure has markedly improved over the past 25 years. The most successful therapy has been attenuation of neurohumoral overactivation with antagonists of the renin-angiotensin-aldosterone system, as well as beta-adrenergic blockade. Cardiac surgical interventions, which include not only aortocoronary artery bypass surgery but also interventions that remodel the heart and repair the mitral valve, have also been advocated. However, randomized clinical trials to prove their benefit and to identify which patients could derive the most benefit from these interventions are lacking. Cardiac devices, such as biventricular pacemakers (for cardiac resynchronization) and implantable cardiac defibrillators, have proved useful in improving survival and quality of life. The treatment of sleep apnea with continuous positive airway pressure has shown some promise, as has immune modulation therapy, but more research to conclusively prove their efficacy is necessary. Cell therapy with skeletal myoblasts or pluripotential stem cells is an interesting and emerging area of research that shows enormous promise. However, fundamental questions regarding the optimal use of this therapy remain unanswered. Finally, although exciting, these developments, along with the changing demographics of the Canadian population, will require a change in the way we provide care for patients with congestive heart failure. These changes will require greater involvement of health care professionals other than physicians, and greater emphasis on outpatient care, early detection and prevention, and evidence-based practice.


Isotropic non-Heisenberg terms in the magnetic coupling of transition metal complexes.
This paper analyzes the different contributions to the magnetic coupling in systems with more than one unpaired electron per center. While in S=12 spin systems the Heisenberg Hamiltonian involving only bilinear exchange interactions is reliable for the description of the magnetic states, biquadratic exchange interactions must be sometimes introduced for S=1 (or higher) spin systems to account for isotropic deviations to Heisenberg behavior. The analysis establishes that the excited atomic states, the so-called non-Hund states, are responsible for the main contribution to the deviations. The kinetic exchange contribution and the spin, hole, and particle polarizations increase the magnetic coupling but essentially maintain the Heisenberg pattern. The importance of the different contributions has been studied for a series of Ni(2) compounds with a polarizable double azido bridge. The coupling between two Fe(3+) ions in the molecular crystal Na(3)FeS(3), which is known experimentally to present large deviations to Heisenberg behavior, has also been investigated.


The olive oil antioxidant hydroxytyrosol efficiently protects against the oxidative stress-induced impairment of the NObullet response of isolated rat aorta.
The Mediterranean diet, which is abundant in antioxidants, is associated with a relatively low incidence of coronary heart disease. Olive oil and olives, which contain the antioxidants hydroxytyrosol, oleuropein, and tyrosol, are important components of this diet. In this study, the effects of oxidative stress on the nitric oxide radical (NO(*))-mediated relaxation of rat aorta and the protection by these antioxidants were determined. Cumene hydroperoxide (CHP) was used to mimic oxidative stress induced by lipid hydroperoxides, which is mediated by the formation of hydroxyl radicals (OH(*)). CHP (300 microM) impaired the NO(*)-mediated relaxation of rat aorta by the acetylcholine receptor agonist carbachol (P < 0.05). This was due to a reduction in NO(*) production. A diminished NO(*)-mediated relaxation disturbs the vascular tone and leads to a rise in blood pressure, which is a well-established risk factor for coronary heart disease. Hydroxytyrosol (10 microM) efficiently protected the aorta against the CHP-induced impairment of the NO(*)-mediated relaxation (P < 0.05). Oleuropein, tyrosol, and homovanillic alcohol, a major metabolite of hydroxytyrosol, did not show protection. Moreover, hydroxytyrosol was found to be a potent OH(*) scavenger, which can be attributed to its catechol moiety. Because of its amphiphilic characteristics (octanol-water partitioning coefficient = 1.1), hydroxytyrosol will readily cross membranes and provide protection in the cytosol and membranes, including the water-lipid interface. The present study provides a molecular basis for the contribution of hydroxytyrosol to the benefits of the Mediterranean diet.


Molecular genetic analysis of transposase-end DNA sequence recognition: cooperativity of three adjacent base-pairs in specific interaction with a mutant Tn5 transposase.
Transposition of Tn5 and IS50 requires the specific binding of transposase (Tnp) to the end inverted repeats, the outside end (OE) and the inside end (IE). OE and IE have 12 identical base-pairs and seven non-identical base-pairs. Previously we described the isolation of a Tnp mutant, EK54, that shows an altered preference for OE versus IE compared to wild-type (wt) Tnp. EK54 enhances OE recognition and decreases IE recognition both in DNA binding and in overall transposition. Here we report that base-pairs 10, 11 and 12 of the OE are critical for the specific recognition by EK54 Tnp. These three adjacent base-pairs act cooperatively; all three must be present in order for EK54 Tnp to interact very favorably with the end DNA. The existence of only one or two of these three base-pairs decreases binding of EK54 Tnp. The combined use of EK54 Tnp and a new OE/IE mosaic end sequence containing the OE base-pairs 10, 11 and 12 gives rise to an extraordinarily high transposition frequency. Just as the Tnp is a multifunctional protein, the nucleotides in the 19 bp Tn5 ends also affect other functions besides Tnp binding. Furthermore, the fact that we were able to isolate end sequence variants that transpose at a higher frequency than the natural ends (OE and IE) with wt Tnp reveals yet another way in which the wt transposition frequency is depressed, i.e. by keeping the end sequences suboptimal.


Occupational risks of zoonotic infections in Dutch forestry workers and muskrat catchers.
Lyme borreliosis (LymeB), Hemorrhagic fever with renal syndrome (HemoFRS), Lymphocytic choriomeningitis (LymphoCM), Tick-borne encephalitis (TickBE), Q Fever (QFever), and Weil's leptospirosis (Lepto) are known to be occupational diseases for rural outdoor workers. We investigated the occupational infection risks for these diseases in greater detail. Antibodies to these agents were assessed in 312 forestry workers and muskrat catchers, and in 356 matched office workers. Three levels of occupational exposure were distinguished: high for active forestry workers, low for supervisory forestry staff and muskrat catchers and zero for office workers. At high exposure the prevalence odds ratios (with 95% CI between brackets) were: LymeB 15 (5.5-42), HemoFRS 11 (1.3-501), LymphoCM 5.4 (1.0-50), TickBE 1.0 (0.3-3.0), QFever 1.0 (0.4-2.1), and Lepto 0 (0.0-33). No significant risk of infection was found at low exposure. Part of the present group had also been studied in 1989 and 1990. Within this cohort the conversion rates to Borrelia burgdorferi have been estimated for the periods 1989-1990 and 1990-1993 as 0.23 and 0.066 year(-1), respectively, and the reversion rate as 0.44 year(-1). The corresponding values for HemoFRS were 0.031, 0.018 and 1.42 year(-1). Active forestry workers in the Netherlands are at high risk of infection by LymeB, HemoFRS and LymphoCM. Prevalence of antibodies to LymeB and HemoFRS appeared to reflect the levels of these infection hazards in recent history.


Postoperative cerebellar mutism syndrome following treatment of medulloblastoma: neuroradiographic features and origin.
The origin and long-term outcome of cerebellar mutism syndrome (CMS), a postoperative syndrome of diminished speech, hypotonia, and ataxia that affects approximately 25% of patients with medulloblastoma, is poorly elucidated. The current study was undertaken to determine factors associated with development of CMS, a means to determine its severity or cause, and outcomes of patients with this syndrome. The study included 28 children with medulloblastoma who either underwent an operation or were referred to the authors' institution soon after surgery. Eleven (39%) of these children had CMS. The preoperative, immediate postoperative, and 1-year postoperative MR images were reviewed by a neuroradiologist blinded to diagnosis of CMS. The severity of mutism and neurological and neurocognitive outcomes were examined. Preoperative MR images showed no differences in tumor size, hydrocephalus, or peritumoral edema in patients with and without CMS. An association with brainstem invasion was significant (p < 0.05), and there was a trend toward an association with involvement of the cerebellomedullary angle (p = 0.08). Images obtained immediately postoperatively showed cerebellar edema in 92% of all patients; there were trends for more middle and superior cerebellar peduncle edema in patients with CMS (p = 0.05 and 0.07, respectively). At 1 year postoperatively, patients with CMS showed more moderate to severe atrophy/gliosis of total cerebellum (p < 0.01), vermis (p < 0.01), and brainstem (p < 0.05). Mean IQ was 16 points lower in patients with CMS (IQ = 84.2 +/- 15.8) compared with those without CMS (IQ = 100.4 +/- 17.4), with a trend toward significance (p = 0.07). This study demonstrates that CMS is associated with postoperative damage to the cerebellum and brainstem, damage not predicted by immediate postoperative MR imaging, and with poorer associated functional outcome.


Familial resemblance in eating behaviors in men and women from the Quebec Family Study.
It is commonly recognized that genetic, environmental, behavioral, and social factors are involved in the development of obesity. The family environment may play a key role in shaping children's eating behaviors. The purpose of this study was to estimate the degree of familial resemblance in eating behavioral traits (cognitive dietary restraint, disinhibition, and susceptibility to hunger). Eating behavioral traits were assessed with the Three-Factor Eating Questionnaire in 282 men and 402 women (202 families) from the Quebec Family Study. Familial resemblance for each trait (adjusted for age, sex, and BMI) was investigated using a familial correlation model. The pattern of familial correlation showed significant spouse correlation for the three eating behavior phenotypes, as well as significant parent-offspring and sibling correlations for disinhibition and susceptibility to hunger. According to the most parsimonious model, generalized heritability estimates (including genetic and shared familial environmental effects) reached 6%, 18%, and 28% for cognitive dietary restraint, disinhibition, and susceptibility to hunger, respectively. These results suggest that there is a significant familial component to eating behavioral traits but that the additive genetic component appears to be small, with generalized heritability estimates ranging from 6% to 28%. Thus, non-familial environmental factors and gene-gene and gene-environmental interactions seem to be the major determinants of the eating/behavioral traits.


Aging and Veterinary Care of Cats, Dogs, and Horses through the Records of Three University Veterinary Hospitals.
The present article examines over 63,000 medical records belonging to the Veterinary Hospitals of the Universities of Bologna, Torino, and Padova, all in Northern Italy, and relative to dogs (approximately 50,000), cats (approximately 12,000), and companion horses (slightly less than 1,000). The animals of the three species were divided into age classes and categorized per sex into males, females, and neutered individuals. The mean age at visit and the effects of age classes and category (analyzed via ANOVA) are presented and discussed. The data indicate that many animals are presented to the hospitals either in the early phases of their life (presumably for vaccination and, in cats and dogs, gonadectomy) or in the advanced age (over 10 years in dogs, over 15 years in cats, and over 17 years in horses). The records of very old individuals of the three species are also reported. On the whole, the results suggest that a growing population of mature to old domestic carnivores or companion horses reaches ages that were considered exceptional only a few years ago. The data also testify an evolution in the animal-owner relationship and a renewed respect for the value of life in companion domestic mammals.


ETV6-RUNX1 + Acute Lymphoblastic Leukaemia in Identical Twins.
Acute leukaemia is the major subtype of paediatric cancer with a cumulative risk of 1 in 2000 for children up to the age of 15 years. Childhood acute lymphoblastic leukaemia (ALL) is a biologically and clinically diverse disease with distinctive subtypes; multiple chromosomal translocations exist within the subtypes and each carries its own prognostic relevance. The most common chromosome translocation observed is the t(12;21) that results in an in-frame fusion between the first five exons of ETV6 (TEL) and almost the entire coding region of RUNX1 (AML1).The natural history of childhood ALL is almost entirely clinically silent and is well advanced at the point of diagnosis. It has, however, been possible to backtrack this process through molecular analysis of appropriate clinical samples: (i) leukaemic clones in monozygotic twins that are either concordant or discordant for ALL; (ii) archived neonatal blood spots or Guthrie cards from individuals who later developed leukaemia; and (iii) stored, viable cord blood cells.Here, we outline our studies on the aetiology and pathology of childhood ALL that provide molecular evidence for a monoclonal, prenatal origin of ETV6-RUNX1+ leukaemia in monozygotic identical twins. We provide mechanistic support for the concept that altered patterns of infection during early childhood can deliver the necessary promotional drive for the progression of ETV6-RUNX1+ pre-leukaemic cells into a postnatal overt leukaemia.


The complete DNA sequence of lymphocystis disease virus.
Lymphocystis disease virus (LCDV) is the causative agent of lymphocystis disease, which has been reported to occur in over 100 different fish species worldwide. LCDV is a member of the family Iridoviridae and the type species of the genus Lymphocystivirus. The virions contain a single linear double-stranded DNA molecule, which is circularly permuted, terminally redundant, and heavily methylated at cytosines in CpG sequences. The complete nucleotide sequence of LCDV-1 (flounder isolate) was determined by automated cycle sequencing and primer walking. The genome of LCDV-1 is 102.653 bp in length and contains 195 open reading frames with coding capacities ranging from 40 to 1199 amino acids. Computer-assisted analyses of the deduced amino acid sequences led to the identification of several putative gene products with significant homologies to entries in protein data banks, such as the two major subunits of the viral DNA-dependent RNA polymerase, DNA polymerase, several protein kinases, two subunits of the ribonucleoside diphosphate reductase, DNA methyltransferase, the viral major capsid protein, insulin-like growth factor, and tumor necrosis factor receptor homolog.


Characteristics of Astigmatism after MyoRing Implantation.
Considering the rising number of MyoRing implantation procedures in keratoconic corneas and the refractive outcomes associated with this treatment modality, this study aimed to evaluate and compare the magnitude and axis orientation of total and corneal astigmatism between before and after MyoRing implantation in 34 eyes of 28 patients with keratoconus (KCN) (mean age: 29.41 ± 7.0 years). The inclusion criterion was a reliable diagnosis of clinical KCN based on corneal biomicroscopic and tomographic findings. The mean total astigmatism of ocular refraction decreased significantly from -4.27 ± 3.15 D (before MyoRing implantation) to -2.18 ± 1.63 D (after MyoRing implantation) (P < 0.001). The mean astigmatism in the anterior and posterior surface of the cornea decreased significantly by 1.16 D (P = 0.001) and 0.24 D (P = 0.009), respectively, after MyoRing implantation. Before MyoRing implantation, the axis orientation of total ocular astigmatism for with-the-rule, oblique, and against-the-rule astigmatism was 21%, 42%, and 37%, respectively; at 6 months after MyoRing implantation, it was 18%, 24%, and 58%, respectively. Before MyoRing implantation, the axis orientation for with-the-rule, against-the-rule, and oblique astigmatism of the anterior surface of the cornea was 59%, 24%, and 17%, respectively; at 6 months after MyoRing implantation, it was 52%, 24%, and 24%, respectively. Before MyoRing implantation, the axis orientation of with-the-rule, oblique, and against-the-rule astigmatism of the posterior surface of the cornea was 68%, 29%, and 3%, respectively; at 6 months after MyoRing implantation, it was 67%, 12%, and 12%, respectively. MyoRing implantation significantly decreased the amount of total, anterior, and posterior corneal astigmatism.


Structural and topological studies of cholesteatoma proteins, in relation to the keratinization process.
For the extraction of soft keratins from bovine snout or human epidermis the best results were obtained with a detergent (sodium dodecyl sulphate, SDS) or hydrogen bond breaking agent (urea) in a reducing medium (2-mercaptoethanol, 2-ME). N-acetylcysteine was a little less effective. Keratins from both sources gave typical sets of protein bands with molecular weights between 40.000 and 70.000 daltons. Upon electrofocusing special precautions had to be taken to avoid reoxidation and reaggregation of protein subunits. Keratins from aural cholesteatomas were obtained by extraction with SDA and 2-ME, with N-acetylcysteine alone and to a lesser extent with urea and 2-ME. The pattern of these keratins on SDS-gel is less complicated than that obtained from human skin or bovine snout. Histophotometric results argue for a clear analogy between the nuclear DNA metabolism in normal skin epidermis and cholesteatoma matrix. The only differences of potential relevance are the much wider range of the nuclear DNA amount in cholesteatoma stratum basale cells compared with basal cells in normal epidermis, and the higher persistence of nuclear DNA in cholesteatoma stratum granulosum, indicating postponement of keratinocyte terminal differentiation.


[Wernicke-Korsakoff syndrome secondary to cytomegalovirus encephalitis: A case report].
Cytomegalovirus (CMV) is one of the opportunistic microorganisms with the highest prevalence in immunocompromised patients. Reactivation has decreased after the introduction of highly active antiretroviral therapy (HAART). Encephalitis has been reported in the coinfection as one of the most frequent presentations.We present the case of a young adult patient with HIV infection and rapid neurological deterioration due to classic clinical symptoms and signs of the Wernicke-Korsakoff syndrome, with no risk factors for thiamine deficiency, with images by nuclear magnetic resonance typical of the syndrome, and identification of cytomegalovirus in cerebrospinal fluid. The specific treatment for CMV managed to control the symptoms with neurological sequelae in progression towards improvement.This is one of the few cases reported in the literature of Wernicke syndrome secondary to cytomegalovirus encephalitis.


Differential expression of Glomus intraradices genes in external mycelium and mycorrhizal roots of tomato and barley.
Relative quantitative RT-PCR and western blotting were used to investigate the expression of three genes with potentially regulatory functions from the arbuscular mycorrhizal fungus Glomus intraradices in symbiosis with tomato and barley. Standardisation of total RNA per sample and determination of different ratios of plant and fungal RNA in roots as colonisation proceeded were achieved by relative quantitative RT-PCR using universal (NS1/NS21) and organism-specific rRNA primers. In addition, generic primers were designed for amplification of plant or fungal beta-tubulin genes and for plant glyceraldehyde-3-phosphate dehydrogenase (GAPDH) genes as these have been suggested as useful controls in symbiotic systems. The fungal genes Ginmyc1 and Ginhb1 were expressed only in the external mycelium and not in colonised roots at both mRNA and protein levels, with the proteins detected almost exclusively in the insoluble fractions. In contrast, mRNA of Ginmyc2 was identified in both external and intraradical mycelium. In mycorrhizal roots, Ginmyc2 and fungal beta-tubulin mRNAs increased in proportion to fungal rRNA as colonisation proceeded, suggesting that accumulation reflected intraradical fungal growth. Fungal alpha-tubulin protein and beta-tubulin mRNA both appeared to be more abundantly accumulated in AM hyphae within heavily colonised roots than in external hyphae, relative to fungal rRNA. Tomato GAPDH mRNA accumulation was proportional to tomato rRNA, but accumulation of tomato beta-tubulin mRNA was reduced in colonised roots compared to non-mycorrhizal roots. These results provide novel evidence of differential spatial and temporal regulation of AM fungal genes, indicate that the expression of tubulin genes of both plant and fungus may be regulated during colonisation and validate the use of multiple 'control' genes in analysis of mycorrhizal gene expression.


Cementless total hip arthroplasty after failed internal fixation of acetabular fractures: A single center experience of 25 consecutive patients.
Total hip arthroplasty (THA) is an available surgical option for failed acetabular fracture, previously managed by open reduction and internal fixation. This study aimed to report the postoperative outcomes of cementless THA in patients with this condition. Between November 2000 and September 2016, 25 consecutive cementless THAs for failed internal fixation after acetabular fractures with a minimum follow-up of 2 years were analyzed. The mean age at the time of surgery was 58 years (36-85 years), and the time elapsed between fracture and THA was 70 months (7-213 months). Clinical and radiologic evaluations were performed on all patients. Clinically, the mean Harris hip score at the last follow-up was 88 points. Walking ability recovered to pre-injury status in 92% patients, and activities of daily living recovered in 96% patients. Radiographically, none of the acetabular cups showed evidence of migration and loosening during the mean follow-up of 50 months. All cases showed stable femoral stem fixation at the last follow-up. Dislocation occurred in three cases (12%). Outcomes of cementless THA after failed internal fixation for acetabular fractures were satisfactory. However, a relatively high incidence of postoperative dislocation is still a concern.


Generation of Micronuclei and Detection of Chromosome Pulverization.
Lagging chromosomes that arise after chromosome mis-segregation during cell division can be encapsulated within small structures known as micronuclei. A link between whole-chromosome mis-segregation and chromothripsis has been demonstrated via micronuclear chromosome pulverization. Here, we describe methods to efficiently generate micronuclei and examine downstream cell fates, specifically with regard to DNA damage and chromosome pulverization.