Repeated administration of gamma-hydroxybutyric acid (GHB) to mice: assessment of the sedative and rewarding effects of GHB.
Because of the sedative/hypnotic and euphoric effects of gamma-hydroxybutyric acid (GHB), the recreational use of the drug has increased significantly. In the current study we investigated the sedative and rewarding effects of GHB in Swiss Webster mice. Although the acute administration of GHB (200 mg/kg) caused marked hypolocomotion, repeated administration of the drug for 6 or 14 days produced tolerance to this effect. In addition, the administration of GHB 300 mg/kg to naive mice caused catalepsy, which dissipated in mice pre-exposed to GHB (200 mg/kg). Consequently, after repeated treatment with GHB, tolerance developed to both the hypolocomotion and cataleptic effects of the drug. The administration of GHB or its precursor gamma-butyrolactone for 14 days increased the striatal content of dopamine. The sedative effects of GHB may be due to hypodopaminergic activity from inhibition of dopamine release and a subsequent increase in the intraneuronal dopamine level. The rewarding effect of GHB was assessed in the conditioned place preference paradigm. Mice treated repeatedly with 250 mg/kg for 7 days developed conditioned preference for the GHB-paired compartment of the cage, suggesting that the GHB cue is rewarding. The development of tolerance to the sedative effects of GHB coupled with the rewarding properties of the drug support the abuse potential of GHB. Further studies are necessary to determine the mechanism underlying the development of tolerance to GHB and the rewarding effect of the drug.


Single-portal arthroscopy: report of a new technique.
A new technique of single-portal arthroscopy using new instrumentation for arthroscopic knee surgery is reported. The procedure is intended for "targeted" surgery to address limited pathology. The arthroscope, cutters, and biters are all introduced into the joint through 1 portal. The technique is generally applicable to knee arthroscopy for isolated conditions and potentially useful in treating other joints. A 2.9-mm-diameter, light-sensitive, high-definition, 20-cm-long arthroscope is inserted through a 4.6-mm cannula. This arthroscope-cannula combination yields fluid flow mechanics similar to a standard 4-mm arthroscope in a 5.8-mm cannula. A Parallel Portal Cannula (PPC) (Stryker Endoscopy) is applied to the arthroscope cannula, producing a "double-barrel" system for entry into the joint. The PPC allows for sliding and rotational freedom along the axis of the arthroscope cannula but also locks in place once a desired position is achieved. PPC devices are available in zero-length, short (25-mm), and long (55-mm) sizes. Cutters that are bent in the mid shaft are available in 3.5- and 4-mm diameters. The instrumentation system allows both viewing with the arthroscope and passage of working cutters and biters through a single 9- to 10-mm portal. Potential advantages of single-portal arthroscopy include decreased patient morbidity and recovery time while still allowing for adequate treatment of limited knee pathology.


Public knowledge of head and neck cancer.
Studies show 60% of patients with newly diagnosed Head & Neck Squamous Cell Cancer in Ireland, present with advanced disease. A poor level of knowledge and awareness among the public of Head & Neck Cancer, is an important consideration in the often delayed presentation for medical attention in many of these cases. Our study surveyed 200 members of the public to assess their knowledge and awareness of Head & Neck Cancer. One hundred and forty (70%) of respondents had never encountered the term "Head & Neck Cancer". One hundred and forty six (73%) failed to identify excessive alcohol consumption as a risk factor. Less than 100 (50%) would have concern about persisting hoarseness or a prolonged oral ulcer. An urgent need exists to raise awareness of Head & Neck Cancer among the public in Ireland.


Altering the speed of a DNA packaging motor from bacteriophage T4.
The speed at which a molecular motor operates is critically important for the survival of a virus or an organism but very little is known about the underlying mechanisms. Tailed bacteriophage T4 employs one of the fastest and most powerful packaging motors, a pentamer of gp17 that translocates DNA at a rate of up to ∼2000-bp/s. We hypothesize, guided by structural and genetic analyses, that a unique hydrophobic environment in the catalytic space of gp17-adenosine triphosphatase (ATPase) determines the rate at which the 'lytic water' molecule is activated and OH- nucleophile is generated, in turn determining the speed of the motor. We tested this hypothesis by identifying two hydrophobic amino acids, M195 and F259, in the catalytic space of gp17-ATPase that are in a position to modulate motor speed. Combinatorial mutagenesis demonstrated that hydrophobic substitutions were tolerated but polar or charged substitutions resulted in null or cold-sensitive/small-plaque phenotypes. Quantitative biochemical and single-molecule analyses showed that the mutant motors exhibited 1.8- to 2.5-fold lower rate of ATP hydrolysis, 2.5- to 4.5-fold lower DNA packaging velocity, and required an activator protein, gp16 for rapid firing of ATPases. These studies uncover a speed control mechanism that might allow selection of motors with optimal performance for organisms' survival.


Age-related requisite concentration of sevoflurane for adequate sedation with combined epidural-general anesthesia.
The requisite anesthetic concentration of sevoflurane required to obtain adequate sedation when sufficient analgesics are supplied has not been determined. The purpose of this study was to determine the requisite age-associated concentration of sevoflurane to obtain an adequate level of anesthesia during combined epidural-general anesthesia by bispectral index (BIS) monitoring. Twenty-seven elective abdominal surgery patients (American Society of Anesthesiologists physical status I-II) were enrolled. The patients were divided into two groups of more or less than 60 years of age. We investigated the concentration of sevoflurane required to obtain an adequate sedation level during combined epidural-general anesthesia, maintaining the BIS value between 40 and 60. The requisite sevoflurane concentration required to keep the BIS value at 40-60 was not stable during surgery. In the younger group, the maximum concentration of sevoflurane needed during surgery was 1.95 ± 0.14 (95% confidence interval: 1.87-2.10) vol%, while it was 1.54 ± 0.44 (95% confidence interval: 1.27-1.80) vol% in the older group (P < 0.01). The requisite concentration of sevoflurane required with combined epidural-general anesthesia was 2.5 vol% for the younger group and 2.0 vol% for the older group as determined by BIS monitoring. We believe that these percentages are sufficient to avoid awareness during surgery with adequate analgesia.


Penetrating keratoplasty in Africa: graft survival and visual outcome.
To study the survival and visual outcome of penetrating keratoplasty in an African setting. A retrospective analysis of 216 corneal grafts, performed on 203 eyes of 186 patients, at Kikuyu Hospital, Kenya over a 5 year period. Half of the transplants were carried out for keratoconus with only 5% of the grafts being undertaken for corneal scarring caused by trachoma or measles. The average follow up was 27.3 months. The probability of graft survival at 2 years was 87.4% (95% CI 80.6%-94.3%) for keratoconus and 64.7% (95% CI 54.8%-74.6%) for other corneal pathologies. Forty seven grafts (21.8%) in 36 patients (17.7%) are known to have become opaque. The commonest causes of graft opacification were bacterial keratitis (6.0%), endothelial failure (6.0%), and graft rejection (5.1%). Preoperatively 55% of keratoconus eyes and 75.7% of non-keratoconus eyes were blind. Postoperatively, 5% of keratoconus eyes and 41.7% of the non-keratoconus eyes were blind. Normal vision was achieved in 53.7% of operated eyes. Grafts carried out for keratoconus had a better visual outcome than grafts performed for other corneal pathologies. Preoperatively, 12.4% of keratoconus and 48.5% of non-keratoconus patients were blind in their better eye. Postoperatively, 1.1% of keratoconus patients and 25.7% of non-keratoconus patients were blind. The number of patients with normal vision in the better eye increased from 32 (17.2%) to 106 (57.0%). Sight was restored to 34 blind patients, but two patients with severe visual impairment preoperatively were blind at their last follow up. There was therefore a net reduction of 32 in the number of blind patients after 216 keratoplasties. Penetrating keratoplasty can be successful in Africa, particularly for keratoconus and other corneal dystrophies. However, penetrating keratoplasty has a limited role in the treatment of blindness from corneal scarring due to trachoma, measles, and vitamin A deficiency for which community based preventive measures must remain the priority.


Transition structures, energetics, and nucleus-independent chemical shifts for 6pi electrocyclizations of dienylketenes to cyclohexadienones: a DFT study.
6pi electrocyclizations of dienylketenes to 2,4-cyclohexadienones have been investigated at the (U)B3LYP/6-31G level and found to be a favored and exothermic process for most dienylketenes. As evidenced by calculations, dienylketene cyclizations proceed via a pseudopericyclic process. If the terminal double bond of dienylketenes is embedded into a benzenoid-type aryl moiety, the partial or complete loss of aromaticity, as indicated by NICS values, increases the activation barrier and makes the reaction less exothermic or even endothermic. The effect of aromaticity is slightly less pronounced for dienylketenes carrying five-membered heterocyclic aromatic substituents. Slightly distorted planar transition structures have been located for these types of cyclizations. Forming bond lengths in transition structures range from 1.950 to 2.339 A.


Impact of a drug bulletin on prescribing oral analgesics in a teaching hospital.
The impact of a drug bulletin on prescribing oral analgesics in a teaching hospital was studied. Using an abbreviated time-series design, prescriptions for oral analgesics for all inpatients were surveyed one, three, and five weeks before and one, three, five, and seven weeks after the distribution of one of the hospital's regular drug bulletins. This bulletin contained guidelines for the treatment of minor, moderate, and severe pain. The 493 patients included in the study were classified by drug category, pain severity, and timer period. The drug categories were: (1) propoxyphene, (2) aspirin or acetaminophen alone or with codeine 8 mg or less, and (3) codeine alone or in combination products with more than codeine 8 mg, or other oral narcotic drugs. Each patient's pain severity was determined by interviewing attendant nursing staff; the validity of this approach was confirmed by correlating nurse and physician perception of pain at one time point. Multivariate contingency table analysis revealed that the drug bulletin significantly (p less than or equal to 0.05) reduced the prescribing of propoxyphene hydrochloride across both the minor and moderate pain categories. An increased use of aspirin and acetaminophen was significant three weeks after the release of the drug bulletin. This effect, however, was not significant at other time points. Drug bulletins can be used to achieve a temporary change in physician prescribing patterns of oral analgesics. For a sustained effect, alternative strategies are needed.


Plasma Inflammatory Cytokines Are Elevated in ALS.
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which leads to death in a median time of 2-3 years. Inflammation has been claimed important to the ALS pathogenesis, but its role is still not well-characterized. In the present study, a panel of five cytokines (IL-2, IL-6, IL-10, IFN-gamma, and TNF-alpha) measured in plasma has been investigated in ALS. These biomarkers of inflammation were measured in a population-based cohort of 79 patients with ALS and 79 age- and sex-matched healthy controls using the Bio-Plex technology (Bio-Rad). All the five cytokines were significantly increased in plasma samples of patients compared with controls (p < 0.0001), with IL-6 having the highest median concentration (10.11 pg/ml) in the ALS group. Furthermore, IL-6 was the plasma cytokine with the highest discrimination ability between patients and controls according to the receiver operating characteristic analysis (area under the curve = 0.93). At a cut-off point of 5.71 pg/ml, it was able to classify patients and controls with 91% of sensitivity and 87% of specificity. In the ALS group, plasma IL-6 concentration correlated with demographic (age: rs = 0.25, p = 0.025) and clinical (revised ALS Functional Rating Scale at evaluation: rs = -0.32, p = 0.007; Manual Muscle Testing: rs = -0.33, p = 0.004; progression: rs = 0.29, p = 0.0395) parameters. In line with previous studies, our results confirm that inflammatory cytokines are elevated in ALS, supporting a possible role of inflammation in disease mechanism and progression. However, the precise role of inflammation in ALS needs to be further investigated on larger samples and with more mechanistic studies.


Generation of a vascularized and functional human liver from an iPSC-derived organ bud transplant.
Generation of functional and vascularized organs from human induced pluripotent stem cells (iPSCs) will facilitate our understanding of human developmental biology and disease modeling, hopefully offering a drug-screening platform and providing novel therapies against end-stage organ failure. Here we describe a protocol for the in vitro generation of a 3D liver bud from human iPSC cultures and the monitoring of further hepatic maturation after transplantation at various ectopic sites. iPSC-derived specified hepatic cells are dissociated and suspended with endothelial cells and mesenchymal stem cells. These mixed cells are then plated onto a presolidified matrix, and they form a 3D spherical tissue mass termed a liver bud (iPSC-LB) in 1-2 d. To facilitate additional maturation, 4-d-old iPSC-LBs are transplanted in the immunodeficient mouse. Live imaging has identified functional blood perfusion into the preformed human vascular networks. Functional analyses show the appearance of multiple hepatic functions in a chronological manner in vivo.


[A neonate with a mass on the upper back].
Immediately after birth, a skin-covered mass with weak consistency was noted on the back of a full-term newborn boy. Ultrasound and MRI (performed to exclude spina bifida occulta) showed a multicystic venolymphatic malformation. Sclerotherapy or surgical excision are possible treatments. In asymptomatic patients, however, a watchful waiting approach is used.


Seroprevalence of infectious bovine rhinotracheitis in mithun (Bos frontalis) in India.
A preliminary study on the seroprevalence of infectious bovine rhinotracheitis (IBR) in different strains of mithun maintained atthe National Research Centre on Mithun, Nagaland, India, revealed that the overall prevalence of IBR in these mithun was 19%. This paper examines the results of that preliminary study. To the knowledge of the authors, this is the first report on the seroprevalence of IBR in mithun in India. The highest prevalence of IBR was observed in mithun found in Arunachal Pradesh (38.46%), followed by those found in Mizoram (18.18%) and Nagaland (15.15%). None of the animals from Manipur were found to test positive for antibodies against IBR. The sex of the animal had no influence on IBR prevalence. The prevalence was found to be highest (27.03%) in mithun above three years of age and lowest (7.69%) in mithun aged between six months and one year. The prevalence of IBR was found to be 88.9% in breeding mithun bulls. In this paper, the authors briefly discuss the possible roles of feral fauna and domestic livestock in the transmission of this disease to mithun and vice versa. Various measures that may help in the prevention and control of IBR in mithun are also surveyed. However, it should be emphasised that this study is a preliminary one, and the authors are currently engaged in further research.


Humeral shaft fractures as predictors of intra-abdominal injury in motor vehicle collision victims.
To assess the utility of humeral shaft fractures as predictors of organ injuries and skeletal injuries in multiply injured patients involved in motor vehicle collisions (MVCs). A prospectively collected database of multiply injured motor vehicle occupants with an Injury Severity Score (ISS) greater than 12 admitted to a level I regional trauma centre during a 102-month period (January 1992 to June 2000) was reviewed to assess skeletal and organ injuries associated with a humeral shaft fracture. The effect of occupant location within the vehicle, the point of collision, and the use of a seat belt restraint was also examined to identify trends in injury patterns. Data from 1070 motor vehicle occupants - 65 with concomitant humeral shaft fractures and 1005 without humeral shaft fractures - revealed that 63% of motor vehicle occupants who sustained humeral fractures were drivers, compared with 77% in the non-humeral fracture group. Those patients who sustained a humeral shaft fracture had a significantly greater number of liver injuries (p = 0.022), forearm/hand fractures (p < 0.001), tibial fractures (p < 0.01) and femoral fractures (p < 0.01) compared with controls. A lateral collision impact showed a trend towards increased splenic and hepatic injuries within the humeral shaft fracture group. The presence of a humeral shaft fracture in a multiply injured patient involved in a MVC is significantly associated with an increased incidence of both upper and lower extremity fractures and liver injury. Moreover, humeral shaft fractures may serve as a predictor of potential intra-abdominal pathology in multiply injured trauma patients involved in MVCs.


Oxidative C-N bond cleavage of (2-pyridylmethyl)amine-based tetradentate supporting ligands in ternary cobalt(ii)-carboxylate complexes.
Three mononuclear cobalt(ii)-carboxylate complexes, [(TPA)CoII(benzilate)]+ (1), [(TPA)CoII(benzoate)]+ (2) and [(iso-BPMEN)CoII(benzoate)]+ (3), of N4 ligands (TPA = tris(2-pyridylmethyl)amine and iso-BPMEN = N1,N1-dimethyl-N2,N2-bis((pyridin-2-yl)methyl)ethane-1,2-diamine) were isolated to investigate their reactivity toward dioxygen. Monodentate (η1) binding of the carboxylates to the metal centre favours the five-coordinate cobalt(ii) complexes (1-3) for dioxygen activation. Complex 1 slowly reacts with dioxygen to enable the oxidative decarboxylation of the coordinated α-hydroxy acid (benzilate). Prolonged exposure of the reaction solution of 2 to dioxygen results in the formation of [(DPA)CoIII(picolinate)(benzoate)]+ (4) and [CoIII(BPCA)2]+ (5) (DPA = di(2-picolyl)amine and HBPCA = bis(2-pyridylcarbonyl)amide), whereas only [(DPEA)CoIII(picolinate)(benzoate)]+ (6) (DPEA = N1,N1-dimethyl-N2-(pyridine-2-ylmethyl)-ethane-1,2-diamine) is isolated from the final oxidised solution of 3. The modified ligand DPA (or DPEA) is formed via the oxidative C-N bond cleavage of the supporting ligands. Further oxidation of the -CH2- moiety to -C([double bond, length as m-dash]O)- takes place in the transformation of DPA to HBPCA on the cobalt(ii) centre. Labelling experiments with 18O2 confirm the incorporation of oxygen atoms from molecular oxygen into the oxidised products. Mixed labelling studies with 16O2 and H2O18 strongly support the involvement of water in the C-N bond cleavage pathway. A comparison of the dioxygen reactivity of the cobalt complexes (1-3) with those of several other five-coordinate mononuclear complexes [(TPA)CoII(X)]+/2+ (X = Cl, CH3CN, acetate, benzoylformate, salicylate and phenylpyruvate) establishes the role of the carboxylate co-ligands in the activation of dioxygen and subsequent oxidative cleavage of the supporting ligands by a metal-oxygen oxidant.


Convergent evolution of mechanically optimal locomotion in aquatic invertebrates and vertebrates.
Examples of animals evolving similar traits despite the absence of that trait in the last common ancestor, such as the wing and camera-type lens eye in vertebrates and invertebrates, are called cases of convergent evolution. Instances of convergent evolution of locomotory patterns that quantitatively agree with the mechanically optimal solution are very rare. Here, we show that, with respect to a very diverse group of aquatic animals, a mechanically optimal method of swimming with elongated fins has evolved independently at least eight times in both vertebrate and invertebrate swimmers across three different phyla. Specifically, if we take the length of an undulation along an animal's fin during swimming and divide it by the mean amplitude of undulations along the fin length, the result is consistently around twenty. We call this value the optimal specific wavelength (OSW). We show that the OSW maximizes the force generated by the body, which also maximizes swimming speed. We hypothesize a mechanical basis for this optimality and suggest reasons for its repeated emergence through evolution.


Metabolic profiling reveals biochemical pathways and potential biomarkers associated with the pathogenesis of Krabbe disease.
Krabbe disease (KD) is caused by mutations in the galactosylceramidase (GALC) gene, which encodes a lysosomal enzyme that degrades galactolipids, including galactosylceramide and galactosylsphingosine (psychosine). GALC deficiency results in progressive intracellular accumulation of psychosine, which is believed to be the main cause for the demyelinating neurodegeneration in KD pathology. Umbilical cord blood transplantation slows disease progression when performed presymptomatically but carries a significant risk of morbidity and mortality. Accurate presymptomatic diagnosis is therefore critical to facilitate the efficacy of existing transplant approaches and to avoid unnecessary treatment of children who will not develop KD. Unfortunately, current diagnostic criteria, including GALC activity, genetic analysis, and psychosine measurement, are insufficient for secure presymptomatic diagnosis. This study performs a global metabolomic analysis to identify pathogenetic metabolic pathways and novel biomarkers implicated in the authentic mouse model of KD known as twitcher. At a time point before onset of signs of disease, twitcher hindbrains had metabolic profiles similar to WT, with the exception of a decrease in metabolites related to glucose energy metabolism. Many metabolic pathways were altered after early signs of disease in the twitcher, including decreased phospholipid turnover, restricted mitochondrial metabolism of branched-chain amino acids, increased inflammation, and changes in neurotransmitter metabolism and osmolytes. Hypoxanthine, a purine derivative, is increased before signs of disease appear, suggesting its potential as a biomarker for early diagnosis of KD. Additionally, given the early changes in glucose metabolism in the pathogenesis of KD, diagnostic modalities that report metabolic function, such as positron emission tomography, may be useful in KD. © 2016 Wiley Periodicals, Inc.


New whole blood analyzers and their impact on cardiac and critical care.
Miniaturized whole blood biosensors, patient-focused hospitals, and rising expectations of patients and physicians are shifting laboratory diagnostics to the point of care. Expanding transplantation and intensive care are increasing the need for rapid test results. Whole blood analysis improves accuracy, eliminates centrifugation, reduces response time, and conserves blood volume. Several hand-held, and over 20 portable or transportable whole blood instruments are now available. Criteria for instrument evaluation include test menus, point-of-care features, analysis time, on-site performance, and information integration. Whole blood analyzers measure several vital indicators (pO2, pCO2, pH, hematocrit, K+, Ca2+, Na+, Cl-, glucose, and lactate) simultaneously in less than 2 min with less than 200 microliters of whole blood. Other in vitro tests are available (Mg2+, osmolality, CO2 content, urea nitrogen, beta-hydroxybutyrate, hemoglobin, coagulation) or under development (HCO3- phosphorus). Some can be monitored in vivo (O2 saturation, pO2, pCO2, pH, glucose) or ex vivo. The clinical impact is demonstrated by ionized calcium, now established in importance for cardiac and neurologic problems, and ionized magnesium, a promising new measurement. The hybrid laboratory (a composite of conventional clinical laboratory and patient-focused testing), performance maps, and quality paths facilitate implementation of new whole blood analyzers for optimal support of cardiac and critical care, and improved patient outcomes (prospects).


Resource use of great hammerhead sharks (Sphyrna mokarran) off eastern Australia.
Great hammerhead sharks Sphyrna mokarran are the largest member of Sphyrnidae, yet the roles of these large sharks in the food webs of coastal ecosystems are still poorly understood. Here we obtained samples of muscle, liver and vertebrae from large S. mokarran (234-383 cm total length; LT ) caught as by-catch off eastern Australia and used stable-isotope analyses of δ15 N, δ13 C and δ34 S to infer their resource use and any associated ontogenetic patterns. The results indicated large S. mokarran are apex predators primarily relying on other sharks and rays for their diet, with a preference for benthic resources such as Australian cownose rays Rhinoperon neglecta during the austral summer. Teleosts, cephalopods and crustaceans were not significant components of S. mokarran diets, though some conspecifics appeared to rely on more diverse resources over the austral summer. Ontogenetic shifts in resource use were detected but trajectories of the increases in trophic level varied among individuals. Most S. mokarran had non-linear trajectories in ontogenetic resource-use shifts implying size was not the main explanatory factor. Stable isotope values of δ13 C and δ34 S in muscle suggest S. mokarran span coastal, pelagic and benthic food webs in eastern Australia.


"You're so powerless": Takatāpui/LGBTIQ+ people's experiences before becoming homeless in Aotearoa New Zealand.
Little is known in Aotearoa New Zealand about experiences of homelessness amongst Takatāpui/LGBTIQ+ identifying people, despite growing international literature regarding LGBTIQ+ homelessness. Using data from semi-structured interviews with eight people who identified as Takatāpui/LGBTIQ+ and had experienced homelessness, this paper explores their experiences prior to becoming homeless. These experiences are placed into the categories of: the pervasiveness of instability (especially in regards to family relationships, finances, and housing), having to grow up fast due to social and material conditions, experiences of looking for housing in stressed markets, and systems failures that resulted in a lack of autonomy. These results show that instability and systems failures are key contributors to Takatāpui/LGBTIQ+ people becoming homeless in Aotearoa New Zealand.


On the relationship between molecular state and single electron pictures in simple electrochemical junctions.
We consider a molecular conduction junction that comprises a redox molecule bridging between metal electrodes, in the limit of weak coupling and high temperature where electron transport is dominated by Marcus electron transfer kinetics. We address the correspondence between the Marcus description in terms of nuclear potential energy surfaces associated with different charging states of the molecular bridge, and the single electron description commonly used in theories of molecular conduction. The relationship between the energy gap, reorganization energy and activation energy parameters of the Marcus theory and the corresponding energy parameters in the single electron description is elucidated. We point out that while transport in the normal Marcus regime involves activated (therefore relatively slow) transitions between at least two charging states of the molecular bridge, deep in the inverted regime only one of these states is locally stable and transitions into this state are activationless. The relatively slow rates that characterize the normal Marcus transport regime manifest themselves in the appearance of hysteresis in the system transport behavior as a function of gate or bias potentials for relatively slow scan rates of these potentials, but not bistability in the junction conduction behavior. We also consider the limit of fast solvent reorganization that may reflect the response of the electronic environment (electronic polarization of a solvent and of the metal electrodes) to the changing charging state of the bridge. In this limit, environmental reorganization appears as renormalization of the bridge electronic energy levels. We show that the effect of this reorganization on the junction conduction properties is not universal and depends on the particular bridge charging states that are involved in the conduction process.


Efficient SPECT scatter calculation in non-uniform media using correlated Monte Carlo simulation.
Accurate simulation of scatter in projection data of single photon emission computed tomography (SPECT) is computationally extremely demanding for activity distribution in non-uniform dense media. This paper suggests how the computation time and memory requirements can be significantly reduced. First the scatter projection of a uniform dense object (P(SDSE)) is calculated using a previously developed accurate and fast method which includes all orders of scatter (slab-derived scatter estimation), and then P(SDSE) is transformed towards the desired projection P which is based on the non-uniform object. The transform of P(SDSE) is based on two first-order Compton scatter Monte Carlo (MC) simulated projections. One is based on the uniform object (P(u)) and the other on the object with non-uniformities (P(nu)). P is estimated by P = P(SDSE) P(nu)/P(u). A tremendous decrease in noise in P is achieved by tracking photon paths for P(nu) identical to those which were tracked for the calculation of P(u) and by using analytical rather than stochastic modelling of the collimator. The method was validated by comparing the results with standard MC-simulated scatter projections (P) of 99mTc and 201Tl point sources in a digital thorax phantom. After correction, excellent agreement was obtained between P and P. The total computation time required to calculate an accurate scatter projection of an extended distribution in a thorax phantom on a PC is a only few tens of seconds per projection, which makes the method attractive for application in accurate scatter correction in clinical SPECT. Furthermore, the method removes the need of excessive computer memory involved with previously proposed 3D model-based scatter correction methods.


Fractured sternal wire causing a cardiac laceration.
Hemopericardium is a serious complication that can occur after cardiac surgery. While most post-operative causes are due to inflammation and bleeding, patients with broken sternal wires and an unstable sternum may develop hemopericardium from penetrating trauma. We present the case of a 62-year-old male who underwent triple coronary bypass surgery and presented five months later with sudden anterior chest wall pain. Chest computed tomography revealed hemopericardium with an associated broken sternal wire that had penetrated into the pericardial space. The patient underwent a redo-sternotomy which revealed a 3.5 cm bleeding, jagged right ventricular laceration that correlated to the imaging findings of a fractured sternal wire projecting in the pericardial space. The laceration was repaired using interrupted 4 - 0 polypropylene sutures in horizontal mattress fashion between strips of bovine pericardium. The patient's recovery was uneventful and he was discharged on post-operative day four without complications. Patients with broken sternal wires and an unstable sternum require careful evaluation and management as these may have potentially life-threatening complications if left untreated.


Retigabine/Ezogabine, a KCNQ/K(V)7 channel opener: pharmacological and clinical data.
Epilepsy is a serious and common chronic neurological disease with an urgent need for novel treatment options, because 30% of all epilepsy patients do not respond to currently available drugs. Retigabine/Ezogabine (RTG) is a third-generation antiepileptic drug (AED) with a novel mechanism of action. It enhances the activity of voltage-gated K(V)7 potassium channels. The mechanism of action of RTG is reported in this paper, along with its pharmacodynamics and pharmacokinetics, based on a literature search from 1995 to 2011. Assessment of clinical efficacy and safety was performed using the published data of one Phase II and two Phase III clinical trials (RESTORE 1 and 2). RTG is an efficacious AED with a unique mechanism of action. It offers a new treatment option which could be particularly interesting for patients who are resistant to currently available AEDs. However, future investigations will show if such a "rational drug therapy" will be truly advantageous. RTG seems to have a low interaction profile, but its interactions with lamotrigine in particular should be further explored. Side effects are common and mainly related to the central nervous system, but also affect peripheral organs, such as the bladder, due its relaxing effect on smooth muscle. Slow titration could be an option to reduce such side effects.


Glucose uptake by the brain on chronic high-protein weight-loss diets with either moderate or low amounts of carbohydrate.
Previous work has shown that hunger and food intake are lower in individuals on high-protein (HP) diets when combined with low carbohydrate (LC) intakes rather than with moderate carbohydrate (MC) intakes and where a more ketogenic state occurs. The aim of the present study was to investigate whether the difference between HPLC and HPMC diets was associated with changes in glucose and ketone body metabolism, particularly within key areas of the brain involved in appetite control. A total of twelve men, mean BMI 34·9 kg/m², took part in a randomised cross-over trial, with two 4-week periods when isoenergetic fixed-intake diets (8·3 MJ/d) were given, with 30% of the energy being given as protein and either (1) a very LC (22 g/d; HPLC) or (2) a MC (182 g/d; HPMC) intake. An ¹⁸fluoro-deoxyglucose positron emission tomography scan of the brain was conducted at the end of each dietary intervention period, following an overnight fast (n 4) or 4 h after consumption of a test meal (n 8). On the next day, whole-body ketone and glucose metabolism was quantified using [1,2,3,4-¹³C]acetoacetate, [2,4-¹³C]3-hydroxybutyrate and [6,6-²H₂]glucose. The composite hunger score was 14% lower (P= 0·013) for the HPLC dietary intervention than for the HPMC diet. Whole-body ketone flux was approximately 4-fold greater for the HPLC dietary intervention than for the HPMC diet (P< 0·001). The 9-fold difference in carbohydrate intakes between the HPLC and HPMC dietary interventions led to a 5% lower supply of glucose to the brain. Despite this, the uptake of glucose by the fifty-four regions of the brain analysed remained similar for the two dietary interventions. In conclusion, differences in the composite hunger score observed for the two dietary interventions are not associated with the use of alternative fuels by the brain.


Cardiovascular health awareness and the effect of an educational intervention on school-aged children in a rural district of India.
India is the second most populous country in the world and two-thirds of its population is less than 35 years old. This survey was conducted to assess the level of health awareness of cardiovascular disease in adolescent school-aged children 14-16 years old, with the goal of establishing school-based health education and development of heart-healthy lifestyle practices. A school-based survey was conducted in the rural district of West Midnapore, India between June and July of 2014. This involved a pre-evaluation of cardiovascular disease (CVD) health awareness, a short presentation on CVD, and a post-evaluation of CVD health awareness. A total of 2995 students (48% response rate) from 20 schools participated in the survey. The mean age of the students in the study sample was 14.7 years, 46% were male, 53% were in the 9th grade, and the rest were in the 10th grade. After assessing students' awareness in six domains with 20 multiple-choice questions with a maximum score of 100, the mean pre-test score was 41.1 (SD±10.5) and the mean post-test score was 48.1 (SD±16.9) (p<0.001). Awareness of CVD and its risk factors was far from optimal among the adolescent school-aged children in this study. A school-based educational program may help improve awareness of CVD and reduce the future disease burden in the community. The results of this study may be useful in formulating a nationwide school health program to deal with the emerging epidemic of CVD in countries such as India.


The impact of health literacy on health status and resource utilization in lumbar degenerative disease.
Health literacy, defined as "the degree to which individuals have the capacity to obtain, process, and understand basic health information and services needed to make appropriate health decisions," has been demonstrated to affect access to care and appropriate healthcare utilization. To determine the impact of health literacy in the evaluation and management of patients with chronic low back pain. Cross sectional. Patients seen at a multisurgeon spine specialty clinic. Oswestry Disability Index, EQ-5D, and Numeric Rating Scales (0-10) for back and leg pain. The Newest Vital Sign (NVS) and Health Literacy Survey, Oswestry Disability Index, EQ-5D and pain scales were administered to patients undergoing evaluation and treatment for lumbar degenerative disease in the outpatient setting. Patients were surveyed regarding their use of medication, therapy, and pain management modalities. Of 201 patients approached for participation, 186 completed the health literacy surveys. Thirty (17%) were assessed as having limited literacy, 52 (28%) as possibly having limited literacy and 104 (56%) having adequate literacy based on their NVS scores. The cohort with low NVS scores also had low Health Literacy Survey Scores. Patients with limited literacy had worse back and leg pain scores compared with patients with possibly limited literacy and adequate literacy. Patients with adequate health literacy were more likely to use medications (80% vs. 53%, p = .017) and were more likely to see a specialist (34% vs. 17%) compared with those with limited literacy. Patients with limited health literacy were not more likely to see a chiropractor (7% vs. 7%), but reported more visits (19 vs. 8). Patients with lower health literacy reported worse back and leg pain scores, indicating either more severe disease or a fundamental difference in their responses to standard health-related quality of life measures. This study also suggests that patients with limited health literacy may underutilize some resources and overutilize other resources. Further study is needed to clarify these patterns, and to examine their impact on health status and clinical outcomes.


How do we know what we don't know? Exploring Deaf people's experiences of supporting their Deaf family member living with dementia.
Deaf sign language users living with dementia and their carers, some of whom are Deaf, routinely face everyday barriers in accessing information, support (both formal and informal) and services. The familial care situation is further complicated given that most Deaf people will choose a life partner who is Deaf and most Deaf couples will have hearing children. This study focussed specifically on the everyday experiences of Deaf carers and the impact of caring for a loved one with dementia. Drawing on data from a wider consultation about dementia care, three Deaf carers were directly interviewed in British Sign Language by a Deaf researcher about their everyday experiences of care, support, and services. Thematic analysis focussed on: access is more than the provision of interpreters; effective care for the carers; and unknowing risk taking. Findings demonstrate the multifaceted effects of barriers to knowledge and information when the care partner is also Deaf, the urgent need for effective support for Deaf carers and unrecognised safeguarding concerns that are a result of lack of access to forms of basic knowledge about living with someone with dementia and potential coping strategies. Nonetheless, the participants demonstrated novel solutions and resilience in the face of these multiple challenges. Implications are drawn for future targeted services to supported Deaf carers of people affected by dementia.


COVID-19 vaccine waning and effectiveness and side-effects of boosters: a prospective community study from the ZOE COVID Study.
With the surge of new SARS-CoV-2 variants, countries have begun offering COVID-19 vaccine booster doses to high-risk groups and, more recently, to the adult population in general. However, uncertainty remains over how long primary vaccination series remain effective, the ideal timing for booster doses, and the safety of heterologous booster regimens. We aimed to investigate COVID-19 primary vaccine series effectiveness and its waning, and the safety and effectiveness of booster doses, in a UK community setting. We used SARS-CoV-2 positivity rates in individuals from a longitudinal, prospective, community-based study (ZOE COVID Study), in which data were self-reported through an app, to assess the effectiveness of three COVID-19 vaccines (ChAdOx1 nCov19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNtech], and mRNA1273 [Moderna]) against infection in the 8 months after completion of primary vaccination series. In individuals receiving boosters, we investigated vaccine effectiveness and reactogenicity, by assessing 16 self-reported systemic and localised side-effects. We used multivariate Poisson regression models adjusting for confounders to estimate vaccine effectiveness. We included 620 793 participants who received two vaccine doses (204 731 [33·0%] received BNT162b2, 405 239 [65·3%] received ChAdOx1 nCoV-19, and 10 823 [1·7%] received mRNA-1273) and subsequently had a SARS-CoV-2 test result between May 23 (chosen to exclude the period of alpha [B.1.1.7] variant dominance) and Nov 23, 2021. 62 172 (10·0%) vaccinated individuals tested positive for SARS-CoV-2 and were compared with 40 345 unvaccinated controls (6726 [16·7%] of whom tested positive). Vaccine effectiveness waned after the second dose: at 5 months, BNT162b2 effectiveness was 82·1% (95% CI 81·3-82·9), ChAdOx1 nCoV-19 effectiveness was 75·7% (74·9-76·4), and mRNA-1273 effectiveness was 84·3% (81·2-86·9). Vaccine effectiveness decreased more among individuals aged 55 years or older and among those with comorbidities. 135 932 individuals aged 55 years or older received a booster (2123 [1·6%] of whom tested positive). Vaccine effectiveness for booster doses in 0-3 months after BNT162b2 primary vaccination was higher than 92·5%, and effectiveness for heterologous boosters after ChAdOx1 nCoV-19 was at least 88·8%. For the booster reactogenicity analysis, in 317 011 participants, the most common systemic symptom was fatigue (in 31 881 [10·1%] participants) and the most common local symptom was tenderness (in 187 767 [59·2%]). Systemic side-effects were more common for heterologous schedules (32 632 [17·9%] of 182 374) than for homologous schedules (17 707 [13·2%] of 134 637; odds ratio 1·5, 95% CI 1·5-1·6, p<0·0001). After 5 months, vaccine effectiveness remained high among individuals younger than 55 years. Booster doses restore vaccine effectiveness. Adverse reactions after booster doses were similar to those after the second dose. Homologous booster schedules had fewer reported systemic side-effects than heterologous boosters. Wellcome Trust, ZOE, National Institute for Health Research, Chronic Disease Research Foundation, National Institutes of Health, Medical Research Council.


A critical review of translation initiation factor eIF2α kinases in plants - regulating protein synthesis during stress.
Eukaryotic cells must cope with environmental stress. One type of general stress response is the downregulation of protein synthesis in order to conserve cellular resources. Protein synthesis is mainly regulated at the level of mRNA translation initiation and when the α subunit of eukaryotic translation initiation factor 2 (eIF2) is phosphorylated, protein synthesis is downregulated. Although eIF2 has the same translation initiation function in all eukaryotes, it is not known whether plants downregulate protein synthesis via eIF2α phosphorylation. Similarly, although there is evidence that plants possess eIF2α kinases, it is not known whether they operate in a similar manner to the well characterised mammalian and yeast eIF2α kinases. Two types of eIF2α kinases have been reported in plants, yet the full understanding of the plant eIF2α phosphorylation mechanism is still lacking. Here we review the current knowledge of the eIF2α phosphorylation mechanism within plants and discuss plant eIF2α, plant eIF2α kinase GCN2 and the data supporting and contradicting the hypothesis that a functional orthologue for the eIF2α kinase PKR, is present and functional in plants.


Mixotrophy in Chlorophytes and Haptophytes-Effect of Irradiance, Macronutrient, Micronutrient and Vitamin Limitation.
Chlorophytes and haptophytes are key contributors to global phytoplankton biomass and productivity. Mixotrophic bacterivory has been detected for both groups, but a shortage of studies with cultured representatives hinders a consistent picture of the ecological relevance and regulation of this trophic strategy. Here, the growth, primary production, fraction of feeding cells (acidotropic probes) and bacterivory rates (surrogate prey) are tested for two species of the chlorophyte genus Nephroselmis and the haptophyte Isochrysis galbana under contrasting regimes of light (high vs. low) and nutrients (non-limited and macronutrient-, micronutrient- and vitamin-limited), at low bacterial concentrations (<107 bacteria mL-1). All three species were obligate phototrophs, unable to compensate for low light conditions through feeding. Under nutrient limitation, N. rotunda and I. galbana fed, but growth ceased or was significantly lower than in the control. Thus, mixotrophic bacterivory could be a survival rather than a growth strategy for certain species. In contrast, nutrient-limited N. pyriformis achieved growth rates equivalent to the control through feeding. This strikingly differs with the classical view of chlorophytes as primarily non-feeders and indicates mixotrophic bacterivory can be a significant trophic strategy for green algae, even at the low bacterial concentrations found in oligotrophic open oceans.


Translocation of enzymes into a mesoporous MOF for enhanced catalytic activity under extreme conditions.
Enzymatic catalysis is of great importance to the chemical industry. However, we are still scratching the surface of the potential of biocatalysis due to the limited operating range of enzymes in harsh environments or their low recyclability. The role of Metal-Organic Frameworks (MOFs) as active supports to help overcome these limitations, mainly by immobilization and stabilization of enzymes, is rapidly expanding. Here we make use of mild heating and a non-polar medium during incubation to induce the translocation of a small enzyme like protease in the mesoporous MOF MIL-101(Al)-NH2. Our proteolytic tests demonstrate that protease@MIL-101(Al)-NH2 displays higher activity than the free enzyme under all the conditions explored and, more importantly, its usability can be extended to extreme conditions of pH and high temperatures. MOF immobilization is also effective in providing the biocomposite with long-term stability, recyclability and excellent compatibility with competing enzymes. This simple, one-step infiltration strategy might accelerate the discovery of new MOF-enzyme biocatalysts that meet the requirements for biotechnological applications.


Trade, production sharing, and the international transmission of business cycles.
Countries that are more engaged in production sharing exhibit higher bilateral manufacturing output correlations. We use data on trade flows between US multinationals and their affiliates as well as trade between the United States and Mexican maquiladoras to measure production-sharing trade and its link with the business cycle. We then develop a quantitative model of international business cycles that generates a positive link between the extent of vertically integrated production-sharing trade and internationally synchronized business cycles. A key assumption in the model is a relatively low elasticity of substitution between home and foreign inputs in the production of the vertically integrated good.


Total vascular resistance, augmentation index, and augmentation pressure increase in patients with peripheral artery disease.
Peripheral arterial disease (PAD) is one of major vascular diseases which frequently coexists with coronary arterial disease and cerebrovascular disease. The patients with PAD have a poor prognosis when it progresses. A new blood pressure testing device enables to simultaneously measure brachial blood pressure (BP), central BP, and several vascular parameters, with easy and non-invasive, in a short time. Here, we aimed to evaluate these arterial stiffness parameters in patients with PAD.In this study, 243 consecutive patients who were suspected of having PAD and referred to our hospital from September 2016 to June 2019, were registered. Several parameters, such as brachial BP, central BP, aortic pulse wave velocity (aPWV), total vascular resistance (TVR), augmentation index (AI) and augmentation pressure (AP), were determined by Mobil-O-Graph. Ankle-brachial pressure index (ABI) was used to define PAD (ABI ≤ 0.9 as PAD). The relationship between PAD and central BP, aPWV, TVR, AI, or AP were investigated.One hundred sixty-two patients (67%) were categorized as the PAD group and 81 patients (33%) as the non-PAD group. In the PAD group, the systolic brachial BP and central systolic BP were significantly higher than those in the non-PAD group (138 ± 24 mmHg vs 131 ± 19 mmHg, P < .05, 125 ± 22 mmHg vs 119 ± 18 mmHg, P < .05, respectively). TVR, AI, and AP were significantly higher in the PAD group (1785 ± 379 dyn s/cm5 vs 1661 ± 317 dyn s/cm5, P < .05, 26.2 ± 13.0% vs 22.2 ± 13.3%, P < .05, 13.5 ± 9.4 mmHg vs 10.7 ± 7.2 mmHg, P < .05, respectively). No significant differences in diastolic BP, central diastolic BP, and aPWV were found between the groups. Multivariate logistic regression analysis revealed that PAD was significantly associated with TVR, AI, and AP (P < .05, respectively).TVR/AP/AI were significantly higher in the PAD group than in the non-PAD group.


Predominant Yeasts During Artisanal Mezcal Fermentation and Their Capacity to Ferment Maguey Juice.
Artisanal mezcal is produced by the natural fermentation of maguey juice, which frequently results in a process that becomes stuck or is sluggish. Using selected indigenous starter inoculums of Saccharomyces and non-Saccharomyces yeasts is considered beneficial in overcoming these problems and thereby preserving the essence of the artisanal process. In this work, three hundred and four yeast isolates were recovered from 17 distilleries and then grouped by the ARDRA analysis, their restriction profiles were clustered in 15 groups. Four of them included 90% of all isolates, and these were identified using the sequence of the D1/D2 domain of the large-subunit rDNA. Pichia kudriavzevii, Pichia manshurica, Saccharomyces cerevisiae, and Kluyveromyces marxianus were detected as predominant species. Both species belonging to the Pichia genus were detected in 88% of the distilleries, followed by S. cerevisiae (70%) and K. marxianus (50%). In order to evaluate the fermentative capacity, one strain of each species was assessed in a pure and mixed culture in two culture media, filtered maguey juice (MJ) and maguey juice including its bagasse (MJB). Findings demonstrated that non-Saccharomyces yeast presented better growth than that of S. cerevisiae. K. marxianus PA16 was more efficient for ethanol production than S. cerevisiae DI14. It produced 32 g/L of ethanol with a yield of 0.47 g/g and efficient of 90%. While, P. kudriavzevii produced more ethyl acetate (280 mg/L) than the others species. All fermentations were characterized by the presence of isobutyl and isoamyl alcohol. The presence of K. marxianus in a mixed culture, improved the ethanol production and volatile compounds increased using co-cultures.


A parameter-free, solid-angle based, nearest-neighbor algorithm.
We propose a parameter-free algorithm for the identification of nearest neighbors. The algorithm is very easy to use and has a number of advantages over existing algorithms to identify nearest-neighbors. This solid-angle based nearest-neighbor algorithm (SANN) attributes to each possible neighbor a solid angle and determines the cutoff radius by the requirement that the sum of the solid angles is 4π. The algorithm can be used to analyze 3D images, both from experiments as well as theory, and as the algorithm has a low computational cost, it can also be used "on the fly" in simulations. In this paper, we describe the SANN algorithm, discuss its properties, and compare it to both a fixed-distance cutoff algorithm and to a Voronoi construction by analyzing its behavior in bulk phases of systems of carbon atoms, Lennard-Jones particles and hard spheres as well as in Lennard-Jones systems with liquid-crystal and liquid-vapor interfaces.


Prevalence of incidental thyroid nodules in ultrasound studies of dogs with hypercalcemia (2008-2013).
Ultrasound is commonly used to evaluate the cervical region in dogs with hypercalcemia due to suspected hyperparathyroidism. Incidental thyroid nodules may be detected during these studies, however little information has been published to guide clinical decision-making when this occurs. The purpose of this cross-sectional study was to determine the prevalence of incidental thyroid nodules in hypercalcemic dogs undergoing cervical ultrasound at our hospital during the period of 2008-2013. Dogs with a palpable neck mass were excluded. Cervical ultrasound images for each dog were retrieved and reviewed by a board certified veterinary radiologist who was unaware of patient outcome. Presence, number, and dimensions of thyroid nodules were recorded. Results of thyroid nodule aspirate, biopsy or necropsy were recorded from medical records when available. Ninety-one dogs met inclusion criteria. Of these, 14/91 (15%) dogs had at least one thyroid nodule. Mean (± standard deviation) thyroid gland nodule length, width, and height were 1.51 ± 0.74, 0.96 ± 0.73, and 0.75 ± 0.36 cm, respectively. A histologic diagnosis was available for the incidental thyroid lesions in eight dogs, including one dog with two nodules. Confirmed diagnoses for these nodules were thyroid cyst (3/9, 33%), thyroid adenoma (3/9, 33%), thyroid adenocarcinoma (2/9, 22%) and nodular hyperplasia (1/9, 11%). Findings indicated that incidental thyroid nodules may be present in hypercalcemic dogs with no palpable neck mass and no clinical signs of thyroid disease. Some of these nodules may be malignant and therefore a recommendation for cytology or biopsy may be justified.


DNA-Dependent Protein Kinase As Molecular Target for Radiosensitization of Neuroblastoma Cells.
Tumor cells might resist therapy with ionizing radiation (IR) by non-homologous end-joining (NHEJ) of IR-induced double-strand breaks. One of the key players in NHEJ is DNA-dependent protein kinase (DNA-PK). The catalytic subunit of DNA-PK, i.e. DNA-PKcs, can be inhibited with the small-molecule inhibitor NU7026. In the current study, the in vitro potential of NU7026 to radiosensitize neuroblastoma cells was investigated. DNA-PKcs is encoded by the PRKDC (protein kinase, DNA-activated, catalytic polypeptide) gene. We showed that PRKDC levels were enhanced in neuroblastoma patients and correlated with a more advanced tumor stage and poor prognosis, making DNA-PKcs an interesting target for radiosensitization of neuroblastoma tumors. Optimal dose finding for combination treatment with NU7026 and IR was performed using NGP cells. One hour pre-treatment with 10 μM NU7026 synergistically sensitized NGP cells to 0.63 Gy IR. Radiosensitizing effects of NU7026 increased in time, with maximum effects observed from 96 h after IR-exposure on. Combined treatment of NGP cells with 10 μM NU7026 and 0.63 Gy IR resulted in apoptosis, while no apoptotic response was observed for either of the therapies alone. Inhibition of IR-induced DNA-PK activation by NU7026 confirmed the capability of NGP cells to, at least partially, resist IR by NHEJ. NU7026 also synergistically radiosensitized other neuroblastoma cell lines, while no synergistic effect was observed for low DNA-PKcs-expressing non-cancerous fibroblasts. Results obtained for NU7026 were confirmed by PRKDC knockdown in NGP cells. Taken together, the current study shows that DNA-PKcs is a promising target for neuroblastoma radiosensitization.


Treating Cancer as an Invasive Species.
To cure a patient's cancer is to eradicate invasive cells from the ecosystem of the body. However, the ecologic complexity of this challenge is not well understood. Here we show how results from eradications of invasive mammalian species from islands-one of the few contexts in which invasive species have been regularly cleared-inform new research directions for treating cancer. We first summarize the epidemiologic characteristics of island invader eradications and cancer treatments by analyzing recent datasets from the Database of Invasive Island Species Eradications and The Cancer Genome Atlas, detailing the superior successes of island eradication projects. Next, we compare how genetic and environmental factors impact success in each system. These comparisons illuminate a number of promising cancer research and treatment directions, such as heterogeneity engineering as motivated by gene drives and adaptive therapy; multiscale analyses of how population heterogeneity potentiates treatment resistance; and application of ecological data mining techniques to high-throughput cancer data. We anticipate that interdisciplinary comparisons between tumor progression and invasive species would inspire development of novel paradigms to cure cancer.


miR-24-mediated knockdown of H2AX damages mitochondria and the insulin signaling pathway.
Mitochondrial deficits or altered expressions of microRNAs are associated with the pathogenesis of various diseases, and microRNA-operated control of mitochondrial activity has been reported. Using a retrovirus-mediated short-hairpin RNA (shRNA) system, we observed that miR-24-mediated H2AX knockdown (H2AX-KD) impaired both mitochondria and the insulin signaling pathway. The overexpression of miR-24 decreased mitochondrial H2AX and disrupted mitochondrial function, as indicated by the ATP content, membrane potential and oxygen consumption. Similar mitochondrial damage was observed in shH2AX-mediated specific H2AX-KD cells. The H2AX-KD reduced the expression levels of mitochondrial transcription factor A (TFAM) and mitochondrial DNA-dependent transcripts. H2AX-KD mitochondria were swollen, and their cristae were destroyed. H2AX-KD also blocked the import of precursor proteins into mitochondria and the insulin-stimulated phosphorylation of IRS-1 (Y632) and Akt (S473 and T308). The rescue of H2AX, but not the nuclear form of ΔC24-H2AX, restored all features of miR-24- or shH2AX-mediated impairment of mitochondria. Hepatic miR-24 levels were significantly increased in db/db and ob/ob mice. A strong feedback loop may be present among miR-24, H2AX, mitochondria and the insulin signaling pathway. Our findings suggest that H2AX-targeting miR-24 may be a novel negative regulator of mitochondrial function and is implicated in the pathogenesis of insulin resistance.


Consumption of animal foods and endometrial cancer risk: a systematic literature review and meta-analysis.
This article summarizes and quantifies the current evidence relating dietary intake of animal products and endometrial cancer. Literature searches were conducted to identify peer-reviewed manuscripts published up to December 2006. Twenty-two manuscripts from three cohort studies and 16 case-control studies were identified. One of these cohort studies evaluated only fried meat and another only milk consumption; they were not included in our meta-analyses. The third cohort study identified did not present exposure levels and could not be included in dose-response meta-analysis. This cohort study did not show an association with meat or red meat consumption. Random-effects dose-response summary estimates for case-control studies evaluating these foods were 1.26 (95% CI: 1.03-1.54) per 100 g/day of total meat, 1.51 (95% CI: 1.19-1.93) per 100 g/day of red meat, 1.03 (95% CI: 0.32-3.28) per 100 g/day of poultry, 1.04 (95% CI: 0.55-1.98) per 100 g/day of fish, and 0.97 (95% CI: 0.93-1.01) per serving of dairy. Our meta-analysis, based on case-control data, suggests that meat consumption, particularly red meat, increases endometrial cancer risk. The current literature does not support an association with dairy products, while the evidence is inconsistent for poultry, fish, and eggs. More studies, particularly prospective studies, are needed.


Feasibility of tomotherapy for postoperative irradiation of lower extremity sarcomas.
To evaluate the effectiveness of helical tomotherapy-based image-guided radiotherapy (IGRT) following surgery for lower extremity sarcoma. A retrospective review of three patients undergoing postoperative irradiation with tomotherapy for lower extremity sarcoma was conducted. Planning target volume (PTV) coverage, acute side effects, long-term complications and functional results were assessed. Tomotherapy allows adequate coverage of the PTV without an excessive radiation dose to the normal adjacent structures. Radiotherapy side effects were acceptable with no treatment breaks. All patients were disease free with no complications and no impairment of their daily activity at the last follow-up. IGRT delivered by tomotherapy may be ideally suited for sarcoma of the extremities because of its ability to achieve a high radiation dose along with excellent normal tissue sparing. Further prospective studies should be conducted to confirm this hypothesis.


[Selection for health resort treatment of patients who have undergone radical surgery for stomach cancer].
The paper deals with the preliminary results of a randomized study on the efficacy of health resort and sanatorium treatment of patients who underwent surgery for stomach tumors. Out of the total number of the patients who had applied for the treatment and had been examined by local oncologists, 35.4% proved to have recurrences and metastases, while the treatment was contraindicated in 25.6% of cases. It is recommended that practising oncologists should consult specialized oncological establishments in each particular case of application for health resort or sanatorium treatment.


Immediate determination of ACPA and rheumatoid factor--a novel point of care test for detection of anti-MCV antibodies and rheumatoid factor using a lateral-flow immunoassay.
Autoantibodies against mutated and citrullinated vimentin (MCV) represent a novel diagnostic marker for rheumatoid arthritis (RA). Recently, an increased sensitivity for anti-MCV compared to autoantibodies against cyclic citrullinated peptides (anti-CCP2) was shown in cohorts of patients with early RA and established disease.The aim of this study was to develop and evaluate a point of care test (POCT) for detection of anti-MCV antibodies immediately at the first visit or at the bed side. A lateral-flow immunoassay was developed for simultaneous detection of anti-MCV antibodies and rheumatoid factor (RF-IgG) and evaluated in a prospective setting. Analyses were performed from whole blood samples of patients with seropositive RA (n=108), seronegative RA as well as other rheumatic disorders (n=122), and healthy blood donors (n=200) and compared to detection via ELISA. Using the POCT, anti-MCV antibodies were detected in 54.6% and RF-IgG in 56.5% of patients with RA. Specificity was 99.1% for anti-MCV antibodies and 91.2% for RF-IgG. Compared to ELISA's results, POCT sensitivity was 69.3% for anti-MCV and 55.6% for RF-IgG, specificity was 99.7% and 97.2%, respectively. This POCT for detection of anti-MCV antibodies and RF-IgG provides high specificity for the diagnosis of RA and is useful in clinical practice due to its simplicity and its reliable performance. This test can greatly improve a timely management of RA and may help in screening patients with suspected RA in non-specialized settings prompting early referrals.


Effect of pre-stroke use of ACE inhibitors on ischemic stroke severity.
Recent trials suggest that angiotensin-converting enzyme inhibitors (ACEI) are effective in prevention of ischemic stroke, as measured by reduced stroke incidence. We aimed to compare stroke severity between stroke patients who were taking ACEI before their stroke onset and those who were not, to examine the effects of pretreatment with ACEI on ischemic stroke severity. We retrospectively studied 126 consecutive patients presenting within 24 hours of ischemic stroke onset, as confirmed by diffusion-weighted magnetic resonance imaging (DWI). We calculated the NIHSS score at presentation, as the primary measure of clinical stroke severity, and categorized stroke severity as mild (NIHSS [less than or equal to] 7), moderate (NIHSS 8-13) or severe (NIHSS [greater than or equal to] 14). We analyzed demographic data, risk-factor profile, blood pressure (BP) and medications on admissions, and determined stroke mechanism according to TOAST criteria. We also measured the volumes of admission diffusion- and perfusion-weighted (DWI /PWI) magnetic resonance imaging lesions, as a secondary measure of ischemic tissue volume. We compared these variables among patients on ACEI and those who were not. Thirty- three patients (26%) were on ACE-inhibitors. The overall median baseline NIHSS score was 5.5 (range 2-21) among ACEI-treated patients vs. 9 (range 1-36) in non-ACEI patients (p = 0.036). Patients on ACEI prior to their stroke had more mild and less severe strokes, and smaller DWI and PWI lesion volumes compared to non-ACEI treated patients. However, none of these differences were significant. Predictably, a higher percentage of patients on ACEI had a history of heart failure (p = 0.03). Age, time-to-imaging or neurological evaluation, risk-factor profile, concomitant therapy with lipid lowering, other antihypertensives or antithrombotic agents, or admission BP were comparable between the two groups. Our results suggest that ACE-inhibitors may reduce the clinical severity of stroke, as measured by NIHSS score. Further, larger-scale, prospective studies are needed to validate our findings, and to elucidate the mechanism(s) of ACEImediated benefits in patients with ischemic stroke.


In-stent restenosis characteristics and repeat stenting underexpansion: insights from optical coherence tomography.
The aim of this study was to use optical coherence tomography (OCT) to predict newly implanted stent expansion for treatment of in-stent restenosis (ISR). With OCT guidance, 143 ISR lesions were treated with a new stent. Stent underexpansion was defined as minimum stent area (MSA) <4.5 mm2 and MSA/average of reference lumen area <70%. New stent underexpansion was found in 33 lesions (23%). These had a smaller old stent MSA (4.13 [3.32-4.62] versus 5.18 [4.01-6.38] mm2, p=0.001), and had a higher prevalence of multiple old stent layers (51.5% versus 10.9%, p<0.001) and neointimal or peri-stent calcium (69.7% versus 37.3%, p=0.001) compared to those without new stent underexpansion. Old stent underexpansion, multiple layers of old stent, maximum calcium angle >180°, and maximum calcium thickness >0.5 mm were independently associated with new stent underexpansion. Patients with new stent underexpansion had a higher prevalence of major adverse cardiac events (35.5% vs 14.3%, p=0.009), mainly driven by a higher rate of myocardial infarction and target vessel revascularisation at two years. When re-stenting an ISR lesion, old stent underexpansion, the amount of neointimal or peri-stent calcium, and multiple old stent strut layers are important determinants of new stent underexpansion which is then associated with adverse long-term outcomes.


AVP-eGFP was significantly upregulated by hypovolemia in the parvocellular division of the paraventricular nucleus in the transgenic rats.
Arginine vasopressin (AVP) is produced in the paraventricular (PVN) and supraoptic nuclei (SON). Peripheral AVP, which is secreted from the posterior pituitary, is produced in the magnocellular division of the PVN (mPVN) and SON. In addition, AVP is produced in the parvocellular division of the PVN (pPVN), where corticotrophin-releasing factor (CRF) is synthesized. These peptides synergistically modulate the hypothalamic-pituitary-adrenal (HPA) axis. Previous studies have revealed that the HPA axis was activated by hypovolemia. However, the detailed dynamics of AVP in the pPVN under hypovolemic state has not been elucidated. Here, we evaluated the effects of hypovolemia and hyperosmolality on the hypothalamus, using AVP-enhanced green fluorescent protein (eGFP) transgenic rats. Polyethylene glycol (PEG) or 3% hypertonic saline (HTN) was intraperitoneally administered to develop hypovolemia or hyperosmolality. AVP-eGFP intensity was robustly upregulated at 3 and 6 h after intraperitoneal administration of PEG or HTN in the mPVN. While in the pPVN, eGFP intensity was significantly increased at 6 h after intraperitoneal administration of PEG with significant induction of Fos-immunoreactive (-ir) neurons. Consistently, eGFP mRNA, AVP hnRNA, and CRF mRNA in the pPVN and plasma AVP and corticosterone were significantly increased at 6 h after intraperitoneal administration of PEG. The results suggest that AVP and CRF syntheses in the pPVN were activated by hypovolemia, resulting in the activation of the HPA axis.


The Role of Ribosomal Proteins eL15 and eL36 in the Early Steps of Yeast 60S Ribosomal Subunit Assembly.
Ribosomal proteins have important roles in maintaining the structure and function of mature ribosomes, but they also drive crucial rearrangement reactions during ribosome biogenesis. The contribution of most, but not all, ribosomal proteins to ribosome synthesis has been previously analyzed in the yeast Saccharomyces cerevisiae. Herein, we characterize the role of yeast eL15 during 60S ribosomal subunit formation. In vivo depletion of eL15 results in a shortage of 60S subunits and the appearance of half-mer polysomes. This is likely due to defective processing of the 27SA3 to the 27SBS pre-rRNA and impaired subsequent processing of both forms of 27SB pre-rRNAs to mature 25S and 5.8S rRNAs. Indeed, eL15 depletion leads to the efficient turnover of the de novo formed 27S pre-rRNAs. Additionally, depletion of eL15 blocks nucleocytoplasmic export of pre-60S particles. Moreover, we have analyzed the impact of depleting either eL15 or eL36 on the composition of early pre-60S particles, thereby revealing that the depletion of eL15 or eL36 not only affects each other's assembly into pre-60S particles but also that of neighboring ribosomal proteins, including eL8. These intermediates also lack most ribosome assembly factors required for 27SA3 and 27SB pre-rRNA processing, named A3- and B-factors, respectively. Importantly, our results recapitulate previous ones obtained upon eL8 depletion. We conclude that assembly of eL15, together with that of eL8 and eL36, is a prerequisite to shape domain I of 5.8S/25S rRNA within early pre-60S particles, through their binding to this rRNA domain and the recruitment of specific groups of assembly factors.


Pleural controversy: optimal chest tube size for drainage.
In recent years, a higher and higher percentage of patients with pleural effusions or pneumothorax are being treated with small-bore (10-14 F) chest tubes rather than large-bore (>20 F). However, there are very few randomized controlled studies comparing the efficacy and complication rates with the small- and large-bore catheters. Moreover, the randomized trials that are available have flaws in their design. The advantages of the small-bore catheters are that they are easier to insert and there is less pain with their insertion while they are in place. The placement of the small-bore catheters is probably more optimal when placement is done with ultrasound guidance. Small-bore chest tubes are recommended when pleurodesis is performed. The success of the small-bore indwelling tunnelled catheters that are left in place for weeks documents that the small-bore tubes do not commonly become obstructed with fibrin. Patients with complicated parapneumonic effusions are probably best managed with small-bore catheters even when the pleural fluid is purulent. Patients with haemothorax are best managed with large-bore catheters because of blood clots and the high volume of pleural fluid. Most patients with pneumothorax can be managed with aspiration or small-bore chest tubes. If these fail, a large-bore chest tube may be necessary. Patients on mechanical ventilation with barotrauma induced pneumothoraces are best managed with large-bore chest tubes.


MUC4 expression increases progressively in pancreatic intraepithelial neoplasia.
Pancreatic adenocarcinoma is believed to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs) that undergo a series of architectural, cytologic, and genetic changes, a progression model similar to the adenoma-carcinoma sequence in the colon. The apomucin MUC4 has been implicated in invasive pancreatic adenocarcinoma. MUC4 expression is not detectable at the RNA level in normal pancreas but is detectable at high levels in invasive pancreatic adenocarcinoma. We documented the pattern of expression of MUC4 in PanINs by studying a series of 71 PanIN lesions immunohistochemically using a new monoclonal antibody to MUC4. Five (17%) of 30 PanIN-1 lesions, 10 (36%) of 28 PanIN-2 lesions, 11 (85%) of 13 PanIN-3 lesions, and 25 (89%) of 28 invasive adenocarcinomas labeled with the MUC4 antibody used in the study. In addition, afew nonneoplastic lesions labeled with the MUC4 antibody, including reactive ducts in chronic pancreatitis, atrophic ducts filled with inspissated secretions, and ducts showing squamous metaplasia. Our data help establish the patterns of MUC4 expression in neoplastic precursors in the pancreas and add further support to the progression model for pancreatic adenocarcinoma.


Selective inhibition of glycoprotein and membrane protein of vesicular stomatitis virus from interferon-treated cells.
A 200-fold inhibition in the titer of infectious vesicular stomatitis virus (VSV) was produced in cultures of Ly cells treated with 30 reference units of interferon per milliliter. Virus particle production, as measured by VSV particle-associated transcriptase, or nucleocapsid protein was inhibited by a maximum of tenfold. The glycoprotein and membrane protein content was reduced in VSV derived from interferon-treated cells. Thus interferon-treated cells may have produced VSV particles with low infectivity, which may be related to the reduced amount of glycoprotein incorporated into such particles. These findings resemble those reported in interferon-treated cells infected with murine leukemia viruses.


Clipping of Basilar Perforator Pure Arterial Malformation Aneurysm: 2-Dimensional Operative Video.
Pure arterial malformations are rarely-encountered intracranial lesions, often mistaken for arteriovenous malformations. A minority of these lesions may harbor associated aneurysms. In a recent series of 12 patients with pure arterial malformations, 3 patients had associated aneurysms.1 As the authors describe, the presentation and natural history of pure arterial malformations generally are considered benign. In over 85% of cases reported in the literature, they are discovered incidentally and in cases with documented follow-up the angio-architecture tends to remain stable.1 However, here we present the case of an aneurysm associated with a pure arterial malformation managed with microsurgical clipping. The patient presented to us with the development of hemorrhage within and/or around the lesion and the development of a partial CN III palsy. Using a cranio-orbital approach, we successfully performed clipping of the offending vessel in the region of the basilar apex. Critical to the successful treatment of this lesion were: the correct identification of the offending vessel, recognition of the presence of perforating arteries, and clipping of the offending artery distal to the origin of the perforating arteries. This case represents a rare instance of a symptomatic pure arterial malformation with associated aneurysm. Verbal consent was provided by the patient for reproduction and publication of her case.


Quality of randomized clinical trials in juvenile idiopathic arthritis.
We evaluated the quality of randomized clinical trials (RCTs) of therapy for juvenile idiopathic arthritis (JIA) using an individual component approach and assessed temporal changes. A systematic review of the literature was performed to identify all RCTs involving exclusively JIA patients. Two investigators independently assessed the identified articles for six quality indicators: generation of allocation sequence, allocation concealment, masking, intention-to-treat (ITT) analysis, dropout rates and clearly stated primary outcome. Fifty-two RCTs involving JIA patients were assessed. Generation of allocation sequence was unclear in 79% of the studies. Reporting of allocation concealment was adequate in only one-third of the studies. Masking was adequate in 73%, inadequate in 19% and unclear in 8% of the reports. ITT analysis was employed in 37% of the reports. Per-protocol analysis was used in 40% and in 23% the method was unclear. Most of the reports (67%) had dropout rates < or = 20%. About half of the reports (n = 25) failed to show a significant effect of the experimental treatment. No significant associations were found between the study results and quality indicators. With the exception of adequate masking and dropout rate, all quality indicators showed a trend of improvement over the decades. The quality of RCTs in JIA based on the selected indicators was poor. Although there were some positive changes over time, the reporting and methodological quality of trials should be improved. New, more powerful and acceptable RCT designs should be developed in this patient population.


Distribution of actin filament lengths and their orientation measured by gel electrophoresis in capillaries.
F-actin was electrophoresed in capillary tubes filled with agarose gel. The use of capillary imparted high resistance on the gel allowing the use of high enough concentration of salts to keep F-actin polymerized, and allowed the application of high electric fields without liberating considerable amount of heat. The intensity profile of the electrophoretic band of F-actin showed a peak, which in 1% agarose in the electric field of 17.8 V cm-1 at 0 degree C, migrated at 3.4 cm hr-1. Microscopic observation of actin filaments extracted from different positions along the gel showed that during electrophoresis filaments distributed themselves in such a manner that the longest polymers migrated slowest and the shortest migrated fastest. Using this observation we calculated the weight and number distributions of filament lengths from corresponding experimental intensity profiles. Phalloidin-labelled F-actin oriented in the gel upon application of an electric field. F-actin showed unusual orientational response: it oriented rapidly when the field was applied, but relaxed very slowly when the field was removed. Orientation of F-actin varied within an electrophoretic band, longest polymers showing the best orientation and short oligomers and monomers not orienting at all. The degree of orientation increased with the size of the electric field. When F-actin was labelled with phalloidin before electrophoresis, it was no longer able to migrate in the gel, but the electric field oriented it in the same way as when it was labelled after the electrophoresis. These results show that the electrophoresis of F-actin in agarose fractionates it according to its length, that by using electrophoresis it is possible to rapidly obtain distribution of filament lengths, and that F-actin migrates in agarose by the process of reptation.


Biosynthetic pathways and related genes regulation of bioactive ingredients in mulberry leaves.
Mulberry leaves are served not only as fodder for silkworms but also as potential functional food, exhibiting nutritional and medical benefits due to the complex and diverse constituents, including alkaloids, flavonoids, phenolic acids, and benzofurans, which possess a wide range of biological activities, such as anti-diabete, anti-oxidant, anti-inflammatory, and so on. Nevertheless, compared with the well-studied phytochemistry and pharmacology of mulberry leaves, the current understanding of the biosynthesis mechanisms and regulatory mechanisms of active ingredients in mulberry leaves remain unclear. Natural resources of these active ingredients are limited owing to their low contents in mulberry leaves tissues and the long growth cycle of mulberry. Biosynthesis is emerging as an alternative means for accumulation of the desired high-value compounds, which can broaden channels for their large-scale green productions. Therefore, this review summarizes the recent research advance on the correlative key genes, enzyme biocatalytic reactions and biosynthetic pathways of valuable natural ingredients (i.e. alkaloids, flavonoids, phenolic acids, and benzofurans) in mulberry leaves, thereby offering important insights for their further biomanufacturing.


Homer-dependent cell surface expression of metabotropic glutamate receptor type 5 in neurons.
The metabotropic glutamate (mGlu) receptors are a family of receptors involved in the tuning of fast excitatory synaptic transmission in the brain. Experiments performed in heterologous expression systems suggest that cell surface expression of group I mGlu receptors is controlled by their auxiliary protein, Homer. However, whether or not this also applies to neurons remains controversial. Here we show that in cultured cerebellar granule cells, the group I mGlu receptor subtype, mGlu5, transfected alone is functionally expressed at the surface of these neurons. Transfected Homer1b caused intracellular retention and clustering of this receptor at synaptic sites. Recombinant Homer1a alone did not affect cell surface expression of the receptor, but in neurons transfected with Homer1b, excitation-induced expression of native Homer1a reversed the intracellular retention of mGlu5 receptors, resulting in the receptor trafficking to synaptic membranes. Transfected Homer1a also increased the latency and amplitude of the mGlu5 receptor Ca2+ response. These results indicate that Homer1 proteins regulate synaptic cycling and Ca2+ signaling of mGlu5 receptors, in response to neuronal activity.


Risk factors predicting the development of widespread pain from chronic back or neck pain.
Emerging evidence suggests that some individuals with regional pain disorders go on to develop chronic widespread pain (CWP). However, the mechanism behind this transition and the nature of risk factors that predispose a person to develop CWP remain to be elucidated. The purpose of this study was to describe the frequency with which participants with chronic back or neck pain develop CWP and to determine the risk factors associated with this development. In a sample of 512 individuals, we found that nearly a quarter (22.6%) of subjects who presented with regional back or neck pain in 2001/2002 had developed CWP by 2007. Logistic regression indicated that 7 factors were associated with the transition to CWP: moderate or severe pain intensity, female gender, history of abuse, family history of CWP, severe interference with general activity, having 1 or more central sensitivity syndromes, and using more pain management strategies. History of abuse was not significant in multivariate analysis. Notably, number of depressive symptoms endorsed, pain duration, age, body mass index, number of medication classes used, and receipt of disability benefits were not significantly associated with this transition. This study offers insight into risk factors associated with the development of CWP. This information not only offers clues as to the mechanism behind the expansion of pain sensitivity from a regional pain locus to a widespread pain disorder but also provides insight as to how clinicians might mitigate this transition.


Adenosine Formed by CD73 on T Cells Inhibits Cardiac Inflammation and Fibrosis and Preserves Contractile Function in Transverse Aortic Constriction-Induced Heart Failure.
Structural damage during heart failure development leads to increased infiltration of leukocytes. Because purinergic signaling on immune cells may impact on the inflammatory response, we evaluated the role of ecto-5'-nucleotidase (CD73) on the development of heart failure after transverse aortic constriction (TAC) using global and T-cell-specific CD73-/- mice. Leukocytes infiltrating the failing heart were analyzed by a multistep enzymatic procedure over a period of 16 weeks using fluorescence-activated cell sorting. TAC significantly enhanced the infiltration of leukocytes, especially T cells. The fraction of CD73 expressing cells increased over time exclusively on cytotoxic T cells, T-helper cells, and regulatory T cells. Cardiac function significantly declined in T-cell-specific CD4-Cre+/-CD73flox/flox mice identical to that observed in global CD73 mutants and was associated with enhanced fibrosis (collagen, laminin, vimentin, periostin). Expression analysis by quantitative reverse transcription polymerase chain reaction of extracellular purine degrading enzymes and P1 and P2 receptors on T cells isolated from the injured heart revealed profound upregulation of the enzymatic machinery for hydrolysis of extracellular adenosine triphosphate and nicotinamide adenine dinucleotide, both pathways converging in the formation of AMP and adenosine via CD73. Among the P1 receptors, only the A2a receptor was significantly upregulated after TAC. T cells isolated from TAC-treated hearts show enhanced production of proinflammatory cytokines (interleukin-3, interleukin-6, interleukin-13, interleukin-17, macrophage inflammatory proteins-1α, and macrophage inflammatory proteins-1β) when CD73 was lacking. Our data provide first evidence that CD73 on T cells plays an important anti-inflammatory role in TAC-induced heart failure, which is associated with antifibrotic activity and reduced production of proinflammatory cytokines most likely by activation of the adenosine A2a receptor.


The repertoire of human efforts to avoid sexually transmissible diseases: past and present. Part 1: Strategies used before or instead of sex.
Despite the focus by public health programmes on condoms, chastity, or monogamy, people use a much wider variety of strategies to minimise their personal risk of sexually transmissible disease (STD). The objective of this study was to compile a comprehensive list of personal and societal STD avoidance strategies. Data from clinical and research observations, computer searches, and historical texts were pooled. In addition to discriminating between potential sexual partners, a variety of behaviours before or instead of sex were identified that have been perceived to alter STD risk. Traditional STD avoidance strategies were often poorly documented and difficult to disentangle from other drives such as the maintenance of social order, paternity guarantee, and eugenics. They also varied in popularity in time and place. Some examples were displacement activities such as masturbation or exercise, circumcision, infibulation, shaving, vaccination, or requiring partners to be tested for infection. Social and moral forces typically discourage non-marital sex, and this affects most people most of the time but few people all of the time. The full spectrum of STD avoidance strategies warrants further study because some are ubiquitous across cultures and because they have the potential to complement or undermine safer sex programmes. Because of their greater acceptability, some less efficacious strategies may have greater public health importance than less popular but more efficacious strategies such as condoms.


An effector-reduced anti-β-amyloid (Aβ) antibody with unique aβ binding properties promotes neuroprotection and glial engulfment of Aβ.
Passive immunization against β-amyloid (Aβ) has become an increasingly desirable strategy as a therapeutic treatment for Alzheimer's disease (AD). However, traditional passive immunization approaches carry the risk of Fcγ receptor-mediated overactivation of microglial cells, which may contribute to an inappropriate proinflammatory response leading to vasogenic edema and cerebral microhemorrhage. Here, we describe the generation of a humanized anti-Aβ monoclonal antibody of an IgG4 isotype, known as MABT5102A (MABT). An IgG4 subclass was selected to reduce the risk of Fcγ receptor-mediated overactivation of microglia. MABT bound with high affinity to multiple forms of Aβ, protected against Aβ1-42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic Aβ oligomers by microglia. Furthermore, MABT-mediated amyloid plaque removal was demonstrated using in vivo live imaging in hAPP((V717I))/PS1 transgenic mice. When compared with a human IgG1 wild-type subclass, containing the same antigen-binding variable domains and with equal binding to Aβ, MABT showed reduced activation of stress-activated p38MAPK (p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNFα. We propose that a humanized IgG4 anti-Aβ antibody that takes advantage of a unique Aβ binding profile, while also possessing reduced effector function, may provide a safer therapeutic alternative for passive immunotherapy for AD. Data from a phase I clinical trial testing MABT is consistent with this hypothesis, showing no signs of vasogenic edema, even in ApoE4 carriers.


Male receiver bias for red agonistic signalling in a yellow-signalling widowbird: a field experiment.
Receiver bias models of signal evolution are typically regarded as alternatives or complements to ornament evolution due to coevolving mate choice, whereas sexually or socially selected agonistic signals are rarely studied with respect to receiver psychology. Against the background of convergent evolution of red agonistic signals from yellow ancestors in the genus Euplectes (widowbirds and bishops), we experimentally test the function of a yellow signal in the montane marsh widowbird (E. psammocromius), as well as a hypothesized receiver bias for redder (longer wavelength) hues. In a field experiment in southern Tanzania, males that had their yellow wing patches blackened lost their territories or lost territorial contests more often than controls or reddened males, which together with a longer wavelength hue in territory holders, indicates an agonistic signal function. Males painted a novel red hue, matching that of red-signalling congeners, retained their territories and won contests more often than controls. To our knowledge, this is the first demonstration of a receiver bias driving agonistic signal evolution. Although the sensory or cognitive origin of this bias is yet unknown, it strengthens our view that genetically constrained signal production (i.e. carotenoid metabolism), rather than differential selection, explains the carotenoid colour diversification in Euplectes.


[Structural reorganization of the myocardium during exposure to extreme environmental conditions].
The left ventricular myocardium of Wistar rats was studied by stereologic methods under the exposure to low temperature (-7 degrees C), after a single overheating (at 43 degrees C), during adaptation to high altitudes (3200 above the sea level) and after transferring to high latitudes (at 69 of the North). It was shown that tissue spatial reorganization of the myocardium proceeded by stages: at the first stage the volume and surface-to-volume ratios of bulk tissue components (especially cardiomyocytes and capillaries) were changed considerably, at the second stage the tendency to normalization of tissue architectonics was observed. This dynamics of tissue reorganization is likely to be conditioned by stress reaction and reveals some structural mechanisms of non-specific response to extreme impact. On the contrary, an ultrastructural spatial reorganization of cardiomyocytes was characterized by continuous disproportional changes of volume ratios of bulk organelles (especially mitochondria and myofibrils), which were evident during influence of environmental factors. These discrepancies in dynamics of tissue and intercellular spatial reorganization of myocardium are supposed to reflect the fundamental peculiarities of spatial-temporal organization of regenerative processes in parenchymal cells and stromal components.


[Influence of umbilical cord entanglement on fetal heart rate].
Umbilical cord entanglement was found in 34% of 555 women in labour. One loop of cord around the neck of the fetus was seen in 29% of the women and two or more loops in 5%. Cardiotocograms of these patients were examined for abnormal heart rate patterns. Cord involvement did not influence the incidence of basal bradycardia or tachycardia, early or late decelerations, loss of beat-to-beat variation or acceleration patterns. Variable decelerations, however, were seen in 23% of the patients with cord entanglement and in 7% without cord involvement. This difference is statistically significant (P less than 0.001). Subclassification of variable deceleration into different grades according to the amplitude of the deceleration, demonstrated the presence of cord involvement in 50% of the patients with moderate variable decelerations. This incidence rose to 65% when severe variable decelerations were demonstrated and to 75% when decelerations had increased during labour. Low Apgar scores at 1 and 5 minutes occurred 2 and 3 times more often, respectively, when cord involvement was present.


Prevalence of red blood cell alloantibodies among blood donors in the French Military Blood Institute: A 10-year retrospective study.
Screening for red blood cell alloantibodies (RBC-Ab) is a critical step in ensuring blood transfusion safety performed by blood donation screening laboratories. We aim to evaluate the prevalence of the RBC-Ab among healthy blood donors. Antibody screening of serum of all voluntary blood donors was performed as a routine immune-haematological procedure by a solid-phase method on a fully automated immunohaematology analyser. Positive sera were further investigated to identify the specificity of RBC-Ab by a commercially available red cell panel. Between January 2012 and December 2021, a total of 212,218 donations were screened for the presence of RBC-Ab, 74% from male donors (n = 157,898) and 26% from female donors (n = 54,320). Mean age at donation time was 32 ± 12 years. A total of 1007 donations were screened positive (0.47%), and 131 were confirmed positive for alloantibodies in their serum, yielding a prevalence of 0.06% (95% confidence interval: 0.05-0.07). Most frequent alloantibodies identified were of RH blood group system (64%), followed by anti-MNS (19%), anti-Kidd and Lewis (6% each) and anti-KEL (4%). The results showed a statistically higher prevalence of alloantibodies in women than men. Our results showed a lower prevalence as compared to the available data, which might be related to our study population. The prevalence of positive antibody screening in healthy donors in this study was found to be 0.47%, while the prevalence of alloantibodies was 0.06%. The most common alloantibodies were anti-RH1 (25%) and anti-RH3 (24%).


Plasticity of bud outgrowth varies at cauline and rosette nodes in Arabidopsis thaliana.
Shoot branching is a complex mechanism in which secondary shoots grow from buds that are initiated from meristems established in leaf axils. The model plant Arabidopsis (Arabidopsis thaliana) has a rosette leaf growth pattern in the vegetative stage. After flowering initiation, the main stem elongates with the top leaf primordia developing into cauline leaves. Meristems in Arabidopsis initiate in the axils of rosette or cauline leaves, giving rise to rosette or cauline buds, respectively. Plasticity in the process of shoot branching is regulated by resource and nutrient availability as well as by plant hormones. However, few studies have attempted to test whether cauline and rosette branching are subject to the same plasticity. Here, we addressed this question by phenotyping cauline and rosette branching in three Arabidopsis ecotypes and several Arabidopsis mutants with varied shoot architectures. Our results showed no negative correlation between cauline and rosette branch numbers in Arabidopsis, demonstrating that there is no tradeoff between cauline and rosette bud outgrowth. Through investigation of the altered branching pattern of flowering pathway mutants and Arabidopsis ecotypes grown in various photoperiods and light regimes, we further elucidated that the number of cauline branches is closely related to flowering time. The number of rosette branches has an enormous plasticity compared with cauline branches and is influenced by genetic background, flowering time, light intensity, and temperature. Our data reveal different levels of plasticity in the regulation of branching at rosette and cauline nodes, and promote a framework for future branching analyses.