Cumulative Effect of Psychological Alterations on Gastrointestinal Symptom Severity in Irritable Bowel Syndrome.
Psychological alterations are common and considered important for symptom generation in irritable bowel syndrome (IBS). However, the possible cumulative effect of having multiple psychological alterations on gastrointestinal (GI) symptom severity in IBS is largely unknown. Patients with IBS (Rome IV) completed validated questionnaires assessing GI symptoms (Gastrointestinal Symptom Rating Scale, IBS version and IBS Severity Scoring System), personality traits (Big Five), posttraumatic stress and psychological alterations, anxiety (Generalized Anxiety Disorder 7-item scale and State-Trait Anxiety Inventory), depression (Patient Health Questionnaire, 9-item version), fatigue (Multidimensional Fatigue Inventory), pain catastrophizing, somatization (Patient Health Questionnaire, 12-item version), stress (Perceived Stress Scale), and GI-specific anxiety (Visceral Sensitivity Index). Of the 18 possible psychological factors, those with significant associations with GI symptom severity, corrected for multiple comparisons, were identified. The associations between increasing number of psychological alterations (validated cutoff values or uppermost tertile) and the severity of GI symptoms were analyzed with linear trend analyses. In total, 106 patients with IBS (Rome IV criteria) were included (72 [68%] women, median age of 35 [interquartile range: 26-45] years). Psychological alterations were common and overlap among these factors were frequently seen. Five psychological factors (physical fatigue, GI-specific anxiety, perceived stress, pain catastrophizing, and trait anxiety) demonstrated significant, noncollinear associations with GI symptom severity. With increasing number of these psychological alterations, a gradual increase was seen in the overall severity of GI symptoms (Gastrointestinal Symptom Rating Scale, IBS version: partial η = 0.268, P < 0.001; IBS Severity Scoring System: partial η = 0.219, P < 0.001, both large effect sizes). Distinct associations were seen between the severity of GI symptoms and individual, as well as an increasing number of psychological alterations. This highlights the importance of understanding different psychological alterations for the disease burden in IBS (visual abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B756).


Patient prioritisation for hospital pharmacy services: current approaches in the UK.
To survey and explore current approaches to deployment of pharmaceutical care prioritisation tools in acute hospitals in the UK. A national online survey was circulated electronically to chief pharmacists of hospitals to determine if they use a prioritisation tool or process. Where such mechanisms exist, respondents were invited to participate in a semistructured telephone interview to explore the development, evaluation and application of their tool and share relevant documentation. Interviews were transcribed and thematically analysed. Seventy hospitals (70/130) used a tool or process to prioritise clinical pharmacy services. Thirty-six interviews were conducted, and two were excluded. The majority of tools had been developed in-house. Few hospitals had undertaken formal evaluations of their prioritisation tool. Pharmacy prioritisation tools ranged in complexity and often included a combination of pharmacy service prioritisation, such as medicines reconciliation, and a section to assign an individual patient prioritisation level. Determining the priority of a patient based on the identification of set indicators instilled confidence in pharmacists by ensuring they were not missing high-risk patients. Electronic prioritisation tools were especially useful at retrieving real-time data to prioritise workload, improving workflow and ensuring continuity in patient care. Drawbacks of using prioritisation tools included lack of tool sensitivity across certain specialties and time spent using the tool if not all information was accessible. Prioritisation tools were seen to be useful for prioritising workload and ensuring the right patients are seen at the right time. As few hospitals had formally evaluated their tools, it is important to rigorously and systematically develop an evidence-based prioritisation tool that is both useable and acceptable. Further research to evaluate such tools would be needed to ensure it improves patient health outcomes and efficiency in pharmacy services.


The West Palaearctic genera of Nematinae (Hymenoptera, Tenthredinidae).
Keys to adults and larvae of the genera of West Palaearctic nematine sawflies are presented. Species of some of the smaller genera are keyed, and their taxonomy, distribution, and host plants reviewed, with a geographic focus on north-western Europe, particularly Sweden. Dinematus Lacourt, 2006 is a new junior subjective synonym of Pristiphora Latreille, 1810, resulting in the new combination Pristiphora krausi (Lacourt, 2006) for the type species of Dinematus. Hemichroa monticola Ermolenko, 1960 is a new junior subjective synonym of Hemichroa australis (Serville, 1823). Lectotypes are designated for Tenthredo opaca Fabricius, 1775, Mesoneura opaca var. nigerrima Enslin, 1914, Mesoneura opaca var. obscuriventris Enslin, 1914, Nematus hypogastricus Hartig, 1837, Nematus alnivorus Hartig, 1840, Leptopus rufipes Förster, 1854, Nematus protensus Förster, 1854, and Platycampus luridiventris var. pleuritica Enslin, 1915. A phylogenetic analysis based on four genes (mitochondrial COI and nuclear NaK, POL2, and TPI) supports the current generic classification.


Optimization of process conditions for preparation of activated carbon from waste Salix psammophila and its adsorption behavior on fluoroquinolone antibiotics.
Salix psammophila (SP), a solid waste abundantly available, was applied as a precursor to prepare the activated carbon by chemical activation method using phosphoric acid (H3PO4). Response surface methodology based on Box-Behnken design was used to optimize the prepared conditions of activated carbon. The effects of concentration of H3PO4, activation temperature and activation time on the adsorption performance (expressed by the adsorption capacity of ciprofloxacin hydrochloride (CIP) and norfloxacin (NOR)) were investigated. The optimum conditions were obtained using H3PO4 concentration of 67.83%, activation temperature of 567.44 °C and activation time of 86.61 min. The optimum activated carbon (SPAC) was characterized with scanning electron microscopy-energy dispersive X-ray spectroscopy (SEM-EDS), Brunauer-Emmett-Teller (BET) and Fourier transform infrared spectroscopy (FTIR). The adsorption behavior of CIP and NOR on SPAC was carried out and the mechanisms for the adsorption process were proposed. The equilibrium data were fitted by the Freundlich and Langmuir isotherm models, which resulted in 251.9 mg/g and 366.9 mg/g of the maximum monolayer adsorption for CIP and NOR at 25 °C, respectively. The best fitted kinetic model was pseudo-second-order, implying that chemisorption dominated in the adsorption process. This study indicated that activated carbon based on Salix psammophila (SPAC) was an excellent adsorbent for removing fluoroquinolone antibiotics from aqueous solutions.


Locust displacing winds in eastern Australia reassessed with observations from an insect monitoring radar.
Based on previous investigations, adult Australian plague locusts are believed to migrate on warm nights (with evening temperatures >25 °C), provided daytime flight is suppressed by surface winds greater than the locusts' flight speed, which has been shown to be 3.1 m s-1. Moreover, adult locusts are believed to undertake briefer 'dispersal' flights on nights with evening temperature >20 °C. To reassess the utility of these conditions for forecasting locust flight, contingency tests were conducted comparing the nights selected on these bases (predicted nights) for the months of November, January, and March and the nights when locust migration were detected with an insect monitoring radar (actual nights) over a 7-year period. In addition, the wind direction distributions and mean wind directions on all predicted nights and actual nights were compared. Observations at around 395 m above ground level (AGL), the height at which radar observations have shown that the greatest number of locusts fly, were used to determine the actual nights. Tests and comparisons were also made for a second height, 990 m AGL, as this was used in the previous investigation. Our analysis shows that the proposed criteria are successful from predicting migratory flight only in March, when the surface temperature is effective as a predicting factor. Surface wind speed has no predicting power. It is suggested that a strong daytime surface wind speed requirement should not be considered and other meteorological variables need to be added to the requirement of a warm surface temperature around dusk for the predictions to have much utility.


Retinal S-opsin dominance in Ansell's mole-rats (Fukomys anselli) is a consequence of naturally low serum thyroxine.
Mammals usually possess a majority of medium-wavelength sensitive (M-) and a minority of short-wavelength sensitive (S-) opsins in the retina, enabling dichromatic vision. Unexpectedly, subterranean rodents from the genus Fukomys exhibit an S-opsin majority, which is exceptional among mammals, albeit with no apparent adaptive value. Because thyroid hormones (THs) are pivotal for M-opsin expression and metabolic rate regulation, we have, for the first time, manipulated TH levels in the Ansell's mole-rat (Fukomys anselli) using osmotic pumps. In Ansell's mole-rats, the TH thyroxine (T4) is naturally low, likely as an adaptation to the harsh subterranean ecological conditions by keeping resting metabolic rate (RMR) low. We measured gene expression levels in the eye, RMR, and body mass (BM) in TH-treated animals. T4 treatment increased both, S- and M-opsin expression, albeit M-opsin expression at a higher degree. However, this plasticity was only given in animals up to approximately 2.5 years. Mass-specific RMR was not affected following T4 treatment, although BM decreased. Furthermore, the T4 inactivation rate is naturally higher in F. anselli compared to laboratory rodents. This is the first experimental evidence that the S-opsin majority in Ansell's mole-rats is a side effect of low T4, which is downregulated to keep RMR low.


Expression and secretion hierarchy in the nonflagellar type III secretion system.
Type III secretion systems that deliver bacterial proteins into eukaryotic cells are the basis for both symbiotic and pathogenic relationships between many Gram-negative bacteria and their hosts. Exploration of the structure, function and assembly of this secretion system has greatly enhanced our knowledge of bacterial ecology in the context of infectious disease and has spawned new avenues in anti-infective research with a view towards inhibiting virulence functions. We outline advances in understanding type III secretion system function with specific focus on how assembly is hierarchically coordinated at the level of expression and how the type III secretion system mediates transitions in substrate specificity.


Cooling does not affect knee proprioception.
The effect of cooling on proprioception of the knee has not been studied extensively. In this study, we investigated the movement reproduction (timing and accuracy) aspect of proprioception. Subjects were tested under two conditions: a 20-minute application of ice and control. Proprioceptive accuracy and timing were measured by passively moving the knee, then comparing the subject's active reproduction of the passive movement. Subjects were blindfolded, then tested in three sectors of the knee's range of motion: 90 degrees to 60 degrees , 60 degrees to 30 degrees , and 30 degrees to full extension. Ice application had no apparent effect on the subject's ability to perform accurate movement reproductions in the sectors tested. However, accuracy of the subject's final angle reproduction varied between the sectors as did the total time of the movement. One possible explanation for the difference between sectors is that different receptors are active at different points in the knee's range of motion. We conclude that cooling the knee joint for 20 minutes does not have an adverse effect on proprioception.


Sodium valproate (Epilim) in the treatment of refractory epilepsy.
Sodium valproate was given to seven children with refractory epilepsy and mental retardation. Four of the children became fit free while another was much improved. Plasma levels of sodium valproate correlated well with the dose prescribed and did not approach the theoretical top-desirable level of 200 microgram/ml despite larger than recommended doses. Side effects were minimal and it is concluded that the drug is safe and useful.


Room for Improvement in Sports Nutrition Knowledge amongst Parents and Caregivers of Male Academy Soccer Players in the UK: A Cross-Sectional Study.
In professional soccer clubs in the UK, nutrition support is often polarised towards senior players or those in the senior academy age groups seeking first team selection/involvement. Accordingly, there is an increased reliance on parents and caregivers to provide support regarding nutritional intake. Therefore, the aim of this study was to evaluate the quality of nutrition knowledge of parents and caregivers of male youth soccer players within developmental academies in the UK. Across a single competitive season, 360 registered parents and caregivers of male soccer players from English Premier League under 9-11 (Foundation Phase) and under 12-16 (Youth Development Phase) age group academies completed an online version of the 88-item validated Nutrition for Sport Knowledge Questionnaire. Nutrition knowledge scores were classified as "poor" (43 ± 23%). Nutrition knowledge scores were significantly greater in respondents with dependents representing Category 1 (45 ± 13%) vs. Category 2 (39 ± 15%) academies and in Foundation Phase (44 ± 13%) vs. Youth Development Phase (41 ± 15%). These results demonstrate that there is room for improvement in the nutrition knowledge levels of parents and caregivers of male soccer academy players. We recommend that club academies provide appropriate resources towards nutritional education for parents and caregivers.


Dentate gyrus mossy cells control spontaneous convulsive seizures and spatial memory.
Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.


Two new terpenoid glycosides from Isodon macrocalyx.
One previously undescribed tricyclo-diterpenoid saponin (1), one undescribed dammarane triterpenoid saponin (2) and four known triterpenoids (3-6) were isolated from the aerial part of Isodon macrocalyx. Their structures were determined using 1 D- and 2 D-NMR, HRESIMS, and comparison of their spectroscopic data with previously reported data. The isolates were evaluated for their anti-HBV activity in vitro using the HBV transfected Hep G2.2.15 cell line. Compounds 2 and 3 exhibited moderate anti-HBV activity.


Using 5D flow MRI to decode the effects of rhythm on left atrial 3D flow dynamics in patients with atrial fibrillation.
This study used a 5D flow framework to explore the influence of arrhythmia on thrombogenic hemodynamic parameters in patients with atrial fibrillation (AF). A fully self-gated, 3D radial, highly accelerated free-running 5D flow sequence with interleaved four-point velocity-encoding was acquired using an in vitro arrhythmic flow phantom and in 25 patients with a history of AF (68 ± 8 y, 6 female). Self-gating signals were used to calculate AF burden, bin data, and tag each k-space line with its RRLength . Data were binned as an RR-resolved dataset with four RR-interval bins (RR1-RR4, short-to-long) for compressed sensing reconstruction. AF burden was calculated as interquartile range of all intrascan RR-intervals divided by median RR-interval, and left atrial (LA) stasis as the percent of the cardiac cycle where the velocity was <0.1 m/s. In vitro results demonstrated successful recovery of RR-binned flow curves using RR-resolved 5D flow compared to a real-time PC reference standard. In vivo, 5D flow was acquired in 8:48 minutes. AF burden was significantly correlated with 5D flow-derived peak (PV) and mean (MV) velocity and stasis (|ρ| = 0.54-0.75, P < .001). Sensitivity analyses determined a threshold for low versus high AF burden at 9.7%. High burden patients had increased LA mean stasis (up to +42%, P < .01), and lower MV and PV (-30%, -40.6%, respectively, P < .01). RR4 deviated furthest from respiratory-resolved reconstruction (end-expiration) with increased mean stasis (7.6% ± 14.0%, P = .10) and decreased PV (-12.7 ± 14.2%, P = .09). RR-resolved 5D flow can capture temporal and RR-resolved 3D hemodynamics in <10 minutes and offers a novel approach to investigate arrhythmias.


Contact Angle and Adhesion Dynamics and Hysteresis on Molecularly Smooth Chemically Homogeneous Surfaces.
Measuring truly equilibrium adhesion energies or contact angles to obtain the thermodynamic values is experimentally difficult because it requires loading/unloading or advancing/receding boundaries to be measured at rates that can be slower than 1 nm/s. We have measured advancing-receding contact angles and loading-unloading adhesion energies for various systems and geometries involving molecularly smooth and chemically homogeneous surfaces moving at different but steady velocities in both directions, ±V, focusing on the thermodynamic limit of ±V → 0. We have used the Bell Theory (1978) to derive expressions for the dynamic (velocity-dependent) adhesion energies and contact angles suitable for both (i) dynamic adhesion measurements using the classic Johnson-Kendall-Roberts (JKR, 1971) theory of "contact mechanics" and (ii) dynamic contact angle hysteresis measurements of both rolling droplets and syringe-controlled (sessile) droplets on various surfaces. We present our results for systems that exhibited both steady and varying velocities from V ≈ 10 mm/s to 1 nm/s, where in all cases but one, the advancing (V > 0) and receding (V < 0) adhesion energies and/or contact angles converged toward the same theoretical (thermodynamic) values as V → 0. Our equations for the dynamic contact angles are similar to the classic equations of Blake & Haynes (1969) and fitted the experimental adhesion data equally well over the range of velocities studied, although with somewhat different fitting parameters for the characteristic molecular length/dimension or area and characteristic bond formation/rupture lifetime or velocity. Our theoretical and experimental methods and results unify previous kinetic theories of adhesion and contact angle hysteresis and offer new experimental methods for testing kinetic models in the thermodynamic, quasi-static, limit. Our analyses are limited to kinetic effects only, and we conclude that hydrodynamic, i.e., viscous, and inertial effects do not play a role at the interfacial velocities of our experiments, i.e., V < (1-10) mm/s (for water and hexadecane, but for viscous polymers it may be different), consistent with previously reported studies.


Interpretation of glycosuria in the teenage diabetic patient.
More than 700 insulin-dependent diabetic patients of both sexes and all ages have attended an education and stabilization course. Twelve adult females and four adult males were subsequently issued the means to monitor their blood glucose in their homes. Two of the adult females were pregnant, while the other 14 patients had one or more of the following: renal failure, an abnormal renal threshold, diabetic retinopathy, or continued and unexplained instability. A number of children were also issued Ames reflectometers. Eleven out of 13 male patients between the ages of 12 and 18 yr had no special difficulties except for a poor correlation between minor degrees of glycosuria and blood glucose estimations. One youth had a renal threshold of 17 mmol/L, while a recently diagnosed youth had a varying renal threshold. Eleven out of 17 teenage female diabetic patients had no correlation between urinary and blood glucose estimations with an apparant varying renal threshold being common. Four of these patients had a reflectometer on loan for 6--8 wk, but in three there was continued instability. Two others, who had continued use of home monitoring of blood glucose, had normoglycemia upon review. One of these patients had what appeared to be a varying renal threshold while unstable but a normal threshold with diabetic stability. Regardless of the cause of the disparity between blood and uninary glucose estimations, it appears that the unstable teenage female diabetic patient cannot rely upon urinalysis as a guide to insulin dosage.


Management of acute postoperative thrombosis following carotid endarterectomy.
We reviewed 326 carotid endarterectomies performed from 1960 through 1981 and encountered five instances of acute postoperative thrombosis. Clinical decompensation occurs with the acute onset of severe neurologic deficits, most characteristically dense hemiplegias contralateral to the side that has been operated on. These deficits developed between two and 72 hours postoperatively. Prompt reoperation with thrombectomy and reestablishment of carotid flow within two hours from the onset of the neurologic deficit was performed on four patients with complete resolution of the deficits in three patients. The fourth patient recovered from a severe hemiplegia but retained a slight residual weakness of the hand. The one patient whose condition did not improve underwent thrombectomy more than 24 hours after the onset of her deficit. Time-consuming diagnostic procedures are not warranted as the success of reoperation depends on rapid reestablishment of cerebral flow.


Collagen microsphere production on a chip.
We have developed an integrated microfluidic material processing chip and demonstrated the rapid production of collagen microspheres encapsulating cells with high uniformity and cell viability. The chip integrated three material processing steps. Monodisperse microdroplets were generated at a microfluidic T junction between aqueous and mineral oil flows. The flow was heated immediately to 37 °C to initiate collagen fiber assembly within a gelation channel. Gelled microspheres were extracted from the mineral oil phase into cell culture media within an extraction chamber. Collagen gelation immediately after microdroplet generation significantly reduced coalescence among microdroplets that led to non-uniform microsphere production. The microfluidic extraction approach led to higher microsphere recovery and cell viability than when a conventional centrifugation extraction approach was employed. These results indicate that chip-based material processing is a promising approach for cell-ECM microenvironment generation for applications such as tissue engineering and stem cell delivery.


Interferon signaling suppresses the unfolded protein response and induces cell death in hepatocytes accumulating hepatitis B surface antigen.
Virus infection, such as hepatitis B virus (HBV), occasionally causes endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is counteractive machinery to ER stress, and the failure of UPR to cope with ER stress results in cell death. Mechanisms that regulate the balance between ER stress and UPR are poorly understood. Type 1 and type 2 interferons have been implicated in hepatic flares during chronic HBV infection. Here, we examined the interplay between ER stress, UPR, and IFNs using transgenic mice that express hepatitis B surface antigen (HBsAg) (HBs-Tg mice) and humanized-liver chimeric mice infected with HBV. IFNα causes severe and moderate liver injury in HBs-Tg mice and HBV infected chimeric mice, respectively. The degree of liver injury is directly correlated with HBsAg levels in the liver, and reduction of HBsAg in the transgenic mice alleviates IFNα mediated liver injury. Analyses of total gene expression and UPR biomarkers' protein expression in the liver revealed that UPR is induced in HBs-Tg mice and HBV infected chimeric mice, indicating that HBsAg accumulation causes ER stress. Notably, IFNα administration transiently suppressed UPR biomarkers before liver injury without affecting intrahepatic HBsAg levels. Furthermore, UPR upregulation by glucose-regulated protein 78 (GRP78) suppression or low dose tunicamycin alleviated IFNα mediated liver injury. These results suggest that IFNα induces ER stress-associated cell death by reducing UPR. IFNγ uses the same mechanism to exert cytotoxicity to HBsAg accumulating hepatocytes. Collectively, our data reveal a previously unknown mechanism of IFN-mediated cell death. This study also identifies UPR as a potential target for regulating ER stress-associated cell death.


Australians with osteoarthritis: satisfaction with health care providers and the perceived helpfulness of treatments and information sources.
The aim of this study was to evaluate the satisfaction of Australian patients who suffer from osteoarthritis (OA) with their health care providers and the perceived helpfulness of treatments and information sources. A self-administered questionnaire was conducted with a sample of 560 Australian patients who suffer from OA with questions about satisfaction with health care providers and the helpfulness of different treatment options and information sources. Logistic regression models were used to assess potential predictors of satisfaction. Thematic analysis was undertaken for attitudinal factors associated with satisfaction. A total of 435 participants returned questionnaires (response rate 78%). Most respondents were highly satisfied with the care provided by their general practitioner (GP) (84%), communication with their GP (88%), time spent with their GP (84%), and their ability to talk freely with their GP about their medical problem (93%), but less satisfied with their ability to talk freely about associated emotional problems (77%). Satisfaction with pharmacists (80%), rheumatologists (76%), and orthopedic surgeons (72%) was high. Joint replacement surgery (91%), prescription anti-inflammatory medications (66%), aids and assistive devices (65%), intra-articular injections (63%), and prescription painkiller medications (62%) were perceived as effective treatments. Less highly rated treatments were exercise (48%), physiotherapy (43%), and complementary medicines (29%). A majority of patients were satisfied with the information to manage their OA (65%). From the multivariable logistic regression analysis, four GP satisfaction factors were found to be predictors of overall satisfaction with GP care: the amount of time that the GP spends with the patient (P=0.005), the information the GP provides about what to expect (P<0.001), the communication between patient and GP (P=0.001), and the information that the GP provides about medications (P=0.042). The study showed that although patients with OA were generally satisfied with their health care providers, there was notable variation in the perceived helpfulness of therapeutic options. The importance to patients of having access to good quality information about their condition was emphasized.


[Electroacupuncture and arrhythmia caused by reperfusion of the coronary arteries in rabbits and rats in hypothermia].
Reperfusion-induced arrhythmias in rats and rabbits are highly temperature-dependent. When the rectal temperature of experimental animals was low, the effects of electroacupuncture at Jian Xi on reperfusion-induced arrhythmias could be observed. The arrhythmias shortened in rabbits, and more ventricular extrasystoles following reperfusion were seen in rats. It is suggested that electroacupuncture at Jian Xi can exert significant influence on reperfusion-induced arrhythmias.


Navigation expertise and the human hippocampus: a structural brain imaging analysis.
Grey matter volume in the posterior hippocampus of London taxi drivers is greater than in age-matched controls, and the size of this increase correlates positively with time spent taxi driving (E.A. Maguire et al., 2000. Proc Natl Acad Sci USA 97: 4398-4403). This change suggests that increased posterior hippocampal grey matter volume is acquired in response to increased taxi driving experience, perhaps reflecting their detailed representation of the city. However, an alternate hypothesis is that the difference in hippocampal volume is instead associated with innate navigational expertise, leading to an increased likelihood of becoming a taxi driver. To investigate this possibility, we used structural brain imaging and voxel-based morphometry (VBM) to examine a group of subjects who were not taxi drivers. Despite this group showing a wide range of navigational expertise, there was no association between expertise and posterior hippocampal grey matter volume (or, indeed, grey matter volume throughout the brain). This failure to find an association between hippocampal volume and navigational expertise thus suggests that structural differences in the human hippocampus reflect the detail and/or duration of use of the spatial representation acquired, and not innate navigational expertise per se.


Identification of Pattern Completion Neurons in Neuronal Ensembles Using Probabilistic Graphical Models.
Neuronal ensembles are groups of neurons with coordinated activity that could represent sensory, motor, or cognitive states. The study of how neuronal ensembles are built, recalled, and involved in the guiding of complex behaviors has been limited by the lack of experimental and analytical tools to reliably identify and manipulate neurons that have the ability to activate entire ensembles. Such pattern completion neurons have also been proposed as key elements of artificial and biological neural networks. Indeed, the relevance of pattern completion neurons is highlighted by growing evidence that targeting them can activate neuronal ensembles and trigger behavior. As a method to reliably detect pattern completion neurons, we use conditional random fields (CRFs), a type of probabilistic graphical model. We apply CRFs to identify pattern completion neurons in ensembles in experiments using in vivo two-photon calcium imaging from primary visual cortex of male mice and confirm the CRFs predictions with two-photon optogenetics. To test the broader applicability of CRFs we also analyze publicly available calcium imaging data (Allen Institute Brain Observatory dataset) and demonstrate that CRFs can reliably identify neurons that predict specific features of visual stimuli. Finally, to explore the scalability of CRFs we apply them to in silico network simulations and show that CRFs-identified pattern completion neurons have increased functional connectivity. These results demonstrate the potential of CRFs to characterize and selectively manipulate neural circuits.SIGNIFICANCE STATEMENT We describe a graph theory method to identify and optically manipulate neurons with pattern completion capability in mouse cortical circuits. Using calcium imaging and two-photon optogenetics in vivo we confirm that key neurons identified by this method can recall entire neuronal ensembles. This method could be broadly applied to manipulate neuronal ensemble activity to trigger behavior or for therapeutic applications in brain prostheses.


MHC class II association study in eight breeds of dog with hypoadrenocorticism.
Canine hypoadrenocorticism is an endocrine disorder characterised by inadequate secretion of steroid hormones from the adrenal glands. Pathology results from immune-mediated destruction of the adrenal cortex, which is similar to that seen in the human Addison's disease. Both the canine and human diseases have similar clinical presentation, with the diagnosis based on performing a dynamic adrenocorticotropic hormone stimulation test. MHC class II has previously been associated with the human and canine diseases. In the current study, we conducted an MHC class II association study in eight breeds of dog with diagnoses of hypoadrenocorticism. We demonstrated significant differences in dog leukocyte antigen (DLA) haplotype frequencies in six of these breeds: Cocker spaniel, Springer spaniel, Labrador, West Highland white terrier (WHWT), Bearded collie, and Standard poodle. In the Springer spaniel, the DLA-DRB1*015:01--DQA1*006:01--DQB1*023:01 haplotype was significantly associated with disease risk (p = 0.014, odds ratio (OR) = 5.14) and showed a similar trend in the Cocker spaniel. This haplotype is related to one associated with hypoadrenocorticism in the Nova Scotia duck tolling retriever. Similar haplotypes shared between breeds were demonstrated, with DLA-DRB1*001:01--DQA1*001:01--DQB1*002:01 more prevalent in both affected Labrador (p = 0.0002, OR = 3.06) and WHWT (p = 0.01, OR = 2.11). Other haplotypes that have not previously been associated with the disease were identified. The inter-breed differences in DLA haplotypes associated with susceptibility to canine hypoadrenocorticism could represent divergent aetiologies. This could have implications for clinical diagnosis and future comparative studies. Alternatively, it may suggest that the gene of interest is closely linked to the MHC.


Early Identification and Treatment of Osteoporosis in a Rural Internal Medicine Clinic: A Quasi-Experimental Approach toQuality Improvement.
Osteoporosis affects more than 44 million individuals in the United States annually while disease management continues to fall short of the recommended guidelines. This study institutes a practice change for osteoporosis/osteopenia screening and treatment founded on current evidence-based guidelines. A retrospective chart review was evaluated for current trends in the identification and treatment of osteoporosis/osteopenia in female patients older than 65 years. Data were then compared with identical data collected after implementing an evidence-based osteoporosis guideline tool. Quantitative analysis indicated poor adherence of established osteoporosis guidelines by providers. In comparison, after implementation of the osteoporosis treatment guideline tool, there was an improvement of more than 40% in the identification and treatment of osteoporosis/osteopenia. Utilization of the evidence-based osteoporosis guideline tool resulted in quality improvement in identifying and treating those with or at risk for osteoporosis/osteopenia.


Combined active and passive immunization enhances the efficacy of immunotherapy against nicotine in rats.
Vaccination against nicotine reduces the behavioral effects of nicotine in rats, and it is under clinical evaluation as a treatment for tobacco addiction. Efficacy is limited by the need for high serum nicotine-specific antibody (NicAb) levels, and currently available nicotine vaccines do not uniformly generate the required NicAb levels. Passive immunization with a nicotine-specific monoclonal antibody (Nic311) has also shown efficacy in rats. The principal aim of this study was to determine whether the combined use of vaccination and passive immunization would produce greater effects than vaccination alone on nicotine pharmacokinetics and locomotor sensitization (LMS) to nicotine. Rats were treated with vaccination alone, Nic311 alone, both, or neither, and then they were administered 10 daily injections of 0.3 mg/kg nicotine s.c. Treatment with Nic311 or vaccination alone increased the binding of nicotine in serum, reduced the unbound serum nicotine concentration and nicotine distribution to brain, and attenuated the development of LMS. Combined use of vaccination and passive immunization produced higher total serum NicAb levels, greater changes in nicotine pharmacokinetics, and a greater attenuation of LMS than either treatment alone. The total serum NicAb concentration was significantly correlated with brain nicotine levels and locomotor activity. These data indicate that providing higher serum NicAb concentrations improves the efficacy of immunotherapy against nicotine and that supplementing vaccination with passive immunization is a potential strategy to accomplish this.


A large-area ionization chamber for portal image calibration.
Methods of removing the effects of linear accelerator (linac) output fluctuation from electronic portal images are described and compared. The output of the linac is measured using a specially constructed large-area ionization chamber during imaging and recorded with the image. The use of a dose-rate signal directly from the linac monitor chamber is discussed. Various versions of a quadratic thickness calibration scheme are tested, incorporating linac output data measured by the ionization chamber. Experimental results are presented showing that the incorporation of data from the ionization chamber gives improved absolute calibration accuracy and flatness. Immediately after calibration, the mean systematic thickness error in calibration of a uniform 136.8 mm water-equivalent slab was shown to be no more than 0.6 mm with a thickness variation within each image also of no more than +/-0.8 mm. This was true even when imaging with an unstable linac beam giving mean thickness errors between images of 8.8 mm and variations within each image of +/-4.9 mm without the ionization chamber correction. Up to one month after calibration, use of the ionization chamber to remove short-term linac fluctuations is shown to still keep mean thickness errors to less than 1.6 mm with variations within each image of no more than +/-1.4 mm.


Emerging obesity and dietary habits among James Bay Cree youth.
To describe dietary habits and extent of overweight and obesity among Cree youth. Dietary intake and habits were assessed by a 24 h recall and FFQ as part of a cross-sectional survey. Three Cree communities in northern Québec, Canada. A total of 125 youth aged 9-18 years. Overall 67·6 % of the study population was either at risk of overweight or overweight. Over 98 % had a usual saturated fat intake over 10 % of energy while 65 % had a lower consumption of fruit/vegetables and 95 % had a lower consumption of milk and milk products than recommended by Canada's Food Guide. The majority (96·8 %) consumed high-fat foods (>40 % of total energy as fat), which accounted for 39 % of total energy intake (EI). Similarly, 92·8 % consumed high-sugar food and beverages (>25 % of total energy as sugar), which accounted for 12·8 % of total EI. Furthermore, 95 % of the youth had a Healthy Eating Index (HEI) below the recommended score of 80 or above. Certain measures of diet quality (traditional food (TF) consumption, HEI and vegetables and fruit consumption) were significantly correlated with adiposity measures. A high prevalence of low-diet quality was found with a high degree of sugar and fat intake and a low consumption of vegetables/fruit and milk/milk alternates and any weekly TF. Dietary interventions are sorely needed.


Impact of initial norwood shunt type on right ventricular deformation: the single ventricle reconstruction trial.
The Single Ventricle Reconstruction trial demonstrated a transplantation-free survival advantage at 12-month follow-up for patients with right ventricle-pulmonary artery shunts (RVPAS) with the Norwood procedure compared with modified Blalock-Taussig shunts but similar survival and decreased global right ventricular (RV) function on longer term follow-up. The impact of the required ventriculotomy for the RVPAS remains unknown. The aim of this study was to compare echocardiography-derived RV deformation indices after stage 2 procedures in survivors with single RV anomalies enrolled in the Single Ventricle Reconstruction trial. Global and regional RV systolic longitudinal and circumferential strain and strain rate, ejection fraction, and short-axis percentage fractional area change were all derived by speckle-tracking echocardiography from protocol echocardiograms obtained at 14.3 ± 1.2 months. Student t tests or Wilcoxon rank sum tests were used to compare groups. The cohort included 275 subjects (129 in the modified Blalock-Taussig shunt group and 146 in the RVPAS group). Longitudinal deformation could be quantified in 214 subjects (78%) and circumferential measures in 182 subjects (66%). RV ejection fraction and percentage fractional area change did not differ between groups. There were no significant differences between groups for global or regional longitudinal deformation. Circumferential indices showed abnormalities in deformation in the RVPAS group, with decreased global circumferential strain (P = .05), strain rate (P = .09), and anterior regional strain rate (P = .07) that approached statistical significance. RV myocardial deformation at 14 months, after stage 2 procedures, was not significantly altered by the type of initial shunt placed. However, abnormal trends were appreciated in circumferential deformation for the RVPAS group in the area of ventriculotomy that may represent early myocardial dysfunction. These data provide a basis for longer term RV deformation assessment in survivors after Norwood procedures.


[Drug therapy of glaucoma with adrenergic and anti-adrenergic agents].
This paper presents a survey for practitioners: The antagonism between the cholinergic and the adrenergic systems originally seemed clear and easy to understand. With the increasing differentiation of the peripheral adrenergic receptors alone into presynaptic alpha 2 and beta 2 and postsynaptic alpha 1, beta 1, and beta 2 subtypes, the current explanation of the antagonism as a simple process, the regulation and correction of aqueous humor dynamics, is increasingly being questioned. For example, the distribution of adrenergic receptors in the extraocular muscles is different in various species of mammals; both stimulation and blockage of beta 2-adrenoreceptors induce a fall in intraocular pressure. With the introduction of adrenergic and antiadrenergic agents into the treatment of the glaucomas, more and more questions arise concerning sympathomimetic action and interaction at subcellular level.


The role of the angiotensin system in cardiac glucose homeostasis: therapeutic implications.
Resistance to the metabolic actions of insulin is thought to play a determining role in the aetiology of a great variety of disorders, including essential hypertension, accelerated atherosclerosis and cardiomyopathies. ACE inhibitors are recognised as being highly effective therapy for hypertension and cardiac insufficiency, and have a more beneficial effect on survival rate than expected on the basis of known mechanisms of action. The mechanism responsible for these extremely positive effects are just beginning to be understood and appear to be linked to the effects these drugs have on metabolism. The relationship between the insulin and angiotensin II (Ang II) signalling pathways needs to be fully clarified in order to prevent or correct the target organ damage resulting from changes in the cross-talk of these two hormonal systems. In recent years, Ang II has been shown to play a central role in cardiovascular and neuroendocrine physiology as well as in cellular cycle control. Moreover, the fact that Ang II utilises the insulin-receptor substrate (IRS)-1 to relay signals towards their intracellular destination, provides the biochemical explanation of how these two systems interact in a healthy organism and in a diseased one. Since it is overactivity of the renin-angiotensin system that seems to impair the intracellular response to insulin signalling, cardiovascular drugs that modulate the cellular transmission of Ang II have attracted particular interest. As well as the already widely-used ACE inhibitors, selective blockers of the Ang II type 1 receptor (AT(1)) have been shown to be clinically effective in the control of haemodynamic parameters, but with perhaps a less striking effect on glucose homeostasis. Many trials have investigated the effect of Ang II blockade on systemic glucose homeostasis. The inhibition of Ang II by ACE-inhibitors frequently showed a positive effect on glycaemia and insulin sensitivity, while information on the effects of AT(1) receptor antagonists on glucose homeostasis is more limited and controversial. An important limitation of these studies has been the short treatment and follow-up periods, even for the 'so called' long-term studies which were only 6 months. Several investigators have focused on the effects of the nuclear factors involved in gene transcriptions, especially with respect to the agonists/antagonists of peroxisome proliferator-activated receptors (PPARs) and their intriguing interconnections with the insulin and Ang II subcellular pathways. In fact, in vitro and in vivo experimental studies have shown that thiazolidinediones (selective PPAR-gamma ligands) are not only powerful insulin sensitisers, but also have anti-hypertensive and anti-atherosclerotic properties. In addition to conventional pharmacological approaches, attempts have been made to use genetic transfer in the treatment of cardiovascular and metabolic disorders. The development of powerful viral vectors carrying target genes has allowed us to restore the expression/function of specific proteins involved in the cellular mechanism of insulin resistance, and research now needs to move beyond animal models. Although a clearer picture is now emerging of the pathophysiological interaction between insulin and Ang II, especially from pre-clinical studies, there is much to be done before experimental findings can be used in daily clinical practice.


A case of camptocormia occurring in psychotherapy.
Although camptocormia has been known to be a functional symptom since its first description in 1837, there has been little opportunity to study the psychodynamics of this symptoms. The author describes the development of this symptom in a patient who had been in psychotherapy for 3 1/2 years and explores the meaning of the symptom for this patient. The author makes suggestions as to proper therapeutic management of patients with this symptom.


Driving Cessation and Late-Life Depressive and Anxiety Symptoms: Findings from the National Health and Aging Trends Study.
To describe the association between driving cessation and depressive and anxiety symptoms over time by assessing depression and anxiety at 1- and 4-years follow-up. The study examined community-dwelling adults aged 65 years and older from the National Health and Aging Trends Study who were driving at the 2015 interview and completed 1-year (N = 4,182) and 4-year (N = 3,102) follow-up interviews. Outcomes were positive screens for depressive and anxiety symptoms in 2016 or 2019, and the primary independent variable was driving cessation within one year of the baseline interview. Adjusting for socio-demographic and clinical characteristics, driving cessation was associated with depressive symptoms at 1 year (OR = 2.25, 95% CI: 1.33-3.82) and 4-year follow-up (OR = 3.55, 95% CI: 1.72-7.29). Driving cessation was also associated with anxiety symptoms at 1 year (OR = 1.71, 95% CI: 1.05-2.79) and 4 year follow up (OR = 3.22, 95% CI: 1.04-9.99). Driving cessation was associated with an increased risk of developing depressive and anxiety symptoms in later life. However, reasons for this association remain unclear. Although the mechanism linking driving cessation with worse mental health symptoms is uncertain, driving facilitates many important activities. Clinicians should monitor the well-being of patients who stop or intend to stop driving.


Concave binding of cationic Li to quadrannulene.
Binding of Li+ to quadrannulene and its influence on buckybowl functionalization are introduced. The concave-trapped Li+ acts as a Lewis acid and the rate of Diels-Alder cycloaddition is enhanced 108 times. A sandwiched bowl-Li+-bowl structure is stabilized via concave-cation-convex interactions, indicating the promoted role of Li+ in buckybowl assembly.


Traumatic lesions of the middle ear: aetiology and results of treatment.
A retrospective investigation of the aetiology and results of treatment for traumatic, conductive hearing loss was performed in 122 patients treated from 1979 to 1983. The mean age at the time of the trauma was 25 years. The average treatment delay was 7 years. The patients were grouped according to the nature of the injury. The group with head injury (40 patients) was characterized by a frequent combination of young men and traffic accidents. Among direct trauma (16 patients) lesions to the tympanic membrane and/or the middle ear were caused by ear syringing or by the introduction of swabs or other instruments into the auditory canal. In the group exposed to indirect trauma (57 patients) the dominant single cause of the trauma in the present material consisted of a blow to the ear and was most often seen among young women. A subgroup exposed to blasts contained more young men. The dominant operative findings were rupture of the tympanic membrane, luxation of the incus, partial bone necrosis and fracture of the auditory ossicles. Ear surgery consisted of closure of the ruptured tympanic membranes and restoration of the sound-transmitting function of the ossicular chain. Normal hearing was restored in 78%, and hearing improved in another 10%. The hearing remained unchanged or deteriorated in 9% of the patients, a group often characterized by a long treatment delay and/or the development of chronic otitis.


Pelvic girdle pain after childbirth: the impact of mode of delivery.
During pregnancy or postpartum period, several women experience some degree of pelvic girdle pain (PGP). In India, information is lacking about the prevalence and possible risk factors of PGP evaluated during postpartum period. This study aims to determine the prevalence of PGP in postpartum women who underwent vaginal or caesarean mode of delivery and to estimate possible associated factors with or without PGP in both modes of deliveries. In this cross-sectional study, 284 postpartum women answered questionnaires and underwent clinical examinations. Clinical examination included pain provocation tests for the pelvis as well as the active straight leg raise (ASLR) test. Probable associated factors were studied using non-parametric tests and logistic regression analysis. In this study of 284 women, 41% reported pain in the pelvic girdle during postpartum period. Overall, 33% of the women experienced PGP after caesarean delivery as compared with 8.3% of women after vaginal delivery. Low back pain (LBP) before pregnancy, parity, active straight leg raise test score ≥ 4, bilateral P4 test, and sitting position during breast-feeding were significantly associated with vaginal delivery group and caesarean delivery group during postpartum period. In both modes of delivery, the association of PGP with these common factors remained after adjustment for other study factors. We found high prevalence of PGP in women who had caesarean delivery than those who had a vaginal delivery. Our finding suggests that, during postpartum period, LBP before pregnancy, parity, ASLR test score ≥ 4, bilateral P4 test, and sitting position during breast-feeding were significantly associated with increased risk of PGP in both vaginal and caesarean modes of deliveries, but further studies are needed for definitive conclusions.


The Mediator Effects of Depressive Symptoms on the Relationship between Family Functioning and Quality of Life in Caregivers of Patients with Heart Failure.
Caregivers of patients with heart failure (HF) report depressive symptoms and poor quality of life (QOL) related to caregiving and poor family functioning, placing them at risk for poor health. The purpose of this study was to examine the effect of depressive symptoms on the relationship between family functioning and quality of life in the HF caregiver. A sample of 92 HF caregivers were enrolled from an ambulatory clinic at a large academic medical center. A mediation analysis was used to analyze data obtained from the Family Assessment Device (FAD), the Patient Health Questionaire-9 (PHQ-9), and the Short Form-12 Health Survey Version 2 (SF-12v2). Depressive symptoms were found to be a significant mediator in the relationship between family functioning and caregiver quality of life. The results of this study suggest that interventions targeting caregiver depression and family functioning could be effective in enhancing HF caregivers' physical and mental QOL.


Intravenous immunoglobulin does not increase FcgammaRIIB expression on monocytes/macrophages during acute Kawasaki disease.
Intravenous immunoglobulin (IVIG) therapy has been reported to be effective for reducing the incidence of coronary artery lesions in Kawasaki disease (KD), an acute febrile vasculitis of unknown aetiology. Regarding the mechanism of IVIG in immune thrombocytopenic purpura (ITP), it has been reported that IVIG increases the expression of the inhibitory Fc receptor, FcgammaRIIB (CD32B), on splenic macrophages in a murine ITP model. Regarding the mechanism of IVIG during acute KD, we investigated whether or not IVIG increases the expression of FcgammaRIIB in peripheral blood CD14+ monocytes/macrophages. The expression of FcgammaRIIB in peripheral blood CD14+ monocytes/macrophages was determined before and after IVIG therapy in 13 patients with acute KD by flow cytometry. The percentage of CD14+ CD32B+ monocytes/macrophages among peripheral blood mononuclear cells, the absolute number of CD14+ CD32B+ monocytes/macrophages and the percentage of CD14+ CD32B+ monocytes/macrophages among CD14+ monocytes/macrophages in patients with acute KD before IVIG therapy were significantly increased compared with those after IVIG therapy and in controls. CD14+ CD32B+ monocytes/macrophages decreased to within the normal range soon after IVIG therapy. IVIG therapy in patients with KD did not increase the expression of FcgammaRIIB in peripheral blood CD14+ monocytes/macrophages during the acute stage.


The immunogenetic impact of European colonization in the Americas.
The introduction of pathogens originating from Eurasia into the Americas during early European contact has been associated with high mortality rates among Indigenous peoples, likely contributing to their historical and precipitous population decline. However, the biological impacts of imported infectious diseases and resulting epidemics, especially in terms of pathogenic effects on the Indigenous immunity, remain poorly understood and highly contentious to this day. Here, we examine multidisciplinary evidence underpinning colonization-related immune genetic change, providing contextualization from anthropological studies, paleomicrobiological evidence of contrasting host-pathogen coevolutionary histories, and the timings of disease emergence. We further summarize current studies examining genetic signals reflecting post-contact Indigenous population bottlenecks, admixture with European and other populations, and the putative effects of natural selection, with a focus on ancient DNA studies and immunity-related findings. Considering current genetic evidence, together with a population genetics theoretical approach, we show that post-contact Indigenous immune adaptation, possibly influenced by selection exerted by introduced pathogens, is highly complex and likely to be affected by multifactorial causes. Disentangling putative adaptive signals from those of genetic drift thus remains a significant challenge, highlighting the need for the implementation of population genetic approaches that model the short time spans and complex demographic histories under consideration. This review adds to current understandings of post-contact immunity evolution in Indigenous peoples of America, with important implications for bettering our understanding of human adaptation in the face of emerging infectious diseases.


Efficient Quartet Representations of Trees and Applications to Supertree and Summary Methods.
Quartet trees displayed by larger phylogenetic trees have long been used as inputs for species tree and supertree reconstruction. Computational constraints prevent the use of all displayed quartets in many practical problems with large numbers of taxa. We introduce the notion of an Efficient Quartet System (EQS) to represent a phylogenetic tree with a subset of the quartets displayed by the tree. We show mathematically that the set of quartets obtained from a tree via an EQS contains all of the combinatorial information of the tree itself. Using performance tests on simulated datasets, we also demonstrate that using an EQS to reduce the number of quartets in both summary method pipelines for species tree inference as well as methods for supertree inference results in only small reductions in accuracy.


The adverse influence of spina bifida occulta on the medical treatment outcome of primary monosymptomatic nocturnal enuresis.
Previous reports have suggested that the incidence of spina bifida occulta (SBO) in patients with primary monosymptomatic nocturnal enuresis (PMNE) is higher than the general population. The purpose of this study was to investigate the effect of spina bifida occulta on the medical treatment outcome of PMNE. Between January 2008 and December 2011, a total of 223 children (151 boys and 72 girls, aged 6-16 years; mean age: 10.1 ± 3.04 years) with PMNE were reviewed retrospectively. All of the children underwent physical examination, urine analysis, urinary tract ultrasonography and kidney ureter bladder (KUB) scout film. All patients were initially treated with a timed voiding program and were given desmopressin acetate when necessary. Spina bifida occulta was detected in 75 children (33.6%). Spina bifida occulta affected L4 in 2 children, L5 in 6 children, L4-L5 in 3 children, S1 in 52 children, S2 in 7 children and S1-S2 in 2 children. Treatment was successful in 79% of the children without SBO, and in only 48% of the children with SBO. Medical treatment success rates differed significantly between the study groups. The presence of spina bifida occulta significantly affects the response to medical treatment in patients with PMNE. Thus, verifying spina bifida occulta status in PMNE can facilitate prognostic predictions about the response to medical treatment.


Label-free glycopeptide quantification for biomarker discovery in human sera.
Glycan moieties of glycoproteins modulate many biological processes in mammals, such as immune response, inflammation, and cell signaling. Numerous studies show that many human diseases are correlated with quantitative alteration of protein glycosylation. In some cases, these changes can occur for certain types of glycans over specific sites in a glycoprotein rather than on the global abundance of the glycoprotein. Conventional analytical techniques that analyze the abundance of glycans cleaved from glycoproteins cannot reveal these subtle effects. Here we present a novel statistical method to quantify the site-specific glycosylation of glycoproteins in complex samples using label-free mass spectrometric techniques. Abundance variations between sites of a glycoprotein as well as different glycoforms, that is, glycopeptides with different glycans attached to the same site, can be detected using these techniques. We applied our method to an esophageal cancer study based on blood serum samples from cancer patients in an attempt to detect potential biomarkers of site-specific N-linked glycosylation. A few glycoproteins, including vitronectin, showed significantly different site-specific glycosylations within cancer/control samples, indicating that our method is ready to be used for the discovery of glycosylated biomarkers.


Monobodies as enabling tools for structural and mechanistic biology.
Monobodies, built with the scaffold of the fibronectin type III domain, are among the most well-established synthetic binding proteins. They promote crystallization of challenging molecular systems. They have strong tendency to bind to functional sites and thus serve as drug-like molecules that perturb the biological functions of their targets. Monobodies lack disulfide bonds and thus they are particularly suited as genetically encoded reagents to be used intracellularly. This article reviews recent monobody-enabled studies that reveal new structures, molecular mechanisms and potential therapeutic opportunities. A systematic analysis of the crystal structures of monobody-target complexes suggests important attributes that make monobodies effective crystallization chaperones.


Is stress concentration relevant for nanocrystalline metals?
Classical fracture mechanics as well as modern strain gradient plasticity theories assert the existence of stress concentration (or strain gradient) ahead of a notch tip, albeit somewhat relaxed in ductile materials. In this study, we present experimental evidence of extreme stress homogenization in nanocrystalline metals that result in immeasurable amount of stress concentration at a notch tip. We performed in situ uniaxial tension tests of 80 nm thick (50 nm average grain size) freestanding, single edge notched aluminum specimens inside a transmission electron microscope. The theoretical stress concentration for the given notch geometry was as high as 8, yet electron diffraction patterns unambiguously showed absence of any measurable stress concentration at the notch tip. To identify possible mechanisms behind such an anomaly, we performed molecular dynamics simulations on scaled down samples. Extensive grain rotation driven by grain boundary diffusion, exemplified by an Ashby-Verrall type of grain switching process, was observed at the notch tip to relieve stress concentration. We conclude that in the absence of dislocations, grain realignment or rotation may have played a critical role in accommodating externally applied strain and neutralizes any stress concentration during the process.


Adenovirus-mediated transfer of viral IL-10 gene inhibits murine collagen-induced arthritis.
IL-10 is a potent anti-inflammatory cytokine that has received growing attention for its therapeutic potential. We examined the efficiency of adenoviral-mediated gene transfer of IL-10 on the incidence and severity of murine collagen-induced arthritis (CIA). Male DBA1 mice immunized with collagen II were treated by systemic administration of 10(9) plaque-forming units of replication-defective adenoviral vector expressing viral IL-10 (vIL-10) on day 30, when clinical symptoms of arthritis start. The transgene was shown to inhibit the onset of CIA, to decrease severity, and profoundly suppress the overall joint histopathology of the experimental arthritis. Significant IL-10 concentrations were obtained in the serum of injected animals for 7 days. Inhibition of arthritis was enhanced by administration of increasing doses of adenovirus-vIL-10. In addition, the local immunosuppressive effect of gene-delivered vIL-10 could be neutralized by a monoclonal anti-vIL-10 Ab. The CIA symptoms in the group treated with the same construct expressing inactive vIL-10 (vIL-10 mut) were similar to those in untreated animals. Our data indicate that a single systemic administration of an adenoviral vector encoding vIL-10 may be a good candidate to suppress arthritis.


The Sundt clip graft.
The Sundt clip graft is a vessel-encircling clip that can be used to repair a significant dehiscence or tear in an intracerebral vessel wall during urgent situations. This article analyzes the use of the Sundt clip in a variety of acute intraoperative situations. Under institutional review board (IRB) approval, a retrospective review of surgical records from 1988 to 2008 was conducted to identify patients in whom the clip graft was used. These patients' medical records and radiographic imaging studies were reviewed and analyzed. Seventeen patients were identified. A variety of vascular wall dehiscences were treated, including 9 with carotid aneurysm blisters. Other vessels repaired included the anterior choroidal artery (ACA), posterior communicating artery (PCA), and middle cerebral artery (MCA). Most were repaired with a 5-to 6-mm clip graft in varying lengths. Postoperative angiography was performed in 16 patients. In 14 patients, the vessel was preserved with a patency of 80% or greater. One patient had a 50% stenosis, and in another the vessel was occluded. The neurologic outcome was related to the underlying pathology and clinical presentation. Overall, 13 patients recovered with a Glasgow Outcome Score (GOS) of 5. Three patients did poorly, with a GOS of 3, and 1 patient died related to subarachnoid hemorrhage (SAH) vasospasm. Neurosurgeons should remember that the Sundt clip graft may be used in emergent situations in which a vascular tear or blister is encountered and the vessel cannot be repaired with suturing or other techniques, including standard encircling aneurysm clips.


Medical therapy of prostate cancer. A review.
Androgen ablation or blockade of androgen action through the androgen receptor (AR) has been the cornerstone of treatment of advanced prostate cancer. The relative merits of monotherapy or combined androgen blockade (CAB) are still the subject of debate. Each treatment strategy/hormonal agent has favourable and unfavourable effects. Patients with advanced prostate cancer will clearly benefit androgen deprivation-based treatment for palliating their symptoms and for improving their quality of life (QOL). However, whether these therapies prolong survival when administered before there are symptoms caused by disease progression remains controversial. Data from multiple recent studies indicate that an earlier treatment in patient's disease course likely leads to better outcome, but it is not easy to predict the best timing of hormonal therapy for asymptomatic advanced disease. For the purpose of delaying the onset of androgen-independent growth of prostate cancer, different regimen of intermittent androgen blockade (IAB) have been applied to patients. The use of IAB is increasing but, despite theoretical advantages in terms of patient QOL, clinical studies have yet to prove superiority over continuous therapy. The role of androgen deprivation in combination with surgery or radiotherapy has been also evaluated. While neoadjuvant hormonal therapy (NHT) can significantly decrease the incidence of positive margins at the time of radical prostatectomy (RP), 3 months of treatment is not long enough to have any significant effect on biochemical recurrence rates. The results of studies investigating longer courses (8 months) of NHT are awaited. High-risk patients should be considered for early adjuvant hormonal therapy (AHT) after surgery, as they may be most likely to benefit. The rationale for the use of NHT in combination with radiotherapy is that it reduces tumour volume and therefore the amount of radiation therapy that is needed to treat the tumour. It has been found that 3-4 months of hormonal treatment reduces prostate volume by 25-50%. Intermediate-risk patients treated with NHT and concomitant hormonal therapy have been found to have a 94% freedom for biochemical failure after 4 years, suggesting that this group is the ideal patient population to receive short-term hormonal therapy in combination with brachytherapy. Several studies suggested the current consensus that patients with clinically localized or locally advanced high-grade tumours benefit from definitive radiation therapy and long-term AHT. The current treatment for advanced prostate cancer remains essentially palliative. However, an increased understanding of the heterogeneous nature of the disease, the mechanisms that lead to hormone-refractory prostate cancer (HRPC) has identified novel therapeutic targets and led to the development of selective new therapies, that may help to prolong survival and maintain QOL for patients with HRPC.


Use of selective mesenteric dilator peptides to examine the role of the intestine in experimental hemorrhagic shock.
If mesenteric vasoconstriction sets in motion the chain of events that leads to shock, then the administration of a selective mesenteric vasodilator (which has no other known cardiovascular actions) should prevent, or at least modify, the hemodynamic events in a standardized shock preparation. We used the Wiggers model of experimental hemorrhagic shock in 20 pentobarbital-anesthetized dogs, giving half the dogs a selective mesenteric dilator peptide, sauvagine, to produce selective dilatation of the superior (cephalic) and inferior (caudal) mesenteric circulations. (Sauvagine does not dilate the coeliac vascular bed.) A third, sham-operated group of four dogs served as a time control. Sauvagine produced no observable beneficial effect in terms of hemodynamic measurements, intestinal oxygen kinetics, or intestinal histology. Since we took the precaution of delivering the peptide close-arterially (to ensure delivery during hypoperfusion), we conclude that mesenteric vasoconstriction per se is not the prime event in initiating shock. Since reduced cardiac output during hypovolemia led to diminished mesenteric flow (in spite of vasodilation), these experiments do not exclude the possibility of diminished intestinal blood flow being a central event in shock.


Dermal exposure to terpenic resin acids in Swedish carpentry workshops and sawmills.
The aim of this study was to evaluate dermal exposure to the resin acids abietic acid, dehydroabietic acid and 7-oxodehydroabietic acid during collecting in sawmills and during sawing in carpentry workshops, respectively. Sampling was performed by fastening patches at 12 different areas on a sampling overall, one patch on the front of a cap, one patch on the chest inside the clothing and one patch on the inner lower right leg. Exposure of the hands was assessed by fastening patches on cotton gloves representing the dorsal sides and the palms of the left and right hands. Sampling was performed on 30 different occasions in the sawmills and in the carpentry workshops with mean sampling times of 120 and 59 min, respectively. The acids were solvent desorbed from the patches. Identification and quantification of the resin acids was performed by gas chromatography-mass spectrometry. The geometric means (GMs) of the potential body exposures to abietic acid, dehydroabietic acid and 7-oxodehydroabietic acid during sawing and collecting of wood from pine and spruce were 3346 and 17 247 micro g/h, respectively. The GM of the potential exposure on the hands was 3020 micro g/h in the carpentry workshops and 4365 micro g/h in the sawmills. Resin acids were detected on the inner chest and inner lower front right leg, respectively. There is a potential dermal exposure to terpenic resin acids in carpentry workshops as well as in sawmills. The hands have the highest exposure during sawing as well as during collecting. There is a spatial distribution of contaminants, with the outer chest, arms and legs showing the highest exposures. Resin acids also contaminated the inner chest and inner lower leg. It is necessary to take action to reduce dermal exposure to these allergenic substances.


Prospective study of congenital cytomegalovirus infection.
The overall incidence of neonates with urinary cytomegalovirus (CMV) excretion was 0.9% of 954 tested. The incidence was twice as high in the lower as in the upper socioeconomic group (SEG). Mothers of infants with CMV infection in the lower SEG reported a greater number of chronic and gestational medical problems and showed a lower mean age than mothers of CMV-infected infants in the upper SEG. The mean age of mothers of CMV-infected infants was not significantly different from the respective control group in either upper or lower SEG. There was no impairment of immune responses in nine prospective or in two referred cases. Although eight of nine prospective cases might have been considered asymptomatic at birth, careful evaluation in the neonatal period showed significant growth inhibition in five, specific clinical changes in seven, and nonspecific clinical changes in all of the nine infants. Thus, "asymptomatic" neonates may demonstrate effects of the infection during the neonatal period.


Mutation analysis of the pRb pathway in 2',3'-dideoxycytidine- and 1, 3-butadiene-induced mouse lymphomas.
The pRb pathway plays a key role in controlling the G1/S transition in cell cycle progression. Aberrations of various components of the pRb pathway, such as retinoblastoma protein and its upstream actors including cyclin D1, cyclin dependence kinase-4 and p16/p15 cyclin dependent kinase inhibitors, have been reported in a variety of human tumors. Furthermore, the alterations of retinoblastoma protein and its upstream components often occur in a reciprocal manner. Previously, we have reported frequent inactivation of the Cdkn2a/Cdkn2b loci encoding p16/p15 cyclin dependent kinase inhibitors in a subset of 2',3'-dideoxycytidine- and 1, 3-butadiene-induced mouse lymphomas (S.-M. Zhuang, A. Schippert, A. Haugen-Strano, R.W. Wiseman, P. Söderkvist, Inactivation of p16(INK4a)-alpha, p16(INK4a)-beta and p15(INK4b) genes in 2', 3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas, Oncogene 16 (1998) 803-808), indicating the involvement of pRb pathway in lymphomagenesis. To investigate whether alteration of other components in pRb pathway is an alternative mechanism underlying the development of these chemically induced lymphomas, we have examined the genetic status of Rb1, Ccnd1 and Cdk4 genes that encode retinoblastoma protein, cyclin D1 and cyclin dependence kinase-4, respectively. Gross alterations of the Rb1, Ccnd1, and Cdk4 genes were not detected by Southern analysis in any of the tumors examined. In addition, single-strand conformation analysis failed to reveal point mutations in the Cdk4 amino terminal domain that is important for its association with Cdkn2a gene products. These results indicate that the mechanisms underlying the development of 2', 3'-dideoxycytidine- and 1,3-butadiene-induced lymphomas involve inactivation of p16/p15 cyclin-dependent kinase inhibitors but not genomic alterations of the Rb1, Ccnd1 and Cdk4 genes.


Treatment patterns, complications, and disease relapse in a real-world population of patients with moderate-to-severe ulcerative colitis initiating immunomodulator therapy.
Immunomodulator (IM) treatments in ulcerative colitis (UC) are not curative and carry increased risk of complications, sometimes leading to therapy changes, reduced treatment benefits, and eventual relapse. We assessed patterns of IM utilization and therapy changes, complications, and disease relapse in a real-world population of patients with moderate-to-severe UC. Claims data from a large commercially insured U.S. population were retrospectively analyzed. Inclusion criteria were (1) ≥2 UC diagnosis claims (ICD-9-CM 556.xx) between January 2005 and July 2010, (2) ≥1 IM claim, where first IM claim defined the index date, (3) ≥12 months preindex health plan enrollment (baseline), and (4) ≥24 months postindex plan enrollment (follow-up). Characteristics of and changes to the index IM therapy during follow-up were descriptively assessed, as were complications and disease relapses. A total of 2136 patients were identified for inclusion (age, mean [SD], 46 [16] years, 54% female). Azathioprine was the most common index IM (46% of patients), followed by 6-mercaptopurine (28%). Switching from the index IM to another therapy class was common (21% of patients), with 5-ASAs (48% of switchers), oral corticosteroids (21%), and biologics (17%) being the most frequent next agents used. Augmentation was also common (25% of patients), with 5-ASA being, by far, the most frequent agent added to the index IM (72% of augmenters). Thirty percent of patients experienced a complication, and 73% of patients relapsed, with the majority of relapses occurring during index IM exposure. This assessment of IM treatments for UC demonstrated frequent changes to therapy and high downstream complication and relapse rates.


Altered amino acid kinetics in rats with progressive tumor growth.
The present study was designed to determine whether alterations in host metabolism associated with progressive tumor growth were a result of the anorexia frequently observed with cancer or could be attributed to other direct tumor effects. Rates of tyrosine flux, oxidation, and incorporation into protein, as well as fractional protein-synthetic rates in nonsecretory liver, muscle, and tumor, were determined in overnight-fasted rats, 5 to 6 (Stage I), 10 to 11 (Stage II), and 15 to 16 (Stage III) days following s.c. implantation of RNC-254 fibrosarcoma. Tumor-bearing rats were allowed to consume a purified diet containing 20% protein ad libitum, and results were compared to non-tumor-bearing rats pair fed quantities of food equivalent to tumor-bearing animals or allowed to consume the diet ad libitum. Results demonstrate that during later stages of tumor growth (Stage III) calorie intake and nontumor body weight gain were reduced in tumor-bearing rats (p less than 0.05). Fifteen and 16 days following implantation, there were significant changes in amino acid kinetics that were not observed after earlier periods of tumor growth and that could not be explained by any reduction in dietary intake. Rates of tyrosine appearance in the plasma and subsequent incorporation into whole-body protein were increased 33 and 34%, respectively (p less than 0.05), when compared to non-tumor-bearing rats fed equivalent quantities of food. Whole-body tyrosine oxidation rates were unchanged. Skeletal protein synthesis, as reflected by gastrocnemius or rectus abdominus muscle, was reduced from 10.5 and 10.1%/day to 7.4 and 6.0%/day, respectively (p less than 0.05), in tumor-bearing compared to pair-fed animals. The findings suggest that significant alterations in protein metabolism occur in advanced stages of experimental neoplastic disease which cannot be explained by reductions in dietary intake and are aimed at providing adequate quantities of endogenous amino acids for net tumor growth.


In vitro osteoinduction of human mesenchymal stem cells in biomimetic surface modified titanium alloy implants.
Interaction between cells and implant surface is crucial for clinical success. This interaction and the associated surface treatment are essential for achieving a fast osseointegration process. Several studies of different topographical or chemical surface modifications have been proposed previously in literature. The Biomimetic Advanced Surface (BAS) topography is a combination of a shot blasting and anodizing procedure. Macroroughness, microporosity of titanium oxide and Calcium/Phosphate ion deposition is obtained. Human mesenchymal stem cells (hMCSs) response in vitro to this treatment has been evaluated. The results obtained show an improved adhesion capacity and a higher proliferation rate when hMSCs are cultured on treated surfaces. This biomimetic modification of the titanium surface induces the expression of osteblastic differentiation markers (RUNX2 and Osteopontin) in the absence of any externally provided differentiation factor. As a main conclusion, our biomimetic surface modification could lead to a substantial improvement in osteoinduction in titanium alloy implants.


[Microvascular dysfunction as an explanation for the metabolic syndrome].
The metabolic syndrome is a cluster of mutually related risk factors that confers an increased risk for both type 2 diabetes mellitus and cardiovascular disease. Although the metabolic syndrome seems to have multiple aetiological factors, microvascular dysfunction is a potential explanation for the above-mentioned cluster of multiple metabolic risk factors such as hypertension, insulin resistance and glucose intolerance. Microvascular dysfunction leads not only to increased peripheral vascular resistance and blood pressure, but may also decrease the insulin-mediated glucose uptake in muscles. The different effect on the microcirculation may explain why some antihypertensive drugs (beta-blockers) lead to an increased incidence of type 2 diabetes, whereas others (angiotensin-converting enzyme (ACE) inhibitors) are associated with a decrease of that risk.


Polarization-modulated smectic liquid crystal phases.
Any polar-ordered material with a spatially uniform polarization field is internally frustrated: The symmetry-required local preference for polarization is to be nonuniform, i.e., to be locally bouquet-like or "splayed." However, it is impossible to achieve splay of a preferred sign everywhere in space unless appropriate defects are introduced into the field. Typically, in materials like ferroelectric crystals or liquid crystals, such defects are not thermally stable, so that the local preference is globally frustrated and the polarization field remains uniform. Here, we report a class of fluid polar smectic liquid crystals in which local splay prevails in the form of periodic supermolecular-scale polarization modulation stripes coupled to layer undulation waves. The polar domains are locally chiral, and organized into patterns of alternating handedness and polarity. The fluid-layer undulations enable an extraordinary menagerie of filament and planar structures that identify such phases.


Evidence for modality-specific but not frequency-specific modulation of human primary auditory cortex by attention.
We used the stimulus-driven 40-Hz auditory steady-state response (ASSR) that localizes tonotopically to the region of primary auditory cortex (A1) to study modulation of this region by top-down attention. Experiment 1 presented amplitude modulated (AM) auditory and visual stimuli simultaneously (AM at 40 Hz and 16 Hz, respectively) while participants responded to targets in one modality or the other. ASSR amplitude increased from an unattended passive baseline during auditory but not visual attention demonstrating modality-specific auditory attention, when attention was required for brief (1 s) but not long (2 min) time intervals. Modality-specific visual attention occurred at both time intervals. Experiment 2 asked whether attention directed to one or the other of two simultaneous auditory streams (carrier frequencies of 250 and 4100 Hz AM at 37 and 41 Hz respectively, counterbalanced) increased ASSR amplitude for the attended stream (frequency-specific auditory attention). Behaviour was strongly controlled by carrier frequency (overall target rate 1.7 Hz), and the cortical sources of the two carriers were resolved by inverse modeling. Despite these conditions favourable to frequency specificity, frequency-specific modulation of ASSR amplitude was not found at either time interval. Frequency-specific modulation of A1 may require re-entrant feedback to the auditory core from auditory percepts that possess distinct spectral attributes and are attended in higher regions of the auditory system.


Aesthetic Surgical Procedures in Men: Major Complications and Associated Risk Factors.
The number of men undergoing cosmetic surgery is increasing in North America. To determine the incidence and risk factors of major complications in males undergoing cosmetic surgery, compare the complication profiles between men and women, and identify specific procedures that are associated with higher risk of complications in males. A prospective cohort of patients undergoing cosmetic surgery between 2008 and 2013 was identified from the CosmetAssure database. Gender specific procedures were excluded. Primary outcome was occurrence of a major complication in males requiring emergency room visit, hospital admission, or reoperation within 30 days of the index operation. Univariate and multivariate analysis evaluated potential risk factors for major complications including age, body mass index (BMI), smoking, diabetes, type of surgical facility, type of procedure, and combined procedures. Of the 129,007 patients, 54,927 underwent gender nonspecific procedures, of which 5801 (10.6%) were males. Women showed a higher mean age (46.4 ± 14.1 vs 45.2 ± 16.7 years, P < 0.01). Men had a higher BMI (27.2 ± 4.7 vs 25.7 ± 4.9 kg/m2, P < 0.01), and were more likely to be smokers (7.1% vs 5.7%, P < 0.01) when compared to women. Men demonstrated similar overall major complication rates compared to women (2.1% vs 2.1%, P = 0.97). When specific complications were analyzed further, men had higher hematoma rates, but lower incidence of surgical site infection. Additionally, major complications after abdominoplasty, facelift surgery, and buttock augmentation were noted to preferentially affect males. On multivariate analysis, independent predictors of major complications in males included BMI (RR 1.05), hospital or ambulatory surgery center procedures (RR 3.47), and combined procedures (RR 2.56). Aesthetic surgery in men is safe with low major complication rates. Modifiable predictors of complications included BMI and combined procedures.


Comprehensive school-based health care: high school students' use of medical, mental health, and substance abuse services.
To explore adolescent students' use of school based health and medical care and mental health and substance abuse counseling services and to compare adolescents' patterns of use of medical, mental health, and substance abuse services located in school-based and traditional settings. Retrospective analysis of computer-stored, standardized data for all student visits during a 4-year period. Three high school-based student health centers. A total of 3818 adolescent students who used services provided by the school-based health centers (SBHCs). Frequencies of student visits to medical providers and mental health and substance abuse counselors and frequencies of diagnostic assignments. During a 38-month period, 3818 students attending senior high school made a total of 27 886 visits to three SBHCs. They represented 63% of students enrolled in the SBHCs and approximately 42% of the total school population. There were no significant demographic differences between students attending the SBHCs and the overall student body. However, compared with students who were enrolled in the SBHCs but did not use them, users were more likely to be female and Hispanic. Ninety-four percent of students using the services had visits with medical providers; 25% had visits with mental health counselors; and 8% of students had visits with substance abuse counselors. The total annual mean number of student visits was 4.7, and the annual mean numbers of visits for students who used the following services were: medical, 3.3; mental health, 5.8; and substance abuse, 6.8. An average of 1.4 diagnoses were made per visit. The most common major diagnostic categories were emotional problems (29% of all diagnoses), health supervision (13%), respiratory problems (11%), reproductive health problems (11%), and substance abuse problems (8%). Almost one fourth of the students had contact with more than one of the three categories of service provicer. Visit frequency increased significantly for students who used two categories of provider (13 to 15 mean total visits compared with 4 to 5 mean total visits for students who used just one category of provider) and escalated to a mean of 32 total visits if all three categories of service were used. Adolescents attending SBHCs had higher rates of visits for health and medical care than adolescents using traditional sources of medical care. The proportions of student users of SBHC mental health and substance abuse counseling services were commensurate with the estimated prevalences of these problems in this country's adolescent population. In addition, the mean numbers of visits to mental health counselors in SBHCs compared favorably with adolescent visit rates for mental health services in other settings. Too little information is available about adolescent use of substance abuse services in non-school-based settings to make similar comparisons. In summary, adolescent users of SBHCs seemed to have a higher use of medical, mental health, and probably substance abuse counseling services than did adolescents in the general populations. These findings are consistent with the interpretation that SBHCs do enhance adolescents' access to care for medical, mental health, and substance abuse problems.


Comparison of effects of ryanodine and caffeine on rat ventricular myocardium.
Ryanodine and caffeine have the ability to diminish sarcoplasmic reticulum (SR) calcium release in cardiac muscle cells. To determine whether these agents also share a common mechanism of action, we compared their effects on rat papillary muscles using two different experimental approaches. First, using the protocol of Jundt et al. (19), in which quiescent rat papillary muscles were exposed to sodium-free solutions, we found that 1 microM ryanodine decreased resting force, phosphorylase alpha activity, and the scattered light intensity fluctuations (SLIF) due to calcium-dependent myofilament interactions. In contrast, 10-20 mM caffeine increased both resting force and phosphorylase alpha levels and initially increased then decreased SLIF to below detectable levels. In a second series of experiments, contractures were elicited by exposing rat papillary muscles to 125 mM KCl. Pretreatment with ryanodine (1 microM) or caffeine (10 mM) abolished the initial phasic component of this response, while increasing the subsequent tonic component. These effects were different from those of isoproterenol, which decreased tonic contracture force. The depression of twitch force produced by ryanodine developed more rapidly in the presence of 125 mM KCl than in normal buffer, suggesting that the negative inotropic effects of this agent may, in part, depend on membrane depolarization. The results of these experiments suggest that ryanodine and caffeine affect SR calcium release through different mechanisms of action. Ryanodine appears to decrease, while caffeine initially increases, cytoplasmic calcium. Once these effects have occurred, the alterations of SR function produced by both agents can similarly alter other inotropic responses.


Malignant transformation of oral leukoplakia: a retrospective cohort study of 218 Chinese patients.
Oral leukoplakia (OL) is the best-known potentially malignant disorder. A new binary system to grade dysplasia was proposed by WHO, but the biological significance in predicting malignant transformation risk is unknown. The objective of this study is to estimate the rate of malignant transformation in a long-term follow-up cohort, explore the usefulness of the new binary system of grading dysplasia and identify significant risk factors of OL malignant transformation in China. A total of 218 patients with clinical and histopathologic diagnosis of OL were retrospectively reviewed. They were selected among all archived files at the Department of Oral Mucosal Diseases, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. The mean follow-up period was 5.3 years. Among 218 cases, 39 (17.9%) OL patients developed oral cancer, with a mean duration of 5.2 years. Cox regression analysis revealed that dysplasia was an independent risk factor for OL malignant transformation, but age, gender, lesion site, diet habit, smoking and ethanol intake were not risk factors. High-risk dysplastic OL was associated with a 4.57-fold (95% confidence interval, 2.36-8.84; P < 0.001) increased risk of malignant transformation, compared with low-risk dysplasia. Consistent with this result, high-risk dysplastic OL had significantly higher malignant incidence than low-risk dysplasia, particularly during the first 2-3 years of follow-up, by Kaplan-Meier analysis (Log-rank test, P < 0.001). The new binary system's function in predicting OL malignant transformation risk was investigated in this survey. The utilization of high-risk dysplasia as a significant indicator for evaluating malignant transformation risk in patients with OL was suggested, which may be helpful to guide treatment selection in clinical practice.


Update on calcium pyrophosphate deposition.
Calcium pyrophosphate crystal deposition (CPPD) associates with ageing, osteoarthritis (OA), uncommon metabolic diseases, mutations and polymorphisms in the ankylosis human gene (ANKH). CPPD is frequently polyarticular, occurs due to a generalised articular predisposition, and the association between CPPD and OA is joint specific, for example CPPD associates with knee OA, but not with hip OA. Other recently identified associations include knee malalignment (knee CC), low cortical BMD and soft-tissue calcification. CPPD is generally asymptomatic. A recent study reported that knees with OA plus CC at the index joint, or at distant joints (in absence of index joint CC), were more likely to have attrition. CPPD can cause acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and is frequently present in joints with OA. Joint aspiration remains the gold standard for diagnosing CPPD, although other promising techniques are emerging. Patients with polyarticular or young onset CPPD should be screened for underlying metabolic abnormalities, however, such testing can be unrewarding. The treatment of CPPD is symptomatic. Acute CPP crystal arthritis is treated with rest, local application of ice-packs, joint aspiration, colchicine and/or intra-articular corticosteroid injection (once infection is excluded). Colchicine, low-dose corticosteroids, hydroxychloroquine and radiosynovectomy are recommended for the treatment of chronic or recurrent acute CPP crystal arthritis. Recent RCTs did not confirm any benefit from methotrexate, and although there is increasing interest in the use of anti-IL1 agents for acute or chronic CPP crystal arthritis, their efficacy has not been formally examined. Unlike gout, currently there are no treatments to eliminate CPP crystal deposits.


Layer-by-Layer Encapsulation of Herbicide-Degrading Bacteria for Improved Surface Properties and Compatibility in Soils.
E. coli cells overexpressing the enzyme atrazine chlorohydrolase were coated using layer-by-layer self-assembly. The polymeric coating was designed to improve the surface properties of the cells and create positively charged, ecologically safe, bio-hybrid capsules that can efficiently degrade the herbicide atrazine in soils. The physio-chemical properties of the bacteria/polymer interface were studied as a function of the polymeric composition of the shell and its thickness. Characterization of cell viability, enzyme activity, morphology, and size of the bio-capsules was done using fluorescence spectroscopy, BET and zeta potential measurements and electron microscopy imaging. Out of several polyelectrolytes, the combination of polydiallyldimethylammonium chloride and polysodium 4-styrenesulfonate improved the surface properties and activity of the cells to the greatest extent. The resulting bio-hybrid capsules were stable, well-dispersed, with a net positive charge and a large surface area compared to the uncoated bacteria. These non-viable, bio-hybrid capsules also exhibited a kinetic advantage in comparison with uncoated cells. When added to soils, they exhibited continuous activity over a six-week period and atrazine concentrations declined by 84%. Thus, the concept of layer-by-layer coated bacteria is a promising avenue for the design of new and sustainable bioremediation and biocatalytic platforms.


Small variations in multiple parameters account for wide variations in HIV-1 set-points: a novel modelling approach.
Steady-state levels of HIV-1 viraemia in the plasma vary more than a 1,000-fold between HIV-positive patients and are thought to be influenced by several different host and viral factors such as host target cell availability, host anti-HIV immune response and the virulence of the virus. Previous mathematical models have taken the form of classical ecological food-chain models and are unable to account for this multifactorial nature of the disease. These models suggest that the steady-state viral load (i.e. the set-point) is determined by immune response parameters only. We have devised a generalized consensus model in which the conventional parameters are replaced by so-called 'process functions'. This very general approach yields results that are insensitive to the precise form of the mathematical model. Here we applied the approach to HIV-1 infections by estimating the steady-state values of several process functions from published patient data. Importantly, these estimates are generic because they are independent of the precise form of the underlying processes. We recorded the variation in the estimated steady-state values of the process functions in a group of HIV-1 patients. We developed a novel model by providing explicit expressions for the process functions having the highest patient-to-patient variation in their estimated values. Small variations from patient to patient for several parameters of the new model collectively accounted for the large variations observed in the steady-state viral burden. The novel model remains in full agreement with previous models and data.