The Effects of Acupuncture Treatment on Sleep Quality and on Emotional Measures among Individuals Living with Schizophrenia: A Pilot Study.
Purpose. To examine the effects of acupuncture on sleep quality and on emotional measures among patients with schizophrenia. Methods. Twenty patients with schizophrenia participated in the study. The study comprised a seven-day running-in no-treatment period, followed by an eight-week experimental period. During the experimental period, participants were treated with acupuncture twice a week. During the first week (no-treatment period) and the last week of the experimental period, participants filled out a broad spectrum of questionnaires and their sleep was continuously monitored by wrist actigraph. Results. A paired-sample t-test was conducted comparing objective and subjective sleep parameters manifested by participants before and after sequential acupuncture treatment. A significant effect of acupuncture treatment was observed for seven objective sleep variables: sleep onset latency, sleep percentage, mean activity level, wake time after sleep onset, mean number of wake episodes, mean wake episode and longest wake episode. However, no significant effects of acupuncture treatment were found for subjective sleep measures. Likewise, the results indicate that acupuncture treatment improved psychopathology levels and emotional measures, that is, depression level and anxiety level. Conclusions. Overall, the findings of this pilot study suggest that acupuncture has beneficial effects as a treatment for insomnia and psychopathology symptoms among patients with schizophrenia.


Structural basis for distinct operational modes and protease activation in AAA+ protease Lon.
Substrate-bound structures of AAA+ protein translocases reveal a conserved asymmetric spiral staircase architecture wherein a sequential ATP hydrolysis cycle drives hand-over-hand substrate translocation. However, this configuration is unlikely to represent the full conformational landscape of these enzymes, as biochemical studies suggest distinct conformational states depending on the presence or absence of substrate. Here, we used cryo-electron microscopy to determine structures of the Yersinia pestis Lon AAA+ protease in the absence and presence of substrate, uncovering the mechanistic basis for two distinct operational modes. In the absence of substrate, Lon adopts a left-handed, "open" spiral organization with autoinhibited proteolytic active sites. Upon the addition of substrate, Lon undergoes a reorganization to assemble an enzymatically active, right-handed "closed" conformer with active protease sites. These findings define the mechanistic principles underlying the operational plasticity required for processing diverse protein substrates.


Comparative Effectiveness of Diabetic Oral Medications Among HIV-Infected and HIV-Uninfected Veterans.
Type 2 diabetes is increasingly common in HIV-infected individuals. The objective of this study was to compare the glycemic effectiveness of oral diabetic medications among patients with and without HIV infection. A longitudinal cohort study was conducted among HIV-infected and uninfected veterans with type 2 diabetes initiating diabetic medications between 1999 and 2010. Generalized estimating equations were used to compare changes in hemoglobin A1c (HbA1c) through the year after medication initiation, adjusting for baseline HbA1c level and clinical covariates. A subanalysis using propensity scores was conducted to account for confounding by indication. A total of 2,454 HIV-infected patients and 8,892 HIV-uninfected patients initiated diabetic medications during the study period. The most commonly prescribed medication was metformin (n = 5,647, 50%), followed by a sulfonylurea (n = 5,554, 49%) and a thiazolidinedione (n = 145, 1%). After adjustment for potential confounders, there was no significant difference in the change in HbA1c level among the three groups of new users. HIV infection was not significantly associated with glycemic response (P = 0.24). Black and Hispanic patients had a poorer response to therapy compared with white patients, with a relative increase in HbA1c level of 0.16% (95% CI 0.08, 0.24) [1.7 mmol/mol (0.9, 2.6)] (P < 0.001) and 0.25% (0.11, 0.39) [2.7 mmol/mol (1.2, 4.3)] (P = 0.001), respectively. We found that glycemic response was independent of the initial class of diabetic medication prescribed among HIV-uninfected and HIV-infected adults with type 2 diabetes. The mechanisms leading to poorer response among black and Hispanic patients, who make up a substantial proportion of those with HIV infection and type 2 diabetes, require further investigation.


Combined respiratory effects of cold air with SO(2) or NO(2) in single 1-hour exposures of hyperventilating guinea pigs.
The present study is a continuation of our previous experiments on repeated 10-min exposures of anesthetized, mechanically ventilated guinea pigs to clean cold dry air (Hälinen et al., 2000a), and to cold air plus gaseous air pollutants (Hälinen et al., 2000b). This time we made continuous 60-min exposures to clean cold dry air, cold air + SO(2) at 1 ppm, cold air + NO(2) at 1 ppm, and warm humid air + NO(2) at 1 ppm, and focused on responses at 10-60 min. Clean cold dry air and cold air + pollutants (n = 8-9 in each group) produced similar cooling in the guinea pig lower respiratory tract. The decreases in intratracheal temperature (T(tr)) reached a plateau at 20 min with mean maximal decreases of 9.7-11.3 degrees C from the pre-exposure control values of 36.0-37.3 degrees C. In contrast, there were progressive decreases in esophageal temperature (T(oe)) during the exposures, indicating constant conductive and evaporative heat losses from the tracheobronchial tissues. The mean maximal decreases in T(oe) were 1.2-1.4 degrees C from the preexposure control values of 37.8-38.0 degrees C. Clean cold dry air induced 4. 5-10.8% mean decreases in peak expiratory flow (PEF) at 10-60 min of exposure, which were statistically nonsignificant due to a relatively large variation between animals. Cold air + SO(2) at 1 ppm induced a mean decrease of 11.4% in PEF at 10 min (p <.05), which was spontaneously abolished during the next 10 min of exposure. Cold air + NO(2) at 1 ppm caused no decrease, but in fact small, nonsignificant increases in PEF at 30-60 min of exposure. Cold air + NO(2) at 1 ppm, and to some extent also cold air + SO(2) at 1 ppm, attenuated significantly the mechanical ventilation induced gradual decrease in tidal volume (V(T)), when compared to clean cold dry air exposure. Cold air + NO(2) at 1 ppm, but not warm humid air + NO(2) at 1 ppm, increased significantly the proportion of macrophages in the differential count of bronchoalveolar lavage fluid (BALF) white cells when compared to both clean warm humid air and cold dry air. None of the exposure conditions caused morphological or inflammatory changes in the respiratory tissues. In conclusion, continuous 60-min exposures to clean cold dry air, cold air + SO(2), and cold air + NO(2) produced weaker functional effects on the lower respiratory tract of guinea pigs than our previous consecutive 10-min exposures to these air conditions. After the first 10 min, there was a strong attenuation of the bronchoconstrictor responses, especially to cold air + NO(2) at 1 ppm. The small airway effects of prolonged mechanical ventilation were significantly modified by NO(2) at 1 ppm in both cold dry and warm humid breathing air. Finally, cold air + NO(2) at 1 ppm increased the proportion of macrophages in BALF white cells.


Effect of Intracanal Glass-Ionomer Barrier Thickness on Microleakage in Coronal Part of Root in Endodontically Treated Teeth: an In Vitro Study.
The most common cause of endodontic treatment failures is improper coronal sealing. Therefore, besides to proper root sealing, coronal sealing which is supported by a proper restoration has a major role in endodontic treatment success, and coronal microleakage should be considered as an etiologic factor in endodontic treatment failure. Glass-ionomer (GI) has been proposed as a coronal barrier for microleakage after endodontic treatment. This study aimed to evaluate the coronal microleakage in GI-obturated root canals in endodontically treated teeth using different thicknesses of GI. In this in vitro study, forty-five single-rooted extracted human teeth with single canals were collected and disinfected with 0.5% chloramine solution. After endodontic treatment, teeth were divided into 3 groups. In the group 1 to 3, 1 to 3mm of gutta-percha was removed and GI was replaced at 1-, 2- and 3-mm thicknesses respectively. Then subgroups were placed in methylene blue dye and the microleakage was assessed using dye penetration. The mean dye penetration in groups 1, 2 and 3 were 5.1, 3.7 and 2.9, respectively, with statistically significant differences. Group 1 exhibited the highest amount of dye penetration while group 3 showed the least one. Moreover, a significant difference between groups 1 and 2 (p= 0.002) and a non-significant difference between groups 2 and 3 (p= 0.098) was detected in mean dye penetration. Thicker layers of GI might decrease the coronal microleakage. GI at 3-mm thickness resulted in the best protective effect on coronal microleakage in endodontically treated teeth, though further studies are needed to confirm these results.


Saccadic eye movement variables as biomarkers for cognitive decline in elderly individuals.
Alzheimer's disease (AD) is the leading cause of Dementia, and mild cognitive impairment (MCI) is often considered a precursor to the development of AD dementia and other types of Dementia. Biomarkers such as amyloid beta are specific and sensitive in identifying AD and can identify individuals who have biological evidence of the disease but have no symptoms, but clinicians and researchers may not easily use them on a large scale. Ocular biomarkers, such as those obtained through eye tracking (ET) technology, have the potential as a diagnostic tool due to their accuracy, affordability, and ease of use. In this study, we show that eye movement (EM) metrics from an interleaved Pro/Anti-saccade (PS/AS) ET task can differentiate between cognitively normal (CN) and MCI subjects and that the presence of Aβ brain deposits, a biomarker of AD, significantly affects performance on these tasks. Individuals with Aβ deposits (Aβ+) performed worse than those without (Aβ-). Our findings suggest that eye-tracking measurements may be a valuable tool for detecting amyloid brain pathology and monitoring changes in cognitive function in CN and MCI individuals over time.Clinical Relevance- The PS/AS paradigm, which measures saccadic eye movements, can accurately detect subtle cognitive impairments and changes in the brain associated with Alzheimer's disease in CN and MCI individuals. This makes it a valuable tool for identifying individuals at risk for cognitive decline and tracking changes in cognitive function over time.


Expression of cyclooxygenase-2 in ovarian serous carcinoma: correlation with angiogenesis, nm23 expression and survival.
To evaluate the expression of cyclooxygenase (COX)-2 in ovarian serous carcinomas (OSC) and its correlation with microvessel density (MVD), nm23 expression, clinicopathologic prognostic factors and survival. Specimens from 44 patients with OSC were evaluated by immunohistochemistry for COX-2 and nm23 expression. Tumor MVD was assessed with CD34 immunostaining. The survival data of the patients were found from data files. 40 specimens (90.1%) showed positive COX-2 staining. Patients with high COX-2-expressed tumors had shorter overall survival, but it was not statistically significant. No correlation was found between COX-2 expression and clinicopathologic variables. There was no significant correlation between COX-2 and nm23 expression or MVD. COX-2 is frequently expressed in OSC. Although we could not confirm the prognostic significance of Cox-2 expression in the present cohort of OSC patients, the p value for overall survival was just slightly greater than alpha, and this result can be referred as almost significant. We considered that the limited number of cases in our study might affect the statistical analysis of our results. Further studies involving a larger number of patients are needed to clarify the prognostic significance of COX-2 expression in ovarian carcinomas.


Effects of vascular risk factors and APOE ε4 on white matter integrity and cognitive decline.
To investigate the effects of vascular risk factors and APOE status on white matter microstructure, and subsequent cognitive decline among older people. This study included 241 participants (age 60 years and older) from the population-based Swedish National Study on Aging and Care in Kungsholmen in central Stockholm, Sweden, who were free of dementia and stroke at baseline (2001-2004). We collected data through interviews, clinical examinations, and laboratory tests. We measured fractional anisotropy (FA) and mean diffusivity (MD) on diffusion tensor imaging, and estimated volume of white matter hyperintensities using automatic segmentation. We assessed global cognitive function with the Mini-Mental State Examination at baseline and at 3- and/or 6-year follow-up. We analyzed the data using multivariate linear regression and linear mixed models. Heavy alcohol consumption, hypertension, and diabetes were significantly associated with lower FA or higher MD (p < 0.05). When aggregating heavy alcohol consumption, hypertension, and diabetes together with current smoking, having an increasing number of these 4 factors concurrently was associated with decreasing FA and increasing MD (ptrend < 0.01), independent of white matter hyperintensities. Vascular risk factors and APOE ε4 allele interacted to negatively affect white matter microstructure; having multiple (≥2) vascular factors was particularly detrimental to white matter integrity among APOE ε4 carriers. Lower tertile of FA and upper tertile of MD were significantly associated with faster Mini-Mental State Examination decline. Vascular risk factors are associated with reduced white matter integrity among older adults, which subsequently predicted faster cognitive decline. The detrimental effects of vascular risk factors on white matter microstructure were exacerbated among APOE ε4 carriers.


Digital IIR filters design using differential evolution algorithm with a controllable probabilistic population size.
Design of a digital infinite-impulse-response (IIR) filter is the process of synthesizing and implementing a recursive filter network so that a set of prescribed excitations results a set of desired responses. However, the error surface of IIR filters is usually non-linear and multi-modal. In order to find the global minimum indeed, an improved differential evolution (DE) is proposed for digital IIR filter design in this paper. The suggested algorithm is a kind of DE variants with a controllable probabilistic (CPDE) population size. It considers the convergence speed and the computational cost simultaneously by nonperiodic partial increasing or declining individuals according to fitness diversities. In addition, we discuss as well some important aspects for IIR filter design, such as the cost function value, the influence of (noise) perturbations, the convergence rate and successful percentage, the parameter measurement, etc. As to the simulation result, it shows that the presented algorithm is viable and comparable. Compared with six existing State-of-the-Art algorithms-based digital IIR filter design methods obtained by numerical experiments, CPDE is relatively more promising and competitive.


[Thoughts regarding researchers utilizing Grounded Theory].
This descriptive-reflexive study was performed with the objective to present the characteristics of researchers who use the Grounded Theory method, and outline the development of aptitudes for the researcher to become a Grounded Theoretician. The theoretical discussion was based on the frameworks of this methodology and supported by the literature. The article presents the main demands of qualitative studies using Grounded Theory, and important behaviors, attitudes and characteristics developed by the researchers. It is concluded that learning about Grounded Theory involves more than operationalizing a group of procedures and techniques. It also involves facing challenges to change one's attitude as a researcher and develop new ways of thinking and researching, gathering knowledge based on data to form a theory.


Oral antivirals for the prevention and treatment of SARS-CoV-2 infection.
Vaccines and antivirals are the classical weapons deployed to contain, prevent, and treat life-threatening viral illnesses. Specifically, for SARS-CoV-2 infection, vaccines protect against severe COVID-19 disease manifestations and complications. However, waning immunity and emergence of vaccine escape mutants remains a growing threat. This is highlighted by the current surge of the omicron COVID-19 variant. Thus, there is a race to find treatment alternatives. We contend that oral small molecule antivirals that halt SARSCoV- 2 infection are essential. Compared to currently available monoclonal antibodies and remdesivir, where parenteral administration is required, oral antivirals offer treatments in an outpatient setting with dissemination available on a larger scale. In response to this need at 2021's end, regulatory agencies provided emergency use authorization for both molnupiravir and nirmatrelvir. These medicines act on the viral polymerase and protease, respectively. Each is given for 5 days and can reduce disease progression by 30% and 89%, respectively. The advent of additional oral antivirals, the assessment of combination therapies, the formulation of extended-release medications, and their benefit for both early treatment and prophylaxis will likely transform the landscape of the COVID-19 pandemic.


Lewis acid/base mediated deep eutectic solvents intensify lignocellulose fractionation to facilitate enzymatic hydrolysis and lignin nanosphere preparation.
In this work, Lewis acids (FeCl3, AlCl3) and bases (Na2CO3, Na2SO3) were incorporated into a neutral deep eutectic solvent (DES, choline chloride/glycerin) to intensify the lignocellulose fractionation. The efficiency of fractionation in terms of the maximum delignification rate (89.7 %) and well-pleasing cellulose saccharification (100 %) could be achieved by the Lewis acid-mediated DES. An in-depth insight of the evolution of lignin structure revealed that Lewis acid-mediated DES could cleave the β-O-4 linkages efficiently to achieve a high yield lignin fragments. Meanwhile, the lignin fragments with the enhanced amphiphilic properties facilitate the preparation of lignin nanospheres (LNSs) via the self-assembly process. The resultant LNSs extracted by Lewis acid-mediated DES exhibited an excellent thermal stability, and enhanced antibacterial capacity, which were associated with the phenolic OH content. However, the extracted lignin by Lewis base-mediated DES was mainly attributed to the cleavage of lignin-carbohydrate complexes bond, especially the lignin-carbohydrate ester bond, which retained more ether bonds and a relatively complete structure. This study illuminated the different mechanisms of lignin extraction and the structural evolution of lignin from Lewis acid/base-mediated DES, and provided guidance to select suitable fractionation techniques for upgrading the downstream products.


Globalization and modernization: an obesogenic combination.
Animal research has well established that a link exists between variations in corticosteroids and the proneness to excess body fat accumulation. Accordingly, it is known that adrenalectomy is an efficient approach to counteract weight gain in most animal models of obesity. In humans, the association between variations in corticosteroids, its stress-related environmental effects and the predisposition to obesity is more difficult to demonstrate. In this paper, we propose that this relationship is accentuated by globalization and modernization which favour a labour context imposing additional stress and changes in life habits promoting a positive energy balance. Our main hypothesis is that the increase in knowledge-based work, and the decrease of quality and duration of sleep both induce an increase in cortisolaemia and glycaemia instability, which results in an increase in food intake, a reduction in energy expenditure and body fat gain. The authors of this paper believe that, from a socioeconomic perspective, globalization leads every nation of the world in conflict with itself and may consequently represent a real problem. On one hand, there are preoccupations related to productivity and money making. On the other hand, people have to adopt a daily lifestyle leading to hyperphagia and decreased energy expenditure in order to maintain their economic competitiveness.


[Burn injuries in children].
Burn injuries in children may cause permanent harm. This study reports data on incidence, injury mechanisms and products that cause burn injuries (in the period 01.01.07-31.12.07) and compares findings with those from previous studies (in 1989 and 1998). Semi-structured questionnaires were filled in by patients or next-of-kin and health workers at Bergen Accident and Emergency Department, casualty centres in three municipalities in western Norway (Fana, Åsane and Loddefjord) and at the National Burns Centre, Haukeland University Hospital. Missing data were retrieved retrospectively from medical records. We recorded 142 children with burn injuries; 35% were boys under two years of age. The annual incidence was the same as earlier; 6.6 per 1,000 under five years and 3.1 per 1,000 children under 15 years living in the community of Bergen. Contact injuries and scalds were most common and were caused by contact with ovens, stoves and hot food or liquids. Most children (93%) had less severe burns; 6% (9) were hospitalized (four of them had a non-western background). Almost 95% were given first aid by cooling. Children under two years, especially boys, are most at risk of burn injuries. Ovens were the cause more often now than before. The incidence has been the same the last 20 years and is the same as that in Trondheim ten years ago. The fact that the small city, Harstad, (northern Norway) attained substantially less injuries after the introduction of preventive actions indicates that such actions are needed to reduce the number of burn injuries among children.


Influence of mitotane on the hypoprothrombinemic effect of warfarin.
Mitotane (o,p'-DDD) is closely related to the organochlorine insecticides and shares their effects on drug metabolism. We have reported the first documented interaction of mitotane and warfarin in a human being. Because the potential for significant toxicity is great when mitotane and warfarin are used concomitantly, caution is recommended when titrating warfarin therapy in patients receiving mitotane. Other drugs susceptible to the influence of enzyme inducers should also be given with caution to patients receiving mitotane.


Population differences in olfaction accompany host shift in Drosophila mojavensis.
Evolutionary shifts in plant-herbivore interactions provide a model for understanding the link among the evolution of behaviour, ecological specialization and incipient speciation. Drosophila mojavensis uses different host cacti across its range, and volatile chemicals emitted by the host are the primary cue for host plant identification. In this study, we show that changes in host plant use between distinct D. mojavensis populations are accompanied by changes in the olfactory system. Specifically, we observe differences in olfactory receptor neuron specificity and sensitivity, as well as changes in sensillar subtype abundance, between populations. Additionally, RNA-seq analyses reveal differential gene expression between populations for members of the odorant receptor gene family. Hence, alterations in host preference are associated with changes in development, regulation and function at the olfactory periphery.


Chaos in fractional-order discrete neural networks with application to image encryption.
In this paper, a three-dimensional fractional-order (FO) discrete Hopfield neural network (FODHNN) in the left Caputo discrete delta's sense is proposed, the dynamic behavior and synchronization of FODHNN are studied, and the system is applied to image encryption. First, FODHNN is shown to exhibit rich nonlinear dynamics behaviors. Phase portraits, bifurcation diagrams and Lyapunov exponents are carried out to verify chaotic dynamics in this system. Moreover, by using stability theorem of FO discrete linear systems, a suitable control scheme is designed to achieve synchronization of the FODHNN. Finally, image encryption system based on the chaotic FODHNN is presented. Some security analysis and tests are given to show the effective of the encryption system.


Induced pluripotent stem cells from GMP-grade hematopoietic progenitor cells and mononuclear myeloid cells.
The induced pluripotent stem cell (iPSC) technology allows generation of patient-specific pluripotent stem cells, thereby providing a novel cell-therapy platform for severe degenerative diseases. One of the key issues for clinical-grade iPSC derivation is the accessibility of donor cells used for reprogramming. We examined the feasibility of reprogramming mobilized GMP-grade hematopoietic progenitor cells (HPCs) and peripheral blood mononuclear cells (PBMCs) and tested the pluripotency of derived iPS clones. Ectopic expression of OCT4, SOX2, KLF4, and c-MYC in HPCs and PBMCs resulted in rapid iPSC derivation. Long-term time-lapse imaging revealed efficient iPSC growth under serum- and feeder-free conditions with frequent mitotic events. HPC- and PBMC-derived iPS cells expressed pluripotency-associated markers, including SSEA-4, TRA-1-60, and NANOG. The global gene-expression profiles demonstrated the induction of endogenous pluripotent genes, such as LIN28, TERT, DPPA4, and PODXL, in derived iPSCs. iPSC clones from blood and other cell sources showed similar ultrastructural morphologies and genome-wide gene-expression profiles. On spontaneous and guided differentiation, HPC- and PBMC-derived iPSCs were differentiated into cells of three germ layers, including insulin-producing cells through endodermal lineage, verifying the pluripotency of the blood-derived iPSC clones. Because the use of blood cells allows minimally invasive tissue procurement under GMP conditions and rapid cellular reprogramming, mobilized HPCs and unmobilized PBMCs would be ideal somatic cell sources for clinical-grade iPSC derivation, especially from diabetes patients complicated by slow-healing wounds.


Partial directed coherence-based information flow in Parkinson's disease patients performing a visually-guided motor task.
We propose a partial directed coherence (PCD) method based on a sparse multivariate autoregressive (mAR) model to investigate patterns of information flow in electroencephalography (EEG) recordings in Parkinson's disease (PD) patients performing a visually-guided motor task. The use of a sparsity constraint on the mAR matrix addresses issues such as sample size, model order selection and number of parameters to be estimated, particularly when the number of EEG channels used is large and the window size is small in order to capture dynamic changes. The proposed PDC-based information flow analysis demonstrated distinctly altered patterns of connectivity between PD patients off medication and healthy subjects, particularly with respect to net information outflow from the left sensorimotor (L Sm) region, which might indicate excessive spreading of activity in the diseased state. Disrupted patterns of connectivity in PD were partially restored by levodopa medication. In addition, PDC-based analysis proved to be more sensitive to temporally-dynamic connectivity changes as compared to traditional spectral analysis, which might be influenced primarily by large-scale changes. We suggest that the proposed sparse-PDC method is a suitable technique to investigate altered connectivity in Parkinson's disease.


A study of voice production characteristics of astronuat speech during Apollo 11 for speaker modeling in space.
Human physiology has evolved to accommodate environmental conditions, including temperature, pressure, and air chemistry unique to Earth. However, the environment in space varies significantly compared to that on Earth and, therefore, variability is expected in astronauts' speech production mechanism. In this study, the variations of astronaut voice characteristics during the NASA Apollo 11 mission are analyzed. Specifically, acoustical features such as fundamental frequency and phoneme formant structure that are closely related to the speech production system are studied. For a further understanding of astronauts' vocal tract spectrum variation in space, a maximum likelihood frequency warping based analysis is proposed to detect the vocal tract spectrum displacement during space conditions. The results from fundamental frequency, formant structure, as well as vocal spectrum displacement indicate that astronauts change their speech production mechanism when in space. Moreover, the experimental results for astronaut voice identification tasks indicate that current speaker recognition solutions are highly vulnerable to astronaut voice production variations in space conditions. Future recommendations from this study suggest that successful applications of speaker recognition during extended space missions require robust speaker modeling techniques that could effectively adapt to voice production variation caused by diverse space conditions.


Bilateral lower eyelid basosquamous cell carcinoma: a rare case.
Basosquamous cell carcinoma is a subtype of basal cell cancer. It is known to be more aggressive than basal cell cancer. A 70-year-old male patient was admitted to our clinic for evaluation of cosmetic problems caused by masses on both lower eyelids for at least two years. The mass excision from and reconstruction of lower eyelids were performed. Histopathological examination of the resected masses was consistent with basosquamous cell carcinoma. We present a case of basosquamous cell carcinoma involving bilateral lower eyelids with a different clinical appearance. To the best of our knowledge, this is the first report of bilateral basosquamous cell carcinoma in a patient.


Differential spatial organization of otolith signals in frog vestibular nuclei.
Activation maps of pre- and postsynaptic field potential components evoked by separate electrical stimulation of utricular, lagenar, and saccular nerve branches in the isolated frog hindbrain were recorded within a stereotactic outline of the vestibular nuclei. Utricular and lagenar nerve-evoked activation maps overlapped strongly in the lateral and descending vestibular nuclei, whereas lagenar amplitudes were greater in the superior vestibular nucleus. In contrast, the saccular nerve-evoked activation map coincided largely with the dorsal nucleus and the adjacent dorsal part of the lateral vestibular nucleus, corroborating a major auditory and lesser vestibular function of the frog saccule. The stereotactic position of individual second-order otolith neurons matched the distribution of the corresponding otolith nerve-evoked activation maps. Furthermore, particular types of second-order utricular and lagenar neurons were clustered with particular types of second-order canal neurons in a topology that anatomically mirrored the preferred convergence pattern of afferent otolith and canal signals in second-order vestibular neurons. Similarities in the spatial organization of functionally equivalent types of second-order otolith and canal neurons between frog and other vertebrates indicated conservation of a common topographical organization principle. However, the absence of a precise afferent sensory topography combined with the presence of spatially segregated groups of particular second-order vestibular neurons suggests that the vestibular circuitry is organized as a premotor map rather than an organotypical sensory map. Moreover, the conserved segmental location of individual vestibular neuronal phenotypes shows linkage of individual components of vestibulomotor pathways with the underlying genetically specified rhombomeric framework.


Loperamide: studies on its mechanism of action.
The effects of loperamide on net solute and water absorption, and prostaglandin E2 (PGE2) and cholera toxin-induced secretion were studied in the rat jejunum using an in vivo steady-state perfusion technique. Loperamide stimulated absorption of fluid, electrolytes, and glucose and reversed PGE2 and cholera toxin-induced secretion to absorption; this opiate analogue had no effect on cholera toxin stimulation of adenylate cyclase activity or the rise of tissue cyclic AMP (cAMP) concentrations. The opiate antagonist, naloxone, reduced the antisecretory effects of loperamide without affecting tissue levels of cAMP. These results indicate that loperamide inhibits PGE2 and cholera toxin-induced secretion, and that this phenomenon is independent of any direct effect that cholera toxin has on the adenylate cyclase system. The action of naloxone suggests, but does not prove, that loperamide exerts its effect via opiate receptors.


Social defeat models in animal science: What we have learned from rodent models.
Studies on stress and its impacts on animals are very important in many fields of science, including animal science, because various stresses influence animal production and animal welfare. In particular, the social stresses within animal groups have profound impact on animals, with the potential to induce abnormal behaviors and health problems. In humans, social stress induces several health problems, including psychiatric disorders. In animal stress models, social defeat models are well characterized and used in various research fields, particularly in studies concerning mental disorders. Recently, we have focused on behavior, nutrition and metabolism in rodent models of social defeat to elucidate how social stresses affect animals. In this review, recent significant progress in studies related to animal social defeat models are described. In the field of animal science, these stress models may contribute to advances in the development of functional foods and in the management of animal welfare.


[Analysis of enamel thickness of anterior teeth and its relation to preparation for porcelain veneers].
The development of porcelain, acrylic and mixed crowns is not under discussion. In the same way, it should not be discussed now the evolution of silicate cements, the acrylics, the glass ionomer and the composite resins in their different techniques. We only want to analyze concisely the actual condition of the investigation and of the clinic, as regards the reconstruction with lamellas of the front part of the mouth. Lit can be deduce from the researches that the measurement of the vestibular thickness of y the enamel upon the incisives, laterals and canines specifies that: 1. As regards form, the most suitable elements for the laying of the porcelain laminate are the square, then the ovoid and finally the triangular ones. 2. The central incisives are the best; secondly the canines and then the laterals (this is directly related to the convexity of the fronts and to the amount of residual enamel). 3. It is advisable to finish the peripheric edge of the cavity 1 mm, above the anatomic neck to assure an adequate thickness of enamel in order to obtain a good adherence of the porcelain laminate veneers. 4. It is convenient to use appropriate techniques during the adamantine preparation in order to control its depth (for example diamond-like stones with ends).


Human Papillomavirus 31 Tyrosine 102 Regulates Interaction with E2 Binding Partners and Episomal Maintenance.
Several serine and threonine residues of the papillomavirus early E2 protein have been found to be phosphorylated. In contrast, only one E2 tyrosine phosphorylation site in BPV-1 (tyrosine 102) and one in HPV-16/31 (tyrosine 138) site have been characterized. Between BPV-1 and HPV-31 E2, 8 of the 11 tyrosines are conserved in the N-terminal domain, suggesting that phosphorylation of tyrosines has an essential role in E2 biology. In this study, we examine the effect of Y102 phosphorylation on HPV-31 E2 biology. Y102 proteins mutated either to the potential phospho-mimetic glutamic acid (Y102E) or to the nonphosphorylated homologue phenylalanine (Y102F) remain nuclear; however, Y102E is more associated with the nuclear matrix fraction. This is consistent with the inability of Y102E to bind TopBP1. Both BPV-1 and HPV-31 Y102E are similar in that neither binds the C terminus of Brd4, but in all other aspects the mutant behaves differently between the two families of papillomaviruses. BPV-1 Y102E was unable to bind E1 and did not replicate in a transient in vitro assay, while HPV-31 Y102E binds E1 and was able to replicate, albeit at lower levels than wild type. To examine the effect of E2 mutations under more native-like infection conditions, a neomycin-selectable marker was inserted into L1/L2 of the HPV-31 genome, creating HPV-31neo. This genome was maintained in every cell line tested for at least 50 days posttransfection/infection. Y102E in both transfection and infection conditions was unable to maintain high episome copy numbers in epithelial cell lines.IMPORTANCE Posttranslational modifications by phosphorylation can change protein activities, binding partners, or localization. Tyrosine 102 is conserved between delta papillomavirus BPV-1 and alpha papillomavirus HPV-31 E2. We characterized mutations of HPV-31 E2 for interactions with relevant cellular binding partners and replication in the context of the viral genome.


Harnessing nerve-muscle cell interactions for biomaterials-based skeletal muscle regeneration.
Nerve cells secrete neurotrophic factors that play a critical role in neuronal survival, proliferation, and regeneration. However, their role in regulating myoblast behavior and skeletal muscle repair remains largely unexplored. In the present study, we investigated the effects of PC12 secreted signaling factors in modulating C2C12 myoblast behavior under physiologically relevant conditions. We showed that PC12 conditioned media modulated myoblast proliferation and differentiation in both 2D culture and 3D aligned electrospun fiber scaffold system in a dose-dependent manner. We further developed a biomimetic, tunable hydrogel consisting of hyaluronic acid, chondroitin sulfate, and polyethylene glycol as a 3D matrix encapsulating PC12 cells. The hydrogel-encapsulated PC12 cells promoted survival and proliferation of myoblasts in co-culture. Further proteomics analysis identified a total of 2,088 proteins from the secretome of the encapsulated PC12 cells and revealed the biological role and overlapping functions of nerve-secreted proteins for skeletal muscle regeneration, potentially through regulating myoblast behavior, nerve function, and angiogenesis. These experiments provide insights into the nerve-muscle interactions and pave the way for developing advanced biomaterials strategies incorporating nerve cell secretome for accelerated skeletal muscle regeneration.


Study of gelatinized marrow stroma osteoblasts and true bone ceramic active bone.
To investigate a new method to construct tissue-engineering bone that will be applicable clinically. The cultured 5th generation rabbit bone marrow stroma osteoblasts (MSO) was dissolved in 3% sodium alginate solution (the final concentration of sodium alginate in the solution being 1%, and MSO, 5x10(6)/L), and then inoculated into prepared true bone ceramic (TBC) and gelatinized the bone by dribbling with calcium gluconate. The standard bone defect models were made in 48 adult New Zealand rabbit's both radius. Among the 48 rabbits, 24 were in Groups A and B, in which the left radius was implanted with gelatinized MSO-TBC (Group A) and right radius implanted with autograft-bone (Group B); and the other 24 were in control group whose left radius was implanted with non-gelatinized MSO-TBC (Group C) and right radius implanted with gelatinized TBC (Group D). Outcomes of the implanted bones were assessed by radiology, pathological histology, osteogenetic quantitative analysis, and biomechanics at 2, 4, 8, 12 weeks postoperatively. In Groups A and B, a satisfactory bone reparation and bony union was noted within 12 weeks. In Groups C and D, bone reparation was not satisfied compared with Group A in terms of ostogenetic quantity and biomechanics. Gelatinized MSO-TBC is an ideal artificial active bone that overcomes TBC shortcomings of fragileness and smooth surface that is not eligible for seed cell's adhesion. It is promising to put into clinical use extensively.


Removal of histone H1 from intact nuclei alters the digestion of nucleosome core DNA by staphylococcal nuclease.
We have examined the gel profiles of staphylococcal nuclease digests of intact nuclei following different extents of removal of histone H1 by low pH. It was found that the submonomer fragment pattern (i.e. fragments less than 140 base pairs (bp) changed dramatically following removal of H1. The most striking feature of this change was a marked increase in the relative intensity of a band migrating at 102 +/- 4 bp when about 20-50% of the nuclear DNA is rendered acid soluble. All other submonomer bands decreased in relative intensity. There was no evidence for an approximately 100-bp repeat pattern accompanying the enhanced generation of the 102-bp fragment following H1 removal. This result, along with the comparisons of gel profiles for different extents of digestion, suggests that removal of histone H1 from nuclei results in an increased susceptibility of the DNA to staphylococcal nuclease at one or both ends of many of the core particles and that a strong block to further digestion occurs within these core particles resulting in the formation of a relatively stable 102-bp fragment.


Long-term Impact of Adenotonsillectomy on the Quality of Life of Children with Sleep-disordered breathing.
Introduction Adenotonsillectomy is the first-line treatment for obstructive sleep apnea secondary to adenotonsillar hypertrophy in children. The physical benefits of this surgery are well known as well as its impact on the quality of life (QoL), mainly according to short-term evaluations. However, the long-term effects of this surgery are still unclear. Objective To evaluate the long-term impact of adenotonsillectomy on the QoL of children with sleep-disordered breathing (SDB). Method This was a prospective non-controlled study. Children between 3 and 13 years of age with symptoms of SDB for whom adenotonsillectomy had been indicated were included. Children with comorbities were excluded. Quality of life was evaluated using the obstructive sleep apnea questionnaire (OSA-18), which was completed prior to, 10 days, 6 months, 12 months and, at least, 18 months after the procedure. For statistical analysis, p -values lower than 0.05 were defined as statistically significant. Results A total of 31 patients were enrolled in the study. The average age was 5.2 years, and 16 patients were male. The OSA-18 scores improved after the procedure in all domains, and this result was maintained until the last evaluation, done 22 ± 3 months after the procedure. Improvement in each domain was not superior to achieved in other domains. No correlation was found between tonsil or adenoid size and OSA-18 scores. Conclusion This is the largest prospective study that evaluated the long-term effects of the surgery on the QoL of children with SDB using the OSA-18. Our results show adenotonsillectomy has a positive impact in children's QoL.


Volatiles from interactions of Maillard reactions and lipids.
This article provides current information on the production of volatile compounds from interactions of Maillard reactions and lipids. It includes a brief introduction outlining the Maillard reactions, the Strecker degradation of amino acids, and the oxidation of lipids. It highlights those compounds derived from these reactions that could interact to form volatile flavor components during the processing or cooking of food. The article discusses results obtained from model systems involving interactions between (1) Maillard reaction products and carbonyl compounds, (2) amino acids and carbonyl compounds, (3) amino acids and derivatives of fatty acids, and (4) Maillard reaction products, triglycerides and phospholipids. The qualitative and quantitative effects that triglycerides and phospholipids have on the formation of volatile Maillard products are also discussed. Particular attention is given to those long-chain alkyl heterocyclic compounds formed during these reactions, proposed methods for their formation, and their aromas. The role that such compounds play in food flavors is discussed with reference to those volatile compounds identified in certain cooked foods, such as meat (beef, lamb, and pork), chicken, potatoes (baked, French-fried, and crisps), and beverages (coffee, tea, and cocoa).


Hemangioblastoma of the spinal cord. Review and report of five cases.
Eighty-five cases of hemangioblastoma of the spinal cord are reviewed, including five new ones. While current views of the incidence, histology, and cytogenesis are presented, the main purpose of this article is to call attention to the identifying clinical and radiological characteristics of these spinal tumors. Median age at onset of symptoms was 30 years. The ratio of men to women was 1.1:1. Presenting symptoms were usually radicular pain or posterior column sensory loss or both. The lesions were most often single (79%), intramedullary (60%), and located in the cervical or thoracic spinal cord. There was associated syringomyelia in 67% of intramedullary cases and meningeal varicosities in 48% of all cases. Lindau disease and hemangioblastomas in other central nervous system locations were present in 33% of cases. The characteristic roentgenographic picture is a densely vascular tumor in association with a larger avascular syrinx and meningeal varicosities. Surgery is the only definitive treatment.


Modulation and induction of eosinophil chemotaxis by granulocyte-macrophage colony-stimulating factor and interleukin-3.
Eosinophilia and eosinophil function are regulated by cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5. We have investigated the modulatory role of GM-CSF and IL-3 on the platelet-activating factor (PAF)-, neutrophil-activating factor (NAF/IL-8)-, leukotriene B4 (LTB4)-, N-formyl-methionyl-leucyl-phenylalanine (FMLP)-, and human complement factor C5a-induced chemotaxis of eosinophils from normal individuals. These eosinophils show a chemotactic response toward PAF, LTB4, and C5a, but not to NAF/IL-8 and FMLP. Preincubation of the eosinophils with picomolar concentrations of GM-CSF caused a significant increase in the response toward LTB4 and induced a significant chemotactic response toward NAF/IL-8 and FMLP. Preincubation of the eosinophils with picomolar concentrations of IL-3 also induced a chemotactic response toward NAF/IL-8 and FMLP, and enhanced the PAF-induced chemotaxis response toward C5a was not influenced by both cytokines. Nanomolar concentrations of GM-CSF or IL-3 caused a significant inhibition of the C5a-induced chemotaxis. The LTB4-induced chemotaxis was also significantly inhibited in case of GM-CSF. At these concentrations both GM-CSF and IL-3 acted as chemotaxins for eosinophils were washed after pretreatment with GM-CSF and IL-3 the potentiation of the chemotactic response remained, whereas the inhibitory mode of action disappeared. Our data indicate that at picomolar concentrations the cytokines GM-CSF and IL-3 can modulate eosinophil chemotaxis and at nanomolar concentrations these cytokines can act as chemotaxins for eosinophils.


Use of predictive algorithms in-home monitoring of chronic obstructive pulmonary disease and asthma: A systematic review.
Major reported factors associated with the limited effectiveness of home telemonitoring interventions in chronic respiratory conditions include the lack of useful early predictors, poor patient compliance and the poor performance of conventional algorithms for detecting deteriorations. This article provides a systematic review of existing algorithms and the factors associated with their performance in detecting exacerbations and supporting clinical decisions in patients with chronic obstructive pulmonary disease (COPD) or asthma. An electronic literature search in Medline, Scopus, Web of Science and Cochrane library was conducted to identify relevant articles published between 2005 and July 2015. A total of 20 studies (16 COPD, 4 asthma) that included research about the use of algorithms in telemonitoring interventions in asthma and COPD were selected. Differences on the applied definition of exacerbation, telemonitoring duration, acquired physiological signals and symptoms, type of technology deployed and algorithms used were found. Predictive models with good clinically reliability have yet to be defined, and are an important goal for the future development of telehealth in chronic respiratory conditions. New predictive models incorporating both symptoms and physiological signals are being tested in telemonitoring interventions with positive outcomes. However, the underpinning algorithms behind these models need be validated in larger samples of patients, for longer periods of time and with well-established protocols. In addition, further research is needed to identify novel predictors that enable the early detection of deteriorations, especially in COPD. Only then will telemonitoring achieve the aim of preventing hospital admissions, contributing to the reduction of health resource utilization and improving the quality of life of patients.


Fitness to plead. A prospective study of the inter-relationships between expert opinion, legal criteria and specific symptomatology.
Psychiatrists are asked to give opinions as to fitness to plead, a legal concept. There is a dearth of research into fitness to plead in the UK, with no prospective studies and no studies involving the comparison of fit and unfit subjects. In particular, there have been no investigations into the meaning of 'unfit to plead' in terms of psychiatric symptomatology, or as to the relative importance of each legal fitness criterion in psychiatrists' conclusions as to fitness. The study comprised a prospective evaluation of 479 consecutive referrals to psychiatrists at court. Individual legal fitness criteria were examined as predictors of unfitness. Associations of unfitness, and of individual legal fitness criteria, were examined with Brief Psychiatric Rating Scale (BPRS) symptom scores. The two most important of the legal criteria in clinical decisions as to unfitness were whether the person could follow the proceedings of the trial or give adequate instructions to their solicitor. The legal criteria concerning trial were more predictive of unfitness than those concerning plea. Unfitness was significantly associated with the presence of positive psychotic symptomatology, in particular conceptual disorganization and delusional thinking, but not with symptoms of anxiety, depression or withdrawal. Unfitness is most significantly associated with symptoms affecting comprehension and communication. The fitness criteria could be simplified without loss of power. These results, predominantly concerned with mental illness, may not generalize to the mentally impaired.


A brucellosis case presenting with mass formation suggestive for tumor in soft tissue.
We report here a 70-year-old female patient who was diagnosed with brucellosis and presented with mass formation resembling a tumor. The mass was protuberant, 10 cm from the skin surface with a diameter of 15 cm, located at the inferior-lateral region of the left scapula. Brucella melitensis was yielded from culture of mass fluid. The patient responded to ceftriaxone, rifampin and doxycycline therapy and recovered without any sequela at the end of surgery and 3 months of medical treatment.


Emerging behavioral strategies for the prevention of HIV in rural areas.
HIV/AIDS prevention efforts have been concentrated in urban areas, despite increases in HIV in nonmetropolitan areas. This study reviews behavioral prevention programs initiated in rural areas and programs that could be adapted for rural contexts. Outcomes from these interventions demonstrate that preventive interventions at the population, community, targeted populations subgroups, and small group levels can reduce high-risk behavior in rural environments and are cost effective to deliver.


Host defenses against influenza virus: the role of anti-hemagglutinin antibody.
In CBA mice the protection provided by transferred immune spleen cells or by antibody has been investigated in immunologically intact, cyclophosphamide-treated and thymus-deprived animals infected with A/PR8 virus. The degree of protection was more closely related to serum antibody levels than to the presence of immune lymphocytes in recipients. Comparison of the protective efficiency of various anti-influenza antisera with different specificities within an influenza A subtype indicated that antibodies recognizing the strain-specific determinants of the influenza hemagglutinin have an important role in protection. Physiologic amounts of transferred antibodies were shown to protect immunodepressed mice, suggesting that, provided a sufficient amount of specific antibodies is secreted, the participation of effectors of cell-mediated immunity is not essential. However, our results suggest that thymus-derived lymphocytes have an indirect role in protection by enhancing, through their helper effect, the secretion of anti-influenza antibodies.


Variation in Orthologous Shell-Forming Proteins Contribute to Molluscan Shell Diversity.
Despite the evolutionary success and ancient heritage of the molluscan shell, little is known about the molecular details of its formation, evolutionary origins, or the interactions between the material properties of the shell and its organic constituents. In contrast to this dearth of information, a growing collection of molluscan shell-forming proteomes and transcriptomes suggest they are comprised of both deeply conserved, and lineage specific elements. Analyses of these sequence data sets have suggested that mechanisms such as exon shuffling, gene co-option, and gene family expansion facilitated the rapid evolution of shell-forming proteomes and supported the diversification of this phylum specific structure. In order to further investigate and test these ideas we have examined the molecular features and spatial expression patterns of two shell-forming genes (Lustrin and ML1A2) and coupled these observations with materials properties measurements of shells from a group of closely related gastropods (abalone). We find that the prominent "GS" domain of Lustrin, a domain believed to confer elastomeric properties to the shell, varies significantly in length between the species we investigated. Furthermore, the spatial expression patterns of Lustrin and ML1A2 also vary significantly between species, suggesting that both protein architecture, and the regulation of spatial gene expression patterns, are important drivers of molluscan shell evolution. Variation in these molecular features might relate to certain materials properties of the shells of these species. These insights reveal an important and underappreciated source of variation within shell-forming proteomes that must contribute to the diversity of molluscan shell phenotypes.


Effects of extracellular nucleotides and their hydrolysis products on regulatory volume decrease of trout hepatocytes.
In trout hepatocytes, hypotonic swelling is followed by a compensatory shrinkage called regulatory volume decrease (RVD). It has been postulated that extracellular ATP and other nucleotides may interact with type 2 receptors (P(2)) to modulate this response. In addition, specific ectoenzymes hydrolyze ATP sequentially down to adenosine, which may bind to type 1 receptors (P(1)) and also influence RVD. Accordingly, in this study, we assessed the role of extracellular nucleoside 5'-tri- and diphosphates and of adenosine on RVD of trout hepatocytes. The extent of RVD after 40 min of maximum swelling was denoted as RVD(40), whereas the initial rate of RVD was called v(RVD). In the presence of hypotonic medium (60% of isotonic), hepatocytes swelled 1.6 times followed by v(RVD) of 1.7 min(-1) and RVD(40) of 60.2%. ATP, UTP, UDP, or ATPgammaS (P(2) agonists; 5 microM) increased v(RVD) 1.5-2 times, whereas no changes were observed in the values of RVD(40). Addition of 100 microM suramin or cibacron blue (P(2) antagonists) to the hypotonic medium produced no effect on v(RVD) but a 53-58% inhibition of RVD(40). Incubation of hepatocytes in the presence of either 5 microM [gamma-(32)P]ATP or [alpha-(32)P]ATP induced the extracellular release of [gamma-(32)P]P(i) (0.21 nmol.10(-6) cells(-1).min(-1)) and [alpha-(32)P]P(i) ( approximately 8 x 10(-3) nmol.10(-6) cells(-1).min(-1)), suggesting the presence of ectoenzymes capable of fully dephosphorylating ATP. Concerning the effect of P(1) activation on RVD, 5 microM adenosine, both in the presence and absence of 100 microM S-(4-nitrobenzil)-6-tioinosine (a blocker of adenosine uptake), decreased RVD(40) by 37-44%, whereas 8-phenyl theophylline, a P(1) antagonist, increased RVD(40) by 15%. Overall, results indicate that ATP, UTP, and UDP, acting via P(2), are important factors promoting RVD of trout hepatocytes, whereas adenosine binding to P(1) inhibits this process.


ICF-Based Assessment of Functioning in Daily Clinical Practice. A Promising Direction Toward Patient-Centred Care in Patients With Low Back Pain.
Background: Patient-centred care has received increased attention in recent years. Patient-Reported Outcomes (PROs) and shared decision-making are key components of Patient-Centred care. Low back pain (LBP) is a complex symptom affected by multiple, interacting factors. Therefore, evidence strongly recommend a biopsychosocial and patient-centred approach in the assessment and management. The International Classification of Functioning, Disability and Health (ICF) provide a biopsychosocial model for describing functioning and disability. ICF is widely acknowledged, but implementation into clinical practice is lacking. To support the use of a biopsychosocial and patient-centred approach in daily clinical practice among patients with LBP we developed a practice-friendly tool based on ICF; the LBP assessment tool. Objective: To compare an ICF-based assessment facilitated by the LBP assessment tool with standard care in terms of the use of PROs and shared decision-making in order to promote patient-centred care in patients with LBP. Methods: A non-randomized controlled design was used. Eligible patients were allocated to one of two groups: the ICF group, assessed with the LBP assessment tool or the control group, assessed with a conventional LBP assessment. Primary outcome includes use of PROs. Secondary outcomes include use of a graphical overview displaying the patient profile and shared decision-making. A patient evaluation questionnaire was used to collect data. Results: Seven hundred ten patients were assessed for eligibility of whom 531 were allocated to the ICF group (n = 299) or the control group (n = 232). A significantly higher use of PRO data (p < 0.00) and the patient profile (p < 0.00) was reported in favor of the ICF group. Patients in the ICF group also experienced being more involved in decision-making (p = 0.01). Conclusions: This study showed that a functioning assessment, by means of the LBP assessment tool, increased use of PROs and shared decision-making when compared to a conventional LBP assessment. Additionally, this study demonstrated that routine use of ICF-based PRO data and shared decision-making promoted patient-centred care in patients with LBP. The LBP assessment tool may be a strong candidate for a user-friendly ICF-based tool with the potential to support health professionals in a shift toward a biopsychosocial and patient-centred approach to patients with LBP.


Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes.
We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.3% [56 mmol/mol] and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-κB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.


Multimodal Haptic Simulation for Ventriculostomy Training.
Freehand ventriculostomy is a frequent surgical procedure and is among the first ones that junior neurosurgery residents learn. Although training simulators exist, none has been adopted in the clinical routine to train junior residents. This paper focuses on a novel multimodal haptic training simulator that will lift the limitations of current simulators. We thus propose an architecture that integrates (1) visual feedback through augmented MRIs, and (2) a physical mock-up of the patient's skull to (3) active haptic feedback.


Income Disparity and Healthcare Utilization: Lessons from Indonesia's National Health Insurance Claim Data.
Indonesia's National Health Insurance Program, known as Jaminan Kesehatan Nasional (JKN), has a variety of membership pathways for those wishing to gain access. Claim data from JKN offers a cost-effective way of observing who is accessing healthcare services and what types of services are being used. This study is a novel attempt to measure disparities amongst JKN users in their engagement with services, providing an opportunity to reflect on patterns of use. Using claims data collected from JKN users between 2015-2016, we used the Ordinary Least Square estimation model to compare health services utilization among subsidized and non-subsidized users. We focused primarily on the individual use of the hospital for outpatient and inpatient treatment. Analysis reveals that subsidized users access primary healthcare services more frequently than non-subsidized users. Conversely, non-subsidized users access secondary and tertiary health care services more frequently than other users. Subsidized users who utilize secondary and tertiary health care tend to suffer more severe health illnesses than non-subsidized members. This study concludes that income disparity affects healthcare utilization. Non-subsidized members are more likely than subsidized members to access secondary and tertiary health care services. Our study offers evidence of the potential underutilization of secondary and tertiary healthcare (STHC) by subsidized members, which could lead to inefficiency since subsidized members seeking STHC treatment had severe health conditions, thus needing to be treated longer and requiring higher healthcare expenditures.


A Systematic Review of Idiopathic Secondary Stenosis Following Index Surgery for Craniosynostosis.
Primary craniosynostosis is a congenital craniofacial disorder in which cranial sutures prematurely close. Iatrogenic secondary stenosis is abnormal cranial suture closure caused by surgical manipulation of the suture. In contrast, idiopathic secondary stenosis develops in a suture that did not undergo surgical manipulation. The objective of this systematic review was to consolidate and characterize the incidence, classification, and management of idiopathic secondary stenosis in the literature. Literature from PubMed, Web Of Science, and EMBASE from 1970 to March 2022 was reviewed. The following information was extracted for individual patients: incidence of idiopathic secondary stenosis, index primary craniosynostosis, primary surgical correction, presenting signs of secondary stenosis, management, and further complications. Seventeen articles detailing 1181 patients were included. Ninety-one developed idiopathic secondary stenosis (7.7%). Only 3 of these patients were syndromic. The most common index craniosynostosis was sagittal synostosis (83.5%). The most common suture undergoing idiopathic secondary stenosis was the coronal suture (91.2%). Patients presented at a median age of 24 months. The most common presenting sign was a radiologic finding (85.7%), although some patients presented with headache or head deformity. Only 2 patients, both syndromic, had complications following surgical correction of secondary stenosis. Idiopathic secondary stenosis is a rare, long-term complication following index surgical repair of craniosynostosis. It can occur following any surgical technique. It most commonly affects the coronal suture but can affect any of the sutures, including pansynostosis. Surgical correction is curative in nonsyndromic patients.


D-pinitol ameliorated H2O2-induced oxidative damage in PC12 cells and prolonged the lifespan by IIS pathway in Caenorhabditis elegans.
D-pinitol (DP) has been extensively regarded as the main active component of legumes for anti-aging. In this study, we intended to explore the anti-aging mechanism of DP, utilizing computer modeling techniques. The results demonstrated that DP significantly delayed H2O2-induced cellular senescence. Model PC12 cells treated with DP exhibited increased cell viability, increased antioxidant enzyme activity (SOD, CAT), and reduced ROS and MDA levels. Furthermore, DP was discovered to have a positive effect on healthy longevity. In C. elegans, DP treatment enhanced lifespan, stress capacity, antioxidant capacity (T-SOD/CAT/GSH-Px/MDA/ROS), and altered aging-related indicators of lipofuscin accumulation, pharyngeal pump rate, motility, and reproduction. Moreover, DP could reduce the toxicity Aβ in transgenic C. elegans CL4176, CL2355, and CL2331. Further mechanistic studies indicated DP increased transcription factor (daf-16, skn-1, hsf-1) expression of insulin/insulin-like growth factor-1 signaling (IIS) pathway. As expected, DP also extended the downstream target genes of the three transcription factors (sod-3, ctl-1, ctl-2, gst-4, hsp-16.1, and hsp-16.2). Further mutant lifespan experiments, network pharmacology, and molecular docking revealed that DP might be life-extending through the IIS pathway. DP deserves extensive investigation and development as a potential anti-aging drug in the future.


[Effect of ascorbic acid on the induction of uterine sarcomas in mice].
Administration of ascorbic acid (0.3, 0.75 or 1.5%) in drinking water started after the treatment of female CBA mice with 1,2-dimethylhydrazine and estradiol-dipropionate inhibited the growth of uterine sarcomas. The inhibitory effect depended upon dosage to some extent. When administered together with estradiol-dipropionate to intact mice, ascorbic acid arrested uterine growth associated with estrogen treatment.


Phase II trial of preoperative chemoradiotherapy followed by surgical resection in patients with superior sulcus non-small-cell lung cancers: report of Japan Clinical Oncology Group trial 9806.
To evaluate the safety and efficacy of preoperative chemoradiotherapy followed by surgical resection for superior sulcus tumors (SSTs). Patients with pathologically documented non-small-cell lung cancer with invasion of the first rib or more superior chest wall were enrolled as eligible; those with distant metastasis, pleural dissemination, and/or mediastinal node involvement were excluded. Patients received two cycles of chemotherapy every 4 weeks as follows; mitomycin 8 mg/m(2) on day 1, vindesine 3 mg/m(2) on days 1 and 8, and cisplatin 80 mg/m(2) on day 1. Radiotherapy directed at the tumor and the ipsilateral supraclavicular nodes was started on day 2 of each course, at the total dose of 45 Gy in 25 fractions, with a 1-week split. Thoracotomy was undertaken 2 to 4 weeks after completion of the chemoradiotherapy. Those with unresectable disease received boost radiotherapy. From May 1999 to November 2002, 76 patients were enrolled, of whom 20 had T4 disease; 75 patients were fully assessable. Chemoradiotherapy was generally well tolerated. Fifty-seven patients (76%) underwent surgical resection, and pathologic complete resection was achieved in 51 patients (68%). There were 12 patients with pathologic complete response. Major postoperative morbidity, including chylothorax, empyema, pneumonitis, adult respiratory distress syndrome, and bleeding, was observed in eight patients. There were three treatment-related deaths, including two deaths owing to postsurgical complications and one death owing to sepsis during chemoradiotherapy. The disease-free and overall survival rates at 3 years were 49% and 61%, respectively; at 5 years, they were 45% and 56%, respectively. This trimodality approach is safe and effective for the treatment of patients with SSTs.


Analysis of lipooligosaccharide biosynthesis in the Neisseriaceae.
Neisserial lipooligosaccharide (LOS) contains three oligosaccharide chains, termed the alpha, beta, and gamma chains. We used Southern hybridization experiments on DNA isolated from various Neisseria spp. to determine if strains considered to be nonpathogenic possessed DNA sequences homologous with genes involved in the biosynthesis of these oligosaccharide chains. The presence or absence of specific genes was compared to the LOS profiles expressed by each strain, as characterized by their mobilities on sodium dodecyl sulfate-polyacrylamide gel electrophoresis gel and their reactivities with various LOS-specific monoclonal antibodies. A great deal of heterogeneity was seen with respect to the presence of genes encoding glycosyltransferases in Neisseria. All pathogenic species were found to possess DNA sequences homologous with the lgt gene cluster, a group of genes needed for the synthesis of the alpha chain. Some of these genes were also found to be present in strains considered to be nonpathogenic, such as Neisseria lactamica, N. subflava, and N. sicca. Some nonpathogenic Neisseria spp. were able to express high-molecular-mass LOS structures, even though they lacked the DNA sequences homologous with rfaF, a gene whose product must act before gonococcal and meningococcal LOS can be elongated. Using a PCR amplification strategy, in combination with DNA sequencing, we demonstrated that N. subflava 44 possessed lgtA, lgtB, and lgtE genes. The predicted amino acid sequence encoded by each of these genes suggested that they encoded functional proteins; however, structural analysis of LOS isolated from this strain indicated that the bulk of its LOS was not modified by these gene products. This suggests the existence of an additional regulatory mechanism that is responsible for the limited expression of these genes in this strain.


Differential diagnosis and treatment of periodontitis-mimicking actinomycosis.
Actinomycosis is an uncommon chronic granulomatous disease that presents as a slowly progressive, indolent, indurated infiltration with multiple abscesses, fistulas, and sinuses. The purpose of this article is to report on a case of actinomycosis with clinical findings similar to periodontitis. A 46-year-old female presented with recurrent throbbing pain on the right first and second molar of the mandible three weeks after root planing. Exploratory flap surgery was performed, and the bluish-gray tissue fragment found in the interproximal area between the two molars was sent for histopathology. The diagnosis from the biopsy was actinomycosis. The clinical and radiographic manifestations of this case were clinically indistinguishable from periodontitis. The patient did not report any symptoms, and she is scheduled for a follow-up visit. The present study has identified periodontitis-mimicking actinomycosis. Actinomycosis should be included in the differential diagnosis in cases with periodontal pain and inflammation that do not respond to nonsurgical treatment for periodontitis. More routine submissions of tissue removed from the oral cavity for biopsies may be beneficial for differential diagnosis.


Transport of cholesterol from the endoplasmic reticulum to the plasma membrane.
We have studied the transport of newly synthesized cholesterol from the endoplasmic reticulum to the plasma membrane in Chinese hamster ovary cells using a cell fractionation assay. We found that transport is dependent on metabolic energy, but that the maintenance of the high differential concentration of cholesterol in the plasma membrane is not an energy-requiring process. We have tested a variety of inhibitors for their effect on cholesterol transport and found that cytochalasin B, colchicine, monensin, cycloheximide, and NH4Cl did not have any effect. The cholesterol transport process shows a sharp temperature dependence; it ceases at 15 degrees C, whereas cholesterol synthesis continues. When synthesis occurs at 15 degrees C, the newly synthesized cholesterol accumulates in the endoplasmic reticulum and in a low density, lipid-rich vesicle fraction. These results suggest that cholesterol is transported via a vesicular system.


Germination of Nosema algerae (Microspora) spores: conditional inhibition by D2O, ethanol and Hg2+ suggests dependence of water influxupon membrane hydration and specific transmembrane pathways.
The germination of microsporidian spores under conditions expected to affect water flow across the plasma membrane-wall complex was studied by assessing their responses to in vitro stimulation with Na+ or K+. Partial or full substitution of common water with D2O, which more effectively coats ions and electrostatically-charged cell surfaces with relatively stable hydration layers, delayed and inhibited spore germination in a concentration-dependent manner; yet, preincubation in 100% D2O did not change the normal response to standard stimulation. Water structure-breaking conditions, such as an increase in temperature (within the 15 degrees C to 40 degrees C range) or in ionic strength (1- to 10-fold normal), opposed the inhibition by D2O and allowed significant stimulation by Li+, the monovalent cation with the largest hydration diameter and a usually weak stimulant action on the spores. Ethanol, known to reduce water permeation across cell membranes and phospholipid bilayers, also caused a powerful and dose-dependent (1% to 4% v/v) inhibition of spore germination, but pretreatment with ethanol did not affect the normal response. HgCl2, an inhibitor of specific water channels, blocked spore germination at just 250 microM in the normal stimulation solution irrespective of the temperature, and permitted only a delayed response in high salt stimulation solutions. However,the inhibition by Hg2+ was abolished by the simultaneous presence of 2-mercaptoethanol in the medium. These results suggest (1) that spore germination is keenly dependent upon the hydration states of both the plasma membrane-wall complex and the stimulant ions, and (2) that osmotic water flows into the spores through specific transmembrane pathways with critical sulfhydryl groups, i.e., analogous to the water channels that facilitate water movements across the plasma membranes of highly permeable cells.


Transient calbindin-D28k-positive systems in the telencephalon: ganglionic eminence, developing striatum and cerebral cortex.
Calbindin-D28k (calbindin) is a member of the superfamily of calcium-binding proteins implicated in the regulation of intracellular calcium. In the mature brain, calbindin is widely expressed in neurons of the forebrain and the hindbrain, and in the telencephalon calbindin-like immunoreactivity is particularly strongly expressed by medium-sized neurons of the striatum and by certain other neurons in the cortex and subcortex. We have traced the development of calbindin expression in the forebrain of the rat, and report here that in addition to the steady development of these calbindin-positive neuronal systems, transient waves of calbindin expression occur in cells of the ventricular zones of the basal ganglia and cortex and in cells of the telencephalic regions derived from these ventricular zones including radial glia of the developing striatum. In the striatum and its ventricular zone (the ganglionic eminence, or GE) we identified four transient calbindin-positive systems in the perinatal period. First, calbindin-immunoreactive cells began to appear in the GE by embryonic day (E)18, and by E20 an extensive dorsal and lateral part of the GE was marked by dense calbindin-like immunoreactivity in the ventricular zone. This calbindin system peaked at postnatal day (P)0-P3 and disappeared by P15. Its presence suggests that the GE is divisible on a molecular basis into lateral and medial districts that may correspond to derivatives of the lateral and medial ventricular ridges. Second, a system of calbindin-positive processes appeared in the dorsal and lateral caudoputamen with temporal and spatial distributions matching the germinal zone system. Many of these processes could be traced from calbindin-positive cells in the ventricular zone of the GE, including processes stretching across the full width of the dorsal caudoputamen. Double-staining experiments demonstrated that these radial processes were Rat.401-positive, suggesting that they form a subset of radial glia in the developing telencephalon. These findings demonstrate that during development calbindin is expressed in glial as well as neural cells. They further suggest that the radial glia associated with the GE form heterogeneous populations, the transient calbindin-positive radial glia being associated with the lateral ridge of the GE and its derivatives. Third, a scattered population of calbindin-positive cells with morphologies different from the common medium-sized calbindin-immunoreactive neurons of the striatum appeared in the dorsal and lateral striatum from about E20 to P15. Some of these cells were close to the transient calbindin-positive radial processes in the same region, but others were not.(ABSTRACT TRUNCATED AT 400 WORDS)


MarkerMiner 1.0: A new application for phylogenetic marker development using angiosperm transcriptomes.
Targeted sequencing using next-generation sequencing (NGS) platforms offers enormous potential for plant systematics by enabling economical acquisition of multilocus data sets that can resolve difficult phylogenetic problems. However, because discovery of single-copy nuclear (SCN) loci from NGS data requires both bioinformatics skills and access to high-performance computing resources, the application of NGS data has been limited. We developed MarkerMiner 1.0, a fully automated, open-access bioinformatic workflow and application for discovery of SCN loci in angiosperms. Our new tool identified as many as 1993 SCN loci from transcriptomic data sampled as part of four independent test cases representing marker development projects at different phylogenetic scales. MarkerMiner is an easy-to-use and effective tool for discovery of putative SCN loci. It can be run locally or via the Web, and its tabular and alignment outputs facilitate efficient downstream assessments of phylogenetic utility, locus selection, intron-exon boundary prediction, and primer or probe development.


A Tandem Guide RNA-Based Strategy for Efficient CRISPR Gene Editing of Cell Populations with Low Heterogeneity of Edited Alleles.
CRISPR/Cas9-based gene knockouts (KOs) enable precise perturbation of target gene function in human cells, which is ideally assessed in an unbiased fashion by molecular omics readouts. Typically, this requires the lengthy process of isolating KO subclones. We show here that KO subclones are phenotypically heterogenous, regardless of the guide RNA used. We present an experimental strategy that avoids subcloning and achieves fast and efficient gene silencing on cell pools, based on the synergistic combination of two guide RNAs mapping at close (40-300 bp) genomic proximity. Our strategy results in better predictable indel generation with a low allelic heterogeneity, concomitant with low or undetectable residual target protein expression, as determined by MS3 mass spectrometry proteomics. Our method is compatible with nondividing primary cells and can also be used to study essential genes. It enables the generation of high confidence omics data which solely reflect the phenotype of the target ablation.


Bacterial copper- and zinc-cofactored superoxide dismutase contributes to the pathogenesis of systemic salmonellosis.
Copper/zinc-cofactored superoxide dismutase ([Cu,Zn]-SOD) has been found in the periplasm of many bacterial species but its biological function is unknown. Here we report the cloning and characterization of sodC, encoding [Cu,Zn]-SOD, from Salmonella typhimurium. The predicted protein sequence shows only 58% identity to Escherichia coil SodC, and from this its chromosomal location and its immediate proximity to a phage gene, sodC, in Salmonella is speculated to have been acquired by bacteriophage-mediated horizontal transfer from an unknown donor. A sodC mutant of S. typhimurium was unimpaired on aerobic growth in rich medium but showed enhanced sensitivity in vitro to the microbicidal action of superoxide. S. typhimurium, S. choleraesuis and S. dublin sodC mutants showed reduced lethality in a mouse model of oral infection and persisted in significantly lower numbers in livers and spleens after intraperitoneal infection, suggesting that [Cu,Zn]-SOD plays a role in pathogenicity, protecting Salmonella against oxygen radical-mediated host defences. There was, however, no observable difference compared with wild type in the interaction of sodC mutants with porcine pleural, mouse peritoneal or J774 macrophages in vitro, perhaps reflecting the hierarchical capacity of different macrophage lines to kill Salmonella, the most efficient overwhelming the proposed protective effect of periplasmic SOD.


Two modes of action by which Xenopus hairy2b establishes tissue demarcation in the Spemann-Mangold organizer.
The Hairy and Enhancer-of-Split (HES) family of transcriptional repressors plays important roles in pattern formation during development throughout the animal kingdom. Generally, HES proteins repress the expression of genes specific for neighboring tissues to maintain the nature of cells expressing HES proteins, resulting in pattern formation. Xhairy2b, a Xenopus HES, establishes the prospective anterior prechordal mesoderm identity in the Spemann-Mangold organizer by both inducing specific genes and repressing the genes specific for neighboring tissues. Here we report that Xhairy2b has two modes of action, each of which corresponds to inductive and repressive functions. We show that the inductive function is independent of direct transcriptional regulation and is exhibited by the C-terminal WRPW tetrapeptide motif alone, although it induces the expression of a wide variety of the organizer genes that Xhairy2b represses. The transcriptional repression by Xhairy2b is responsible for only the repressive function. We propose that the activity of the WRPW motif intrinsically induces the expression of genes specific for the organizer in a rather non-specific manner to ensure the organizer environment. Then, the transcriptional repression selectively down-regulates the expression of some of these genes, resulting in the regionalization of the axial mesoderm. Our study provides new insight into how a region of the vertebrate embryo is demarcated by one dual-functional transcription factor in the early stages of development.


Pest select database: a new tool to use selective pesticides for IPM.
Crop pests can be naturally controlled by a set of beneficial arthropods, as entomophagous predators or parasites, leading to a global reduction of pest occurrence and insecticide use. The selectivity of plant protection products for these beneficial arthropods is a key factor in the success of IPM strategies. An abundant scientific literature concerning this subject exists, but for the final pesticide users, the information is not always easily accessible or understood. The IOBC working group "Pesticides and Beneficial Organisms" (PBO) has developed a new database to compile all data concerning pesticide selectivity on beneficial arthropods, obtained with methods that followed the IOBC test standard characteristics. These standards have been developed since the 70's by the Working group Pesticide and Beneficial Organisms, in the context of IPM. This database includes a first set of data previously published, coming from the different Joint Pesticide Testing Programs, with the addition of results published later in the IOBC Bulletin. The second set of data has been extracted from the Public verse of the Draft Assessment Report (DAR), established by the different EU member' states in the context of the registration process at the European Level and available online on the EFSA website. As nearly all active ingredients have to be tested on at least 2 to 4 selected beneficial arthropod species with methods that followed the IOBC standard characteristics, these DAR represent an important source of information for pesticide users dealing with beneficial arthropods and selectivity, with about 50% of the actual records. This source was previously only exploited for registration purposes and not accessible to a large public, but a lot of results, mainly from the first tier testing, have been compiled and interpreted for IPM. The new database is available online on the area restricted to the IOBC-members (http:// www.iobc-wprs.org/restricted_member/toolbox.cfm). This database will be updated regularly on basis of the new IOBC publications, EFSA Draft Assessment Report and scientific publication results that followed IOBC standard characteristics.


Cardiovascular magnetic resonance reference values of mitral and tricuspid annular dimensions: the UK Biobank cohort.
Mitral valve (MV) and tricuspid valve (TV) apparatus geometry are essential to define mechanisms and etiologies of regurgitation and to inform surgical or transcatheter interventions. Given the increasing use of cardiovascular magnetic resonance (CMR) for the evaluation of valvular heart disease, we aimed to establish CMR-derived age- and sex-specific reference values for mitral annular (MA) and tricuspid annular (TA) dimensions and tethering indices derived from truly healthy Caucasian adults. 5065 consecutive UK Biobank participants underwent CMR using cine balanced steady-state free precession imaging at 1.5 T. Participants with non-Caucasian ethnicity, prevalent cardiovascular disease and other conditions known to affect cardiac chamber size and function were excluded. Absolute and indexed reference ranges for MA and TA diameters and tethering indices were stratified by gender and age (45-54, 55-64, 65-74 years). Overall, 721 (14.2%) truly healthy participants aged 45-74 years (54% women) formed the reference cohort. Absolute MA and TA diameters, MV tenting length and MV tenting area, were significantly larger in men. Mean ± standard deviation (SD) end-diastolic and end-systolic MA diameters in the 3-chamber view (anteroposterior diameter) were 2.9 ± 0.4 cm (1.5 ± 0.2 cm/m2) and 3.3 ± 0.4 cm (1.7 ± 0.2 cm/m2) in men, and 2.6 ± 0.4 cm (1.6 ± 0.2 cm/m2) and 3.0 ± 0.4 cm (1.8 ± 0.2 cm/m2) in women, respectively. Mean ± SD end-diastolic and end-systolic TA diameters in the 4-chamber view were 3.2 ± 0.5 cm (1.6 ± 0.3 cm/m2) and 3.2 ± 0.5 cm (1.7 ± 0.3 cm/m2) in men, and 2.9 ± 0.4 cm (1.7 ± 0.2 cm/m2) and 2.8 ± 0.4 cm (1.7 ± 0.3 cm/m2) in women, respectively. With advancing age, end-diastolic TA diameter became larger and posterior MV leaflet angle smaller in both sexes. Reproducibility of measurements was good to excellent with an inter-rater intraclass correlation coefficient (ICC) between 0.92 and 0.98 and an intra-rater ICC between 0.90 and 0.97. We described age- and sex-specific reference ranges of MA and TA dimensions and tethering indices in the largest validated healthy Caucasian population. Reference ranges presented in this study may help to improve the distinction between normal and pathological states, prompting the identification of subjects that may benefit from advanced cardiac imaging for annular sizing and planning of valvular interventions.


The effectiveness of splenic autotransplantation: an experimental study.
The purpose of this study was to establish the effects of spleen autotransplantation on immunity and to examine the viability of autotransplanted spleen tissue. Three groups were assigned and following operations were performed in twenty New Zealand rabbits. 1st group: sham laparotomy, 2nd group: splenectomy and 3rd group: splenectomy and splenic autotransplantation. Scintigraphic methods, hematological-immunological tests and histopathological examination were used to evaluate the effects of splenic autotransplantation. Histopathological findings showed that eight rabbits had splenic regrowth and two had necrosis of autotransplanted splenic tissue. Preoperative hematological and immunological findings compared with those at sixth week postoperatively. In group 3, postoperative immunoglobulin G, immunoglobulin M and interleukin-1 levels were significantly increased when compared with preoperative levels. Between all groups, postoperative leukocyte counts were found to be significantly higher in group 2 comparing with group 1. In group 2, postoperative platelet counts were significantly higher in comparison to group 1 and 3. No statistically significant difference was detected between the groups for immunoglobulin G, immunoglobulin M and interleukin-1 levels. Conservative treatment is important in patients with splenic injury. However when splenectomy is indicated, splenic autotransplantation into the omentum pouch could be a reliable method for reconstruction of splenic functions and the viability of the implanted spleen tissue can be monitored by scintigraphy and laboratory examination.


Targeting the IRE1α/XBP1 Endoplasmic Reticulum Stress Response Pathway in ARID1A-Mutant Ovarian Cancers.
The SWI/SNF chromatin-remodeling complex is frequently altered in human cancers. For example, the SWI/SNF component ARID1A is mutated in more than 50% of ovarian clear cell carcinomas (OCCC), for which effective treatments are lacking. Here, we report that ARID1A transcriptionally represses the IRE1α-XBP1 axis of the endoplasmic reticulum (ER) stress response, which confers sensitivity to inhibition of the IRE1α-XBP1 pathway in ARID1A-mutant OCCC. ARID1A mutational status correlated with response to inhibition of the IRE1α-XBP1 pathway. In a conditional Arid1aflox/flox/Pik3caH1047R genetic mouse model, Xbp1 knockout significantly improved survival of mice bearing OCCCs. Furthermore, the IRE1α inhibitor B-I09 suppressed the growth of ARID1A-inactivated OCCCs in vivo in orthotopic xenograft, patient-derived xenograft, and the genetic mouse models. Finally, B-I09 synergized with inhibition of HDAC6, a known regulator of the ER stress response, in suppressing the growth of ARID1A-inactivated OCCCs. These studies define the IRE1α-XBP1 axis of the ER stress response as a targetable vulnerability for ARID1A-mutant OCCCs, revealing a promising therapeutic approach for treating ARID1A-mutant ovarian cancers. SIGNIFICANCE: These findings indicate that pharmacological inhibition of the IRE1α-XBP1 pathway alone or in combination with HDAC6 inhibition represents an urgently needed therapeutic strategy for ARID1A-mutant ovarian cancers.


A microbiological assay on microtitre plates of thiamine in biological fluids and foods.
A microbiological method for the determination of thiamine in biological fluids and food using 96-well microtitre plates and automatic plate reader, suitable for using in routine clinical diagnosis is described. Thiamine was extracted from samples by acid digestion (acetate buffer, pH 4.5) at 110 degrees C for 20 minutes. Assay recovery and reproducibility were optimally evaluated. Results obtained from this method were compared with those obtained using traditional microbiological and HPLC methods. The values resulting from this method were more or less the same as those of the traditional microbiological method, but much higher than those of HPLC assay. However, the new assay presents many advantages: it reduces the use of serum volume, which is a main benefit for clinical analysis. It lowers also the reagent costs and increases the number of analyses as well as it is easy to perform for routine clinical laboratory.


Sleep and interrogation: does losing sleep impact criminal history disclosure?
Despite centuries of using sleep deprivation to interrogate, there is virtually no scientific evidence on how sleep shapes behavior within interrogation settings. To evaluate the impact of sleeplessness on participants' behavior during investigative interviews, an experimental study examined the impact of sleep restriction on disclosure of past illegal behavior. Healthy participants from a university community (N = 143) either maintained or curbed their sleep (up to 4 h a night) across 2 days with sleep monitored via actigraphy. They were then asked to disclose past illegal acts and interviewed about them. Next, they were reinterviewed following an example of a detailed memory account (model statement). Disclosures were blindly coded for quantity and quality by two independent raters. Sleep-restricted individuals reported similar offenses, but less information during their disclosure with slightly less precision. Model statement increased disclosure but did not reduce the inhibiting impact of sleep loss. Mediation analysis confirmed the causal role of sleep as responsible for experimental differences in amount of information, and participants' reports suggested impaired motivation to recall information played a role. The findings suggest that even moderate sleep loss can inhibit criminal disclosure during interviews, point to motivational factors as responsible, and suggest investigators should be cautious when interrogating sleepy participants.


Prevalence of mutation and phenotypic expression associated with sulfadoxine-pyrimethamine resistance in Plasmodium falciparum and Plasmodium vivax.
Therapeutic efficacy of sulfadoxine-pyrimethamine (SP), which is commonly used to treat falciparum malaria, was assessed in isolates of Plasmodium falciparum (Welch, 1897) and Plasmodium vivax (Grassi et Feletti, 1890) ofAligarh, Uttar Pradesh, North India and Taif, Saudi Arabia during 2011-2012. Both the species showed mutations in dihydrofolate reductase (DHFR) enzyme as they have common biochemical drug targets. Mutation rate for pfdhfr was higher compared to pvdhfr because the drug was mainly given to treat falciparum malaria. Since both the species coexist, P. vivax was also exposed to SP due to faulty species diagnosis or medication without specific diagnosis. Low level of mutations against SP in P. falciparum of Saudi isolates indicates that the SP combination is still effective for the treatment of falciparum malaria. Since SP is used as first-line of treatment because of high level of resistance against chloroquine (CQ), it may result in spread of higher level of mutations resulting in drug resistance and treatment failure in near future. Therefore, to avoid further higher mutations in the parasite, use of better treatment regimens such as artesunate combination therapy must be introduced against SP combination.


A randomised controlled trial to assess whether prehabilitation improves fitness in patients undergoing neoadjuvant treatment prior to oesophagogastric cancer surgery: study protocol.
Neoadjuvant therapy prior to oesophagogastric resection is the gold standard of care for patients with T2 and/or nodal disease. Despite this, studies have taught us that chemotherapy decreases patients' functional capacity as assessed by cardiopulmonary exercise (CPX) testing. We aim to show that a multimodal prehabilitation programme, comprising supervised exercise, psychological coaching and nutritional support, will physically, psychologically and metabolically optimise these patients prior to oesophagogastric cancer surgery so they may better withstand the immense physical and metabolic stress placed on them by radical curative major surgery. This will be a prospective, randomised, controlled, parallel, single-centre superiority trial comparing a multimodal 'prehabilitation' intervention with 'standard care' in patients with oesophagogastric malignancy who are treated with neoadjuvant therapy prior to surgical resection. The primary aim is to demonstrate an improvement in baseline cardiopulmonary function as assessed by anaerobic threshold during CPX testing in an interventional (prehab) group following a 15-week preoperative exercise programme, throughout and following neoadjuvant treatment, when compared with those that undergo standard care (control group). Secondary objectives include changes in peak oxygen uptake and work rate (total watts achieved) at CPX testing, insulin resistance, quality of life, chemotherapy-related toxicity and completion, nutritional assessment, postoperative complication rate, length of stay and overall mortality. This study has been approved by the London-Bromley Research Ethics Committee and registered on ClinicalTrials.gov. The results will be disseminated in a peer-reviewed journal. NCT02950324; Pre-results.