African mitochondrial DNA subhaplogroups and peripheral neuropathy during antiretroviral therapy.
Susceptibility to peripheral neuropathy during antiretroviral therapy with nucleoside reverse-transcriptase inhibitors was previously associated with a European mitochondrial DNA (mtDNA) haplogroup among non-Hispanic white persons. To determine whether nucleoside reverse-transcriptase inhibitor-associated peripheral neuropathy was related to mtDNA variation in non-Hispanic black persons, we sequenced mtDNA of participants from AIDS Clinical Trials Group study 384. Of 156 non-Hispanic black persons with genomic data, 51 (33%) developed peripheral neuropathy. In a multivariate model, African mtDNA subhaplogroup L1c was an independent predictor of peripheral neuropathy (odds ratio, 3.7 [95% confidence interval, 1.1-12.0]). An African mtDNA subhaplogroup is for the first time implicated in susceptibility to nucleoside reverse-transcriptase inhibitor-associated toxicity.


Multimode dynamics of a coupled ultracold atomic-molecular system.
We analyze the coherent multimode dynamics of a system of coupled atomic and molecular Bose gases. Starting from an atomic Bose-Einstein condensate with a small thermal component, we observe a complete depletion of the atomic and molecular condensate modes on a short time scale due to a significant population of excited states. Giant coherent oscillations between the two condensates for typical parameters are almost completely suppressed. Our results cast serious doubts on the common use of the 2-mode model for the description of coupled ultracold atomic-molecular systems and should be considered when planning future experiments with ultracold molecules.


Transsacral versus modified pelvic landmarks for percutaneous iliosacral screw placement--a computed tomographic analysis and cadaveric study.
The alar roots of the first sacral body are the usual confines for iliosacral screw (IS) placement when stabilizing a sacroiliac joint injury or sacral fracture. The traditional transsacral method of IS placement aligns the screw horizontally through the sacral ala on both the inlet and outlet views of the sacrum. A modified oblique method of IS placement aligns the screw in an oblique fashion, directed inferiorly to superiorly and posteriorly to anteriorly. The purpose of this investigation was to first define the S-1 segment boundaries for both methods of placement by analyzing the 3-dimensional (3-D) composites of 40 pelvic computed tomography (CT) scans, and then to evaluate the actual placement of ISs under fluoroscopy in 10 cadaveric pelves comparing the transsacral with the modified oblique techniques. Critical dimensions of 7.3 mm and 14.6 mm were considered as the diameter sizes of one and two cannulated screws, respectively. From the 3-D CT composites, the mean anterior/posterior (A/P) measurements were 10.9 mm and 18.0 mm, comparing transsacral with modified oblique methods, respectively. Moreover, 9/40 (22.5%) of the transsacral A/P measurements were <7.3 mm, while all of the modified oblique A/P measurements were >7.3 mm. The mean superior/inferior (S/I) measurements were 18.0 mm for transsacral and 26.2 mm for modified oblique placement. Out of 40 transsacral S/I measurements, 4 (10%) were <14.6 mm, while all the modified oblique S/I measurements were >14.6 mm. In the second part of this study, 10 uninjured cadaveric pelves had unilateral percutaneous IS placed under fluoroscopic guidance (inlet, outlet, and lateral projections) by one orthopedic traumatologist. The final position of all 10 screws was confirmed on fluoroscopy by two independent orthopedic trauma surgeons. The first 5 screws were placed by using transsacral pelvic landmarks. Modified landmarks guided the other 5 screws. The accuracy of final screw position was determined by "postoperative" CT scans interpreted by a blinded musculoskeletal radiologist. The screws inserted using transsacral pelvic landmarks were errant in 3 of the 5 cases. Neurovascular complications could be expected from the extraosseous position of all 3 screws. All 5 screws were located within the confines of the S-1 segment by means of the modified oblique technique. Thus, the modified oblique placement technique allowed greater accuracy and reliability over transsacral landmarks in placing percutaneous ISs. The use of the modified oblique pelvic landmarks is warranted during percutaneous iliosacral screw stabilization of the posterior pelvis.


Comparison of the Force Released by Intermaxillary Elastics Used for Different Time Periods.
The objective of the present study was to compare the strength degradation of the force of intermaxillary elastic used for different periods. The sample included intermaxillary elastics used for 20 adult patients with bilateral Class II or III malocclusion in orthodontic treatment with fixed appliances, with a mean age of 27.25 years. Latex orthodontic elastics with 3/16 inch of diameter were used, with an average stretching of three times its diameter. The elastics were used in the same patient bilaterally for different periods, with each pair of elastics used for 1, 12, 24, and 48h. Thus, the sample consisted of 200 elastics, with 40 being used in each period (one pair used by each patient) and 40 new elastics without use tested as control. Elastics were tested using a universal testing machine, stretched with a velocity of 30 mm/min, and the force was evaluated in stretches of 15, 20, 25, and 30 mm. The degradation force was compared in the four different times of use and control by one-way ANOVA (analysis of variance) and Tukey tests. There were significant differences among the groups in all evaluated stretches (15, 20, 25, and 30 mm). The control elastics presented higher average forces numerically and statistically significant for all tested times, except for the elastic used for 1h. The elastics used for 1, 12, and 24h had similar forces among them, with a significant difference to the elastics used for 48h. It is recommended to change the intermaxillary elastics after 24 h of use.


Does soccer cleat design influence the rotational interaction with the playing surface?
Non-contact injuries in soccer players may be related to the interplay between cleat type and playing surface, and bladed shoes were often blamed for non-contact injuries with no research support. The aim of this study was to compare the rotational resistance (stiffness and peak sustainable torque) among three types of soccer cleats (metal studs, molded rubber studs, and bladed) in a controlled laboratory environment. The shoes were tested on both natural and artificial turfs under a compressive preload of 1000 N and with internal and external rotations. The three shoe models showed comparable performances with a good repeatability for each individual test on both playing surfaces. A less stiff behavior was observed for the natural turf. A tendency toward highest peak torque was observed in the studded model on natural surface. The bladed cleats provided peak torque and rotational stiffness comparable to the other models. Studded and bladed cleats did not significantly differ in their interaction with the playing surface. Therefore, soccer shoes with bladed cleats should not be banned in the context of presumed higher risk for non-contact injuries.


Human yaw rotation aftereffects with brief duration rotations are inconsistent with velocity storage.
In many sensory systems, perception of stimuli is influenced by previous stimulus exposure such that subsequent stimuli may be perceived as more neutral. This phenomenon is known as an aftereffect and has been studied for vision, audition, and some vestibular stimuli including roll and translation. Previous data on yaw rotation perception has focused on low-frequency stimuli on the order of a minute which may not be directly applicable to frequencies during ambulation. The aim of the current study is to look at the influence of yaw rotation on subsequent perception near 1 Hz, the predominant frequency of yaw rotation during human ambulation. Humans were rotated with 12 ° whole body adapting stimulus over 1 or 1.5 s. After an interstimulus interval (ISI) of 0.5, 1.0, 1.5, or 3 s, a test stimulus the same duration as the adapting stimulus was presented, and subjects pushed a button to identify the direction of the test stimulus as right or left. The direction and magnitude of the test stimulus was adjusted based on prior responses to find the stimulus at which no rotation was perceived. Experiments were conducted both in darkness and with a visual fixation point. The presence of a fixation point did not influence the aftereffect which was largest at 0.5 s with an average size of 0.78 ± 0.18°/s (mean ± SE). The aftereffect diminished with a time constant of ~1 s. Thresholds were elevated after the adapting stimulus and also decreased with a time constant of ~1 s. These findings demonstrate that short adapting stimuli can induce significant aftereffects in yaw rotation perception and that these aftereffects are independent from the previously described velocity storage.


Correlation of needle core biopsy with excision histology in screen-detected B3 lesions: the Merrion Breast Screening Unit experience.
Needle core biopsy (NCB) is a widely-used technique for non-operative evaluation of screen-detected breast lesions. Although most NCBs are B2 (benign) or B5 (malignant), some fall into the B3 category of "uncertain malignant potential". This study aims to categorise the lesions prompting a B3 NCB in the Merrion Breast Screening Unit, and establish the incidence of malignancy on subsequent excision biopsy. Patients attending the Merrion Breast Screening Unit in Dublin between 2000 and 2008 who had a B3 NCB were identified. The NCB pathology reports were reviewed and the diagnosis correlated with excision histology; the latter was classified as benign, atypical or malignant. Lesion-specific positive predictive values (PPVs) for malignancy were derived. 141 patients with a B3 NCB were identified. The most frequent lesions on NCB were radial scar (RS; n = 57), atypical intraductal epithelial proliferation (AIDEP; n = 25) and papillary lesion (n = 24). The final diagnosis was malignant in 22 patients (16%), atypical in 40 (28%) and benign in 79 (56%). Two of the patients with a malignant diagnosis had invasive carcinoma. The lesion-specific PPVs were: lobular neoplasia 50%, AIDEP 32%, columnar cell lesion with atypia 12.5%, RS 12.3%, papillary lesion 8.3%, suspected phyllodes tumour 7.7%, and spindle cell lesion 0%. Atypia on RS NCB predicted an atypical or malignant excision diagnosis, but atypia on papillary lesion NCB did not. One-sixth of B3 NCBs in this series proved to be malignant on excision. The PPV for malignancy varied according to lesion type.


Depression and diabetes in Iranian patients: a comparative study.
The aim of the present study was determine the rate of depression in people with diabetes in an Iranian population. A hospital-based prospective study with a comparison group was conducted in Firozgar Teaching Hospital in Tehran, Iran. The condition of depression and relationship to diabetes was assessed among 375 individuals (206 people with diabetes and 169 without diabetes) who consecutively presented for this prospective study. Of the total participation, 206 (54.9%) had diabetes (type 1 = 66 and type 2 = 140). Female made up 63.7% (n = 239). The mean age of entire study was 47.2 years (SD = 16.3 range, 15-87 years). Major depression was present among 71.8% of this sample with diabetes (both types; type 1 and type 2). Depression was more prevalent among women with diabetes than men (Adjusted OR = 2.1 (95% CI 1.4-3.2)). Of the 375 participants, 135 (36%) had BID scores lower than 11 and 240 (64%) had BDI scores indicating moderate to severe depression (> 16). Diabetes appears to increase the risk of developing depression; therefore early detection and treatment intervention provide the best protective mechanisms available against the effects of depression on diabetes outcomes, and a psychological service provision for people with diabetes is needed.


Development of novel efficient SIN vectors with improved safety features for Wiskott-Aldrich syndrome stem cell based gene therapy.
Gene therapy is a promising therapeutic approach to treat primary immunodeficiencies. Indeed, the clinical trial for the Wiskott-Aldrich Syndrome (WAS) that is currently ongoing at the Hannover Medical School (Germany) has recently reported the correction of all affected cell lineages of the hematopoietic system in the first treated patients. However, an extensive study of the clonal inventory of those patients reveals that LMO2, CCND2 and MDS1/EVI1 were preferentially prevalent. Moreover, a first leukemia case was observed in this study, thus reinforcing the need of developing safer vectors for gene transfer into HSC in general. Here we present a novel self-inactivating (SIN) vector for the gene therapy of WAS that combines improved safety features. We used the elongation factor 1 alpha (EFS) promoter, which has been extensively evaluated in terms of safety profile, to drive a codon-optimized human WASP cDNA. To test vector performance in a more clinically relevant setting, we transduced murine HSPC as well as human CD34+ cells and also analyzed vector efficacy in their differentiated myeloid progeny. Our results show that our novel vector generates comparable WAS protein levels and is as effective as the clinically used LTR-driven vector. Therefore, the described SIN vectors appear to be good candidates for potential use in a safer new gene therapy protocol for WAS, with decreased risk of insertional mutagenesis.


Titan solar occultation observations reveal transit spectra of a hazy world.
High-altitude clouds and hazes are integral to understanding exoplanet observations, and are proposed to explain observed featureless transit spectra. However, it is difficult to make inferences from these data because of the need to disentangle effects of gas absorption from haze extinction. Here, we turn to the quintessential hazy world, Titan, to clarify how high-altitude hazes influence transit spectra. We use solar occultation observations of Titan's atmosphere from the Visual and Infrared Mapping Spectrometer aboard National Aeronautics and Space Administration's (NASA) Cassini spacecraft to generate transit spectra. Data span 0.88-5 μm at a resolution of 12-18 nm, with uncertainties typically smaller than 1%. Our approach exploits symmetry between occultations and transits, producing transit radius spectra that inherently include the effects of haze multiple scattering, refraction, and gas absorption. We use a simple model of haze extinction to explore how Titan's haze affects its transit spectrum. Our spectra show strong methane-absorption features, and weaker features due to other gases. Most importantly, the data demonstrate that high-altitude hazes can severely limit the atmospheric depths probed by transit spectra, bounding observations to pressures smaller than 0.1-10 mbar, depending on wavelength. Unlike the usual assumption made when modeling and interpreting transit observations of potentially hazy worlds, the slope set by haze in our spectra is not flat, and creates a variation in transit height whose magnitude is comparable to those from the strongest gaseous-absorption features. These findings have important consequences for interpreting future exoplanet observations, including those from NASA's James Webb Space Telescope.


Cricothyrotomy performed with the Melker™ set or the QuickTrach™ kit: procedure times, learning curves and operators' preference.
Cricothyroidotomy is a surgical airway technique in which an airway device is inserted into the trachea through an incision made at the cricothyroid membrane. It is used for the management of the "difficult airways" and may be a lifesaving procedure in "can't intubate, can't oxygenate" situations. However, many healthcare professionals working in emergency settings have little of no experience with this procedure. Achievement of theoretical and practical knowledge of different cricothyrotomy techniques is therefore a fundamental prerequisite for those healthcare professionals. In this study, 40 volunteers representative of different categories of healthcare professionals were enrolled for the theoretical and practical 1-day training course on cricothyrotomy. Two commercially available device for cricothyrotomy were used during the course, the Melker™ set, which involves the Seldinger technique, and the QuickTrach™ kit, which does not rely on the use of a guide-wire. Each participant performed a series of 5 attempts on a manikin with each kit. Procedure time was recorded, and satisfaction with the course, preference for each cricothyrotomy kit and self-rating of cricothyrotomy skills were assessed by a self-administered questionnaire. Mean procedure time significantly decreased from the first to the last attempt (48.7±21.9 and 27.8±13.7 seconds, respectively; p<0.0001). The Melker™ set was the most preferred, being rated as "excellent" by 62% of participants. This preference was even more pronounced among anaesthesiologists, that are more familiar with the Seldinger technique. Participants' satisfaction was high: the course was rated as "excellent" by 66.7% of attendees, the theoretical and practical knowledge achieved was rated as "very useful" by 94% of all attendees and by 100% of the anaesthesiologists. A systematic approach to teach healthcare professionals in the application of various devices for the management of the socalled "difficult airways" may maximize intubation success and minimize complication. The present study provides evidence for the efficacy of training courses in Emergency Departments aimed at improving theoretical and practical cricothyrotomy skills in emergency situations.


Comparative study of the floral biology and of the response of productivity to insect visitation in two rapeseed cultivars (Brassica napus L.) in Rio Grande do Sul.
Planning the artificial pollination of agricultural crops requires knowledge of the floral biology and reproductive system of the crop in question. Many studies have shown that rapeseed (Brassica napus Linnaeus) is self-compatible and self-pollinated, but its productivity may be increased by insect visitation. In the present study, the floral biology and the response of productivity to insect visitation of two rapeseed cultivars (Hyola 420 and Hyola 61) were analyzed and compared in three regions of Rio Grande do Sul, Brazil. The rapeseed flowers presented three stages during anthesis, with the time periods varying between the cultivars. Both cultivars are self-compatible, but free visitation of insects increased productivity by 17% in the Hyola 420 cultivar and by approximately 30% in the Hyola 61 cultivar. Therefore, it is concluded that the cultivar Hyola 61 is more dependent on insect pollination than Hyola 420.


Effects of dry needling of the obliquus capitis inferior on sensorimotor control and cervical mobility in people with neck pain: A double-blind, randomized sham-controlled trial.
Impairments of sensorimotor control relating to head and eye movement control and postural stability are often present in people with neck pain. The upper cervical spine and particularly the obliquus capitis inferior (OCI) play an important proprioceptive role; and its impairment may alter cervical sensorimotor control. Dry needling (DN) is a valid technique to target the OCI. To investigate if a single DN session of the OCI muscle improves head and eye movement control-related outcomes, postural stability, and cervical mobility in people with neck pain. Forty people with neck pain were randomly assigned to receive a single session of DN or sham needling of the OCI. Cervical joint position error (JPE), cervical movement sense, standing balance and oculomotor control were examined at baseline, immediately post-intervention, and at one-week follow-up. Active cervical rotation range of motion and the flexion rotation test were used to examine the global and upper cervical rotation mobility, respectively. Linear mixed-models revealed that the DN group showed a decrease of JPE immediately post-intervention compared to the sham group (mean difference [MD]= -0.93°; 95% confidence interval [CI]: -1.85, -0.02) which was maintained at one-week follow-up (MD= -1.64°; 95%CI: -2.85, -0.43). No effects on standing balance or cervical movement sense were observed in both groups. Upper cervical mobility showed an increase immediately after DN compared to the sham group (MD= 5.14°; 95%CI: 0.77, 9.75) which remained stable at one-week follow-up (MD= 6.98°; 95%CI: 1.31, 12.40). Both group showed an immediate increase in global cervical mobility (MD= -0.14°; 95%CI: -5.29, 4.89). The results from the current study suggest that a single session of DN of the OCI reduces JPE deficits and increases upper cervical mobility in patients with neck pain. Future trials should examine if the addition of this technique to sensorimotor control training add further benefits in the management of neck pain.


Workload and GP burnout - survey and register-based study in Danish general practice.
Burnout is common among general practitioners (GPs). Previous studies have indicated an association between high workload and burnout among doctors. To assess the risk of burnout among single-handed GPs in Denmark in relation to self-reported and register-based workload. Questionnaire data from 312 Danish single-handed GPs and register data on their patients and provided services. Burnout was measured using the Maslach Burnout Inventory (MBI). A composite burnout score of quartile points was calculated. The questionnaire provided information on working hours. Register data included number of services and patient list size. Association between composite burnout score and workload was estimated with binomial regression analyses adjusting for the GPs' age and gender, and social deprivation score of their patient lists. Working more than five days a week in practice increased the risk of a high burnout score (RRadjusted =2.34, 95% CI [1.62-3.37]). Spending more than 7.5 hours a day on patient-related tasks increased the risk of a high burnout score, highest among GPs spending 8.5-9.5 hours a day on patient-related tasks (RRadjusted =2.01, 95% CI [0.90-4.51]), although not statistically significant. There was no association between number of services and risk of burnout. Working more than five days a week in practice significantly increased the risk of burnout in Danish single-handed GPs. Spending more than 7.5 hours a day on patient-related tasks tended to increase the risk. We found no association between a high number of services and increased risk of burnout.


Prediction of protein function and pathways in the genome era.
The growing number of completely sequenced genomes adds new dimensions to the use of sequence analysis to predict protein function. Compared with the classical knowledge transfer from one protein to a similar sequence (homology-based function prediction), knowledge about the corresponding genes in other genomes (orthology-based function prediction) provides more specific information about the protein's function, while the analysis of the sequence in its genomic context (context-based function prediction) provides information about its functional context. Whereas homology-based methods predict the molecular function of a protein, genomic context methods predict the biological process in which it plays a role. These complementary approaches can be combined to elucidate complete functional networks and biochemical pathways from the genome sequence of an organism. Here we review recent advances in the field of genomic-context based methods of protein function prediction. Techniques are highlighted with examples, including an analysis that combines information from genomic-context with homology to predict a role of the RNase L inhibitor in the maturation of ribosomal RNA.


Safety performance analysis of horizontal curves in urban areas.
While numerous studies have examined horizontal curve risk factors in rural areas, there is only one study for urban areas. Moreover, previous studies have used limited datasets, which tend to generate an intrinsic bias on results either by the sample size or due to a lack of understanding of all the risk factors associated with curve safety. This study aims to narrow this knowledge gap in three aspects: it focuses on urban areas; it uses a large novel GIS dataset of about 25,000 urban curves; and it expands the traditional curve risk factor pool by examining the spatial relationship of curves to adjacent curves and intersections. Using this curve dataset and six years of statewide fatal and injury crash data in the state of Florida, the study develops customized safety performance functions (SPFs) for urban curves based on different spatial relationships of curves to intersections. The results confirm that the traditional risk factors for rural curves, such as traffic volume, curve radius and length, speed limit, functional classification, and the number of lanes, also apply to curves in urban areas. However, the new finding is that curve safety in urban areas is affected by the proximity of curves to adjacent curves and intersections. The curves with intersections and isolated curves (with no adjacent nearby curves) are at high risk. There are also risk factor differences between single and dual-centerline roads. We also observed differences between the travel directions on divided roadway curves, but these differences will require more research.


Pediatric Liver Transplant Recipients Who Undergo Transfer to the Adult Healthcare Service Have Good Long-Term Outcomes.
Liver transplantation has transformed survival for children with liver disease necessitating the transfer of a growing number of patients to the adult healthcare service. The impact of transfer on outcomes remains unclear. The aim of this single-center study of 137 consecutive pediatric liver transplant recipients was to examine the effect of transfer on patient and graft survival. The median time from transplant to transfer was 10.4 years and the median age of the patients at transfer was 18.6 years. After transfer, there were 5 re-transplants and 12 deaths in 14 patients. The estimated posttransfer 10-year patient and graft survival was 89.9% and 86.2%, respectively. Overall, 4 patients demonstrated graft loss as a consequence of chronic rejection. Graft loss was associated with older age at first transplant (p = 0.008). When compared to young adult patients transplanted in the adult center, the transferred patients did not have inferior graft survival from the point of transfer (HR 0.28; 95% CI 0.10-0.77, p = 0.014). This suggests that transfer did not impact significantly on graft longevity. In conclusion, pediatric liver transplant recipients who undergo transfer to the adult service have good long-term outcomes.


Typology reconfigured: from the metaphysics of essentialism to the epistemology of representation.
The goal of this paper is to encourage a reconfiguration of the discussion about typology in biology away from the metaphysics of essentialism and toward the epistemology of classifying natural phenomena for the purposes of empirical inquiry. First, I briefly review arguments concerning 'typological thinking', essentialism, species, and natural kinds, highlighting their predominantly metaphysical nature. Second, I use a distinction between the aims, strategies, and tactics of science to suggest how a shift from metaphysics to epistemology might be accomplished. Typological thinking can be understood as a scientific tactic that involves representing natural phenomena using idealizations and approximations, which facilitates explanation, investigation, and theorizing via abstraction and generalization. Third, a variety of typologies from different areas of biology are introduced to emphasize the diversity of this representational reasoning. One particular example is used to examine how there can be epistemological conflict between typology and evolutionary analysis. This demonstrates that alternative strategies of typological thinking arise due to the divergent explanatory goals of researchers working in different disciplines with disparate methodologies. I conclude with several research questions that emerge from an epistemological reconfiguration of typology.


Meprobamate reduces accuracy of physiological detection of deception.
Normal male subjects attempted to deceive an experimenter recording electrodermal, respiratory, an cardiovascular activity. Those who had ingested a placebo or nothing were detected with statistically significant frequency on the basis of their phasic electrodermal responses, which clearly distinguished them from truthful suspects. That was not the case with deceptive subjects who had ingested 400 milligrams of meprobamate, nor did the examiner detect which subjects had received the drug.


Extracorporeal membrane oxygenation in cardiac arrest.
The survival of cardiac arrest patients is dependent on the efficient and timely application of the chain of survival. This includes early identification of cardiac arrest and activation of the emergency response system, high-quality cardiopulmonary resuscitation (CPR), rapid defibrillation, basic and advanced medical services, and advanced life support and post-cardiac arrest care. However, some patients may be refractory to these measures. Extracorporeal membrane oxygenation CPR (ECPR), otherwise known as extracorporeal life support, offers an alternative to such refractory cardiac arrest cases. As hospitals have limited resources, it is important to devise effective patient selection methods, and improve our understanding and experience of ECPR to ensure the best outcome. It is also vital to understand that ECPR constitutes only one component of post-cardiac arrest care, which includes other aspects such as therapeutic hypothermia and early perfusion for best patient outcome.


Mouse model of radiation retinopathy reveals vascular and neuronal injury.
To characterize the neuronal and vascular pathology in vivo and in vitro in a mouse model of radiation retinopathy. C57Bl/6J mice underwent cranial irradiation with 12 Gy and in vivo imaging by optical coherence tomography and of relative blood flow velocity by laser speckle flowgraphy for up to 3-6 months after irradiation. Retinal architecture, vascular density and leakage and apoptosis were analyzed by histology and immunohistochemistry before irradiation or at 10, 30, 240, and 365 days after treatment. The vascular density decreased in the plexiform layers starting at 30 days after irradiation. No impairment in retinal flow velocity was seen. Subtle perivascular leakage was present at 10 days, in particular in the outer plexiform layer. This corresponded to increased width of this layer. However, no significant change in the retinal thickness was detected by OCT-B scans. At 365 days after irradiation, the nuclear density was significantly reduced compared to baseline. Apoptosis was detected at 30 days and less prominent at 365 days. By histology, vascular leakage at 10 days was followed by increased neuronal apoptosis and loss of neuronal and vascular density. However, in vivo imaging approaches that are commonly used in human patients did not detect pathology in mice.


Current treatments for sleep disturbances in individuals with dementia.
Sleep disturbances are widespread among older adults. Degenerative neurologic disorders that cause dementia, such as Alzheimer's disease and Parkinson's disease, exacerbate age-related changes in sleep, as do many common comorbid medical and psychiatric conditions. Medications used to treat chronic illness and insomnia have many side effects that can further disrupt sleep and place patients at risk for injury. This article reviews the neurophysiology of sleep in normal aging and sleep changes associated with common dementia subtypes and comorbid conditions. Current pharmacologic and nonpharmacologic evidence-based treatment options are discussed, including the use of light therapy, increased physical and social activity, and multicomponent cognitive-behavioral interventions for improving sleep in institutionalized and community-dwelling adults with dementia.


Evaluation of Anatomical Variations of the Maxillary Sinus in Patients With and Without Mucous Retention Cyst.
Objectives: Mucous retention cyst (MRC) is a benign and self-limited lesion that can be caused by many risk factors, including anatomical variations of the sinonasal region. This study aims to investigate the relationship between anatomical variations and the presence of MRC. Materials and Methods: In total, 2109 sinonasal cone beam computed tomography images were evaluated for the presence of MRC, and the sinonasal anatomical regions such as the osteomeatal complex (OMC), infundibulum length, ostium height, the diameter of the ostium, the presence of accessory ostium, concha bullosa, and mucosal thickening of the maxillary sinuses. Shapiro-Wilk normality test, independent sample t-test, and chi-square test were used for statistical analysis, and P < .05 was considered significant. Results: The prevalence of MRC was 119 (5.6%) cases. The average diameter of the ostium in cases with and without MRC was 0.49 ± 0.41 mm and 0.99 ± 0.76 mm, respectively, which showed a significant inverse relationship(P < .001). A significant relationship was found between the septum deviation, the ostium height, the concha bullosa, and the accessory ostium with the presence of MRC (P < .001). Conclusions: Sinonasal anatomical variations such as ostium diameter, ostium height, septal deviation, the presence of accessory ostium, and concha bullosa can cause MRC development, and considering that surgery may be necessary in some cases; this could be of great importance to clinicians and surgeons for treatment and prevention of development or recurrence of these pseudocysts in patients.


Introduction and immunopathogenesis of acquired immune deficiency syndrome.
India has a large number of patients with acquired immune deficiency syndrome (AIDS), the third largest population of this group in the world. This disease was first described in patients with Pneumocystis pneumonia in 1981. Ocular lesions can occur at any stage of the disease but are more commonly seen at the late stages. Human immunodeficiency virus (HIV), the causative agent of AIDS is a retrovirus with RNA genome and a unique 'Reverse transcriptase enzyme' and is of two types, HIV-1 and 2. Most human diseases are caused by HIV-1. The HIV-1 subtypes prevalent in India are A, B and C. They act predominantly by reducing the CD4+ cells and thus the patient becomes susceptible to opportunistic infections. High viral titers in the peripheral blood during primary infection lead to decrease in the number of CD4+ T lymphocytes. Onset of HIV-1-specific cellular immune response with synthesis of HIV-1 specific antibodies leads to the decline of plasma viral load and chronification of HIV-1 infection. However, the asymptomatic stage of infection may lead to persistent viral replication and a rapid turnover of plasma virions which is the clinical latency. During this period, there is further decrease in the CD4+ counts which makes the patient's immune system incapable of controlling opportunistic pathogens and thus life-threatening AIDS-defining diseases emerge. Advent of highly active antiretroviral treatment (HAART) has revolutionized the management of AIDS though there is associated increased development of immune recovery uveitis in a few of these patients.


Sexual behaviors: study in the youth.
To characterize sexual behaviors in a sample of adolescents and youth. An analytical descriptive study using a questionnaire about sexual behaviors, adapted from the World Health Organization. It was distributed to students from a Portuguese city aged 14-24 years, during two months. Two age groups were defined: G1 - students aged 14-19 years; G2 - aged 20-24 years. The sample included 2,369 students, 61% females and 70% in G1. The mean age of first sexual intercourse was 16.4±1.8 years; 93% used some contraceptive method in the first sexual intercourse. Out of those who did not use contraception in the first sexual intercourse, 83% were in G1 (p<0.001). Emergency contraception was used at least once by 54% (63% in G2, p<0.001). Among those who had unprotected sexual intercourses, 9% were under the influence of alcohol, 53.6% were female and 53.4% were in G2 (p<0.001). Homosexual contacts occurred in 21% of cases; in that, 62% in G1 and 84% among females (p<0.001). The use of contraceptionin the first sexual intercourse was common in our sample. However, the number of adolescents not using any contraceptive method in subsequent sexual intercourses, and the high percentage of them who consider it unnecessary, are a concern. Unprotected sexual intercourses, as well as unplanned intercourses and under influence of alcohol or drugs, especially in the youngest, urge the need for intervention regarding sexual education.


Characterization of Aeromonas trota strains that cross-react with Vibrio cholerae O139 Bengal.
It has previously been shown that Vibrio cholerae O139 Bengal shares antigens with V. cholerae serogroups O22 and O155. We detected six surface water isolates of Aeromonas trota that agglutinated in polyclonal antisera to V. cholerae O139 and V. cholerae O22 but not in antiserum to V. cholerae O155. On the basis of agglutinin-absorption studies, the antigenic relationship between the cross-reacting bacteria were found to be in an a,b-a,c fashion, where a is the common antigenic epitope and b and c are unique epitopes. The antigen sharing between A. trota strains and V. cholerae O139 was confirmed in immunoblot studies. However, A. trota strains did not react with two monoclonal antibodies specific for V. cholerae O139 and, consequently, tested negative in the Bengal SMART rapid diagnostic test for V. cholerae O139 which uses one of the monoclonal antibodies. A polyclonal antiserum to a cross-reacting A. trota strain cross-protected infant mice against cholera on challenge with virulent V. cholerae O139. All A. trota strains were cytotoxic for HeLa cells, positive for adherence to HEp-2 cells, and weakly invasive for HEp-2 cells; one strain was heat-stable toxin positive in the suckling mouse assay; however, all strains were negative for cholera toxin-like enterotoxin. Studies on bacteria that share somatic antigen with V. cholerae O139 may shed further light on the genesis of V. cholerae O139.


Stability of complex food webs: resilience, resistance and the average interaction strength.
In the face of stochastic climatic perturbations, the overall stability of an ecosystem will be determined by the balance between its resilience and its resistance, but their relative importance is still unknown. Using aquatic food web models we study ecosystem stability as a function of food web complexity. We measured three dynamical stability properties: resilience, resistance, and variability. Specifically, we evaluate how a decrease in the strength of predator-prey interactions with food web complexity, reflecting a decrease in predation efficiency with the number of prey per predator, affects the overall stability of the ecosystem. We find that in mass conservative ecosystems, a lower interaction strength slows down the mass cycling rate in the system and this increases its resistance to perturbations of the growth rate of primary producers. Furthermore, we show that the overall stability of the food webs is mostly given by their resistance, and not by their resilience. Resilience and resistance display opposite trends, although they are shown not to be simply opposite concepts but rather independent properties. The ecological implication is that weaker predator-prey interactions in closed ecosystems can stabilize food web dynamics by increasing its resistance to climatic perturbations.


Immune responses in experimental allergic neuritis.
The antibody and cell mediated immune responses were investigated in inbred Lewis rats with experimental allergic neuritis (EAN) induced by either P2, a protein purified from the bovine cauda equina nerve roots, or whole bovine nerve root myelin. In the P2 immunised animals both antibodies to P2 detected by radioimmunoassay and cell-mediated immunity to P2 assayed by skin testing appeared before the onset of EAN and persisted during and after the disease. In the myelin immunised animals the antibody titres were lower and somewhat delayed and the skin tests became negative at the height of the disease. Complement-fixing antibodies to galactocerebroside, which have been implicated in the production of demyelination under some circumstances, could not be detected in the serum after immunisation with either P2 or myelin. EAN was transferred passively with lymph node cells from rats immunised with either P2 or myelin although anti-P2 antibodies could not be detected in the serum of recipients with EAN. The results favour a cell-mediated immune response to P2 as the most important pathogenetic mechanism in EAN induced wtih whole myelin in the rat.


Surface EMG based hand gesture identification using semi blind ICA: validation of ICA matrix analysis.
Surface electromyogram (sEMG) has numerous applications. It has been widely used in various biosignal and neuro rehabilitation applications. There is an urgent need for establishing a simple yet robust system that can be used to identify subtle complex hand actions and gestures for control of prosthesis and other computer assisted devices. Earlier work to identify the hand actions and gestures based on sEMG suffers from limitation that these are suitable for gross actions where there is only one prime-mover muscle involved and not suitable for small subtle and complex muscle contraction. This paper presents the hand gesture identification using sEMG decomposed using semi-blind independent component analysis combined with neural network based classifier. The aim was to provide reliable and natural control for rehabilitation and human computer interaction applications. We have proposed a model based approach where the hand muscle anatomy is known. The system was tested on 5 subjects and with experiments repeated on different days. The system was compared with raw sEMG as used by other researchers. The system is able to classify the different hand actions 100%. In comparison, the classification of the traditional ICA and raw sEMG for the same experiments and similar features was a poor 65% and 60% respectively. This research demonstrates that sEMG can be decomposed to the individual muscle activities using semi-blind ICA. The muscle activity after decomposition can be used to accurately identify small and subtle hand actions and gestures. Finally the ICA source separation was validated with mixing matrix analysis.


The significance of heavy pornography involvement for romantic partners: research and clinical implications.
This article presents a paradigm case portrait of female romantic partners of heavy pornography users. Based on a sample of 100 personal letters, this portrait focuses on their often traumatic discovery of the pornography usage and the significance they attach to this usage for (a) their relationships, (b) their own worth and desirability, and (c) the character of their partners. Finally, we provide a number of therapeutic recommendations for helping these women to think and act more effectively in their very difficult circumstances.


Assembling novel heterotrimetallic Cu/Co/Ni and Cu/Co/Cd cores supported by diethanolamine ligand in one-pot reactions of zerovalent copper with metal salts.
The three novel heterotrimetallic complexes [Ni(H2L)2][CoCu(L)2(H2L)(NCS)]2(NCS)2 (1), [Ni(H2L)2][CuCo(L)2(H2L)(NCS)]2Br2.2H2O (2), and [CuCoCd(H2L)2(L)2(NCS)Br2].CH3OH (3) have been prepared using zerovalent copper; cobalt thiocyanate; nickel thiocyanate (1), nickel bromide (2), or cadmium bromide (3); and methanol solutions of diethanolamine in air. The most prominent feature of the structures of 1 and 2 is the formation of the "pentanuclear"aggregate [[Ni(H2L)2][CoCu(L)2(H2L)(NCS)]2]2+ made up of two neutral [CoCu(L)2(H2L)(NCS)] units and the previously unknown cation [Ni(H2L)2]2+ "glued together" by strong complementary hydrogen bonds. With Cd2+ instead of Ni2+, a different structure is obtained: the [CoCu(L)2(H2L)(NCS)] unit is now linked to the Cd center through coordination of the oxygens of L groups on the Co atom to form the discrete heterotrimetallic molecular species 3. Cryomagnetic measurements of the compounds show that, in all cases, the magnetic behavior is paramagnetic; the polycrystalline EPR spectra contain signals due to monomeric copper species only. At the same time, the EPR spectra of frozen DMF and methanol solutions of 1-3 reveal the presence of triplet-state species that can be generated only by a coupling of the Cu2+ centers within a dimer. The species responsible for the appearance of transitions within the triplet state are thought to be Cu(II) dimeric centers formed by aggregation of two [CuCo(H2L)(L)2] fragments of 1-3 present in solution. The residual monomeric spectra in the g approximately 2 region are indicative of the existence of an equilibrium in solution between the dimeric and monomeric Cu(II) centers in aggregated and free [CuCo(H2L)(L)2] fragments, respectively, with varying degrees of stability. The fragmentation process of 1-3 in solution was screened by electrospray ionization mass spectrometry.


Efficacy of chlortetracycline against Mycoplasma synoviae isolated in two periods.
Isolates obtained in 1954-55 were generally more pathogenic for the synovial membranes than those obtained in 1969-73. All isolates were capable of producing synovitis when inoculated into the foot pad. Chlortetracycline was effective in controlling signs of infectious synovitis at the 100-g/ton concentration. The 50-g concentration prevented mortality and reduced morbidity. All concentrations of chlortetracycline used (50, 100, or 200 g/ton of feed) reduced immune response, positive agglutination tests, and isolation of MS below that of inoculated untreated birds. Chlortetracycline at all concentrations prevented the spread of MS in contact controls. Chlortetracycline was more effective against the 1954-55 isolates than the 1969-73 isolates when measured by gross lesions, development of agglutinins, and isolation of mycoplasma. No difference in efficacy was found in mortality, weight gain, and feed efficiency.


Interaction between bone and glucose metabolism [Review].
Accumulating evidence has shown that bone and glucose metabolism are closely associated with each other. Since the risk of osteoporotic fractures is increased in patients with diabetes mellitus (DM), osteoporosis is recently recognized as one of diabetic complications, called DM-induced bone fragility. Previous studies showed that collagen cross-links of advanced glycation end products (AGEs) and dysfunctions of osteoblast and osteocyte are involved in DM-induced bone fragility. Circulating levels of AGEs and homocysteine are increased in patients with DM, and they directly impair the functions of osteoblast and osteocyte, resulting in decreased bone formation and bone remodeling. On the other hand, bone is recently recognized as an endocrine organ. Previous studies based on in vitro and animal studies showed that osteocalcin, which is specifically expressed in osteoblasts and secreted into the circulation, may regulate glucose homeostasis. Although several clinical studies reported the relationship between osteocalcin and glucose metabolism, further large-scale and intervention studies are necessary to confirm the beneficial effects of osteocalcin on glucose metabolism in human. It has been shown that adenosine monophosphate-activated protein kinase (AMPK), an intracellular energy sensor, is involved in bone metabolism. Adiponectin and metformin stimulate osteocalcin expression and the differentiation of osteoblasts via AMPK activation. Also, AMPK activation protects against oxidative stress-induced apoptosis of osteocytes. These findings suggest that AMPK in osteoblasts and osteocytes may be a therapeutic target for DM-induced bone fragility.


Rates of genomic divergence in humans, chimpanzees and their lice.
The rate of DNA mutation and divergence is highly variable across the tree of life. However, the reasons underlying this variation are not well understood. Comparing the rates of genetic changes between hosts and parasite lineages that diverged at the same time is one way to begin to understand differences in genetic mutation and substitution rates. Such studies have indicated that the rate of genetic divergence in parasites is often faster than that of their hosts when comparing single genes. However, the variation in this relative rate of molecular evolution across different genes in the genome is unknown. We compared the rate of DNA sequence divergence between humans, chimpanzees and their ectoparasitic lice for 1534 protein-coding genes across their genomes. The rate of DNA substitution in these orthologous genes was on average 14 times faster for lice than for humans and chimpanzees. In addition, these rates were positively correlated across genes. Because this correlation only occurred for substitutions that changed the amino acid, this pattern is probably produced by similar functional constraints across the same genes in humans, chimpanzees and their ectoparasites.


Effect of dysphasia and dysphagia on inpatient mortality and hospital length of stay: a database study.
To examine the effect of dysphasia and dysphagia on stroke outcome. Retrospective database study. Norfolk, United Kingdom. Two thousand nine hundred eighty-three men and women with stroke admitted to the hospital between 1997 and 2001. Inpatient mortality and likelihood of longer length of hospital stay, defined as longer than median length of stay (LOS). Dysphagia was defined as difficulty swallowing any liquid (including saliva) or solid material. Dysphasia was defined as speech disorders in which there was impairment of the power of expression by speech, writing, or signs or impairment of the power of comprehension of spoken or written language. An experienced team assessed dysphagia and dysphasia using explicit criteria. Two thousand nine hundred eighty-three patients (1,330 (44.6%) male), median age 78 (range 17-105), were included, of whom 77.7% had ischemic, 10.5% had hemorrhagic, and 11.8% had undetermined stroke types. Dysphasia was present in 41.2% (1,230) and dysphagia in 50.5% (1,506), and 27.7% (827) had both conditions. Having either or both conditions was associated with greater mortality and longer LOS (P<.001 for all). Using multiple logistic regression models controlling for age, sex, premorbid Rankin score, previous disabling stroke, and stroke type, corresponding odds ratios for death and longer LOS were 2.2 (95% confidence interval (CI)=1.8-2.7) and 1.4 (95% CI=1.2-1.6) for dysphasia; 12.5 (95% CI=8.9-17.3) and 3.9 (95% CI=3.3-4.6) for dysphagia, 5.5 (95% CI=3.7-8.2), 1.9 (95% CI=1.6-2.3) for either, and 13.8 (95% CI=9.4-20.4) and 3.7 (95% CI=3.1-4.6) if they had both, versus having no dysphasia, no dysphagia, or none of these conditions, respectively. Patients with dysphagia have worse outcome in terms of inpatient mortality and length of hospital stay than those with dysphasia. When both conditions are present, the presence of dysphagia appears to determine the likelihood of poor outcome. Whether this effect is related just to stroke severity or results from problems related directly to dysphagia is unclear.


Calcineurin-mediated YB-1 dephosphorylation regulates CCL5 expression during monocyte differentiation.
Y-box (YB) protein-1 serves as a master regulator in gene transcription and mRNA translation. YB-1 itself is regulated at various levels, e.g. through post-translational modifications. In our previous work, we identified RANTES/CCL5 as a transcriptional target of YB-1. We previously demonstrated that YB-1 protein is transiently up-regulated during monocyte/macrophage differentiation evidenced in monocytic cells (THP-1 cells) that were differentiated using phorbol myristate acetate (PMA). Here we provide evidence that YB-1 phosphorylation, specifically at its serine residue 102 (Ser-102), increases early on in THP-1 cells following PMA treatment as well as in differentiated primary human monocytes. This process is mediated through the Akt signaling pathway. Ser-102-phosphorylated YB-1 displays stronger binding affinity and trans-activating capacity at the CCL5 gene promoter. Notably, Ser-102-phosphorylated YB-1 disappears at later stages of the monocyte/macrophage differentiation process. We demonstrate that serine-threonine phosphatase calcineurin (CN) dephosphorylates YB-1 preventing it from binding to and trans-activating the CCL5 promoter. Co-immunoprecipitation assays prove a direct YB-1/CN interaction. Furthermore, analyses in kidney tissues from mice that were treated with the CN inhibitor cyclosporine A revealed an in vivo effect of CN on the YB-1 phosphorylation status. We conclude that YB-1 phosphorylation at Ser-102 is an important prerequisite for CCL5 promoter activation during macrophage differentiation. Our findings point to a critical role of YB-1 in the resolution of inflammatory processes which may largely be due to CN-mediated dephosphorylation.


Do Inattention/Hyperactivity and Motor Timing Predict Children's Virtual Road-Crossing Performance?
The goal of this investigation was to examine how individual variation in inattention and hyperactivity is related to motor timing difficulties and whether children's performance on simple laboratory timing tasks is related to their performance on a virtual road-crossing task using a head-mounted virtual reality display system. Participants were a community sample of 92 9- to 11-year-old children. Parents completed questionnaires assessing their child's inattention and hyperactivity. Children completed two simple motor timing tasks (duration discrimination and synchronization-continuation) and crossed roads with continuous traffic in a head-mounted VR system. Higher parent-reported inattention and hyperactivity predicted poorer performance in the duration discrimination and synchronization-continuation tasks, but not the virtual pedestrian road-crossing task. Children with higher tap onset asynchrony in the synchronization-continuation task had poorer timing of entry into the gap in the virtual pedestrian road-crossing task. The findings provide further evidence that timing deficits are associated with individual differences in inattention and hyperactivity and that timing difficulties may be a risk factor for functional difficulties in everyday life.


When is the absence of evidence, evidence of absence? Use of equivalence-based analyses in genetic epidemiology and a conclusion for the KIF1B rs10492972*C allelic association in multiple sclerosis.
Statistical equivalence methods have been in development since the late 1980s in order to provide an appropriate statistical methodology to address nondifferences in biological experiments. This is analogous to genetic association studies in which a polymorphism "is not associated" with a trait. We applied the equivalence method to genetic data to confirm that an association between the KIF1B (kinesin family member1B) rs10492972 allele and multiple sclerosis (MS), reported in Nature Genetics in 2008, is present neither in eight data sets of cases and controls nor in three independent data sets of the International Multiple Sclerosis Genetic Consortium. When the data sets are considered together, a nonsuperiority test excludes the rs10492972*C allele as a major "risk" allele for MS with a high degree of confidence (P = 1.18 × 10(-4) ). We propose that equivalence methods are more appropriate for stating that a polymorphism does not contribute to disease susceptibility. If an equivalence test applied to genetic data sets fails to reveal an association based on standard methods, it demonstrates that there is no genetic association-i.e., the absence of evidence is evidence of absence. When reporting genetic association based on a cohort of a limited size, caution is needed regardless of how attractive the underlying biological rationale is. The data gathered for KIF1B in MS also underscore the need for very large sample sizes with the appropriate equivalence statistical methods in order to exclude reported false-positive results.


An allosteric propofol-binding site in kinesin disrupts kinesin-mediated processive movement on microtubules.
Microtubule-based molecular motors mediate transport of intracellular cargo to subdomains in neurons. Previous evidence has suggested that the anesthetic propofol decreases the average run-length potential of the major anterograde transporters kinesin-1 and kinesin-2 without altering their velocity. This effect on kinesin has not been observed with other inhibitors, stimulating considerable interest in the underlying mechanism. Here, we used a photoactive derivative of propofol, meta-azipropofol (AziPm), to search for potential propofol-binding sites in kinesin. Single-molecule motility assays confirmed that AziPm and propofol similarly inhibit kinesin-1 and kinesin-2. We then applied AziPm in semiquantitative radiolabeling and MS microsequencing assays to identify propofol-binding sites within microtubule-kinesin complexes. The radiolabeling experiments suggested preferential AziPm binding to the ATP-bound microtubule-kinesin complex. The photolabeled residues were contained within the kinesin motor domain rather than at the motor domain-β-tubulin interface. No residues within the P-loop of kinesin were photolabeled, indicating an inhibitory mechanism that does not directly affect ATPase activity and has an effect on run length without changing velocity. Our results also indicated that when the kinesin motor interacts with the microtubule during its processive run, a site forms in kinesin to which propofol can then bind and allosterically disrupt the kinesin-microtubule interaction, resulting in kinesin detachment and run termination. The discovery of the propofol-binding allosteric site in kinesin may improve our understanding of the strict coordination of the motor heads during the processive run. We hypothesize that propofol's potent effect on intracellular transport contributes to various components of its anesthetic action.


[Primary hemangiopericytoma of the lung (author's transl)].
Primary hemangiopericytoma of the lung is exceedingly rare. The following characteristics were found in a survey of the 34 cases published so far in the world literature and in one case of our own, a 29 year old man with this mesenchymal tumor. It does not show specific clinical signs. In radiographs an isolated round unidentifiable focus is seen. The differential diagnosis has to rely on the histology. About one half of these tumors are discovered by accident. It appears that it occurs at a somewhat younger age in men than in women. Both sexes are equally represented. The treatments of choice are either lobectomy or pneumonectomy. Patients with small tumors without clinical signs appear to have a better prognosis. When recurrence or metastases develop they will be noticed within a few months. Intensive follow-up of patients operated on is essential, since histology cannot provide safe criteria on which one could decide whether the tumor was benign or malignant.


Ambiguity aversion in schizophrenia: An fMRI study of decision-making under risk and ambiguity.
When making decisions in everyday life, we often have to choose between uncertain outcomes. Economic studies have demonstrated that healthy people tend to prefer options with known probabilities (risk) than those with unknown probabilities (ambiguity), which is referred to as "ambiguity aversion." However, it remains unclear how patients with schizophrenia behave under ambiguity, despite growing evidence of their altered decision-making under uncertainty. In this study, combining economic tools and functional magnetic resonance imaging (fMRI), we assessed the attitudes toward risk/ambiguity and investigated the neural correlates during decision-making under risk/ambiguity in schizophrenia. Although no significant difference in attitudes under risk was observed, patients with schizophrenia chose ambiguity significantly more often than the healthy controls. Attitudes under risk and ambiguity did not correlate across patients with schizophrenia. Furthermore, unlike in the healthy controls, activation of the left lateral orbitofrontal cortex was not increased during decision-making under ambiguity compared to under risk in schizophrenia. These results suggest that ambiguity aversion, a well-established subjective bias, is attenuated in patients with schizophrenia, highlighting the need to distinguish between risk and ambiguity when assessing decision-making under these situations. Our findings, comprising important clinical implications, contribute to improved understanding of the mechanisms underlying altered decision-making in patients with schizophrenia.


Hydrogen Bonding in Bis(6-amino-1,3-dimethyluracil-5-yl)-methane Derivatives: Dynamic NMR and DFT Evaluation.
Three bis(6-amino-1,3-dimethyluracil-5-yl)-methane derivatives were studied experimentally by variable-temperature (1)H NMR in polar aprotic solutions (CD2Cl2, C5D5N, C2D2Cl4) and computationally by DFT. The unusual for diarylmethanes coplanar conformation of dimethyluracil rings of each molecule is held by a pair of unequal intramolecular N-H···O hydrogen bonds. We show the presence of two dynamic processes involving breakage/formation of these bonds. First, it is two independent NH2 group rotations, each coupled to nitrogen inversion. Second, it is uracil ring rotations (ring flips). The thermodynamic parameters (ΔH(‡), ΔS(‡), and ΔG(‡)) of both processes were estimated by the full line shape analysis of NMR signals and also by DFT calculations. We demonstrate that, though the ring flips exchange pairs of NH protons, the two processes are not coupled: during the ring flip NH2 groups do not rotate, and during the NH2 rotation the rings do not necessarily rotate. Unlike in many other diarylmethanes, the ring flips in the studied compounds are happening stepwise; i.e., the configuration when both rings are "in flight" at the same time is energetically unfavorable (small degree of "cog wheel effect"). The signs of the ΔS(‡) values indicate that the molecular flexibility increases during the NH2 rotations, but decreases during the ring flips.


'It's not the easy part': the experience of significant others of women with early stage breast cancer, at treatment completion.
Partners of women with breast cancer are intimately affected by their disease. This study describes the lived experience of the significant others of women with early stage breast cancer at the point of their partners' completion of adjuvant therapies. Significant others describe their need to adapt to the fear of losing their partner, the impact on their own mortality and their new role of caregiver for which they were unprepared. The greatest divergence between patient and partner was at the point of treatment completion. Whereas the women were continuing to experience difficulties at this time, their significant others were focused on 'getting back to normal.' There is a need to increase our understanding of the psychosocial needs of primary carers in order to better support them, as integral members of the care team.


Canakinumab treatment in renal transplant recipients with familial Mediterranean fever.
Colchicine is the first-line treatment for familial Mediterranean fever (FMF), preventing both inflammatory attacks as well as the development of amyloidosis in the majority of the patients. However approximately 5-10% of patients are colchicine resistant/intolerant. Side effects of colchicine are more prominent in renal transplant recipients due to interaction with immunosuppressive drugs. Anti-interleukin (IL)-1 drugs (anakinra, canakinumab and rilonacept) have emerged as the most promising drugs in the treatment of colchicine-resistant and/or intolerant FMF. There are no existing reports in the literature on canakinumab use in renal transplant recipients with FMF. We report here the efficacy and safety of canakinumab in three renal transplant recipients who achieved a complete clinical response with elimination of attacks and normalization of serum C-reactive protein (CRP) levels without significant side effects. This highlights the advantage of use of this drug in this setting, which has a better tolerability compared to anakinra.


[Diagnostic criteria of multiple myeloma].
Multiple myeloma is a disease showing heterogeneous symptoms and varieties of laboratory findings. Although there have been many efforts trying to diagnose this disease in a simple way, no simple criteria was available until International Myeloma Working Group (IMWG) criteria has proposed. In this review, detailed IMWG criteria for diagnosis of multiple myeloma are described.


Social health insurance and drug spending among cancer inpatients in China.
A social health insurance (SHI) program has been established in China to ensure that people can obtain health care economically and equitably. Our analysis indicates that in 2005-06, 66.5 percent of Chinese citizens were non-SHI inpatients. We also found that drug spending for SHI inpatients was significantly higher than that for non-SHI inpatients. After adjusting for other variables, we found that the SHI coverage was also associated positively with higher drug costs. We present evidence to show that drug spending differences are attributable at least in part to differences in insurance courage.


Semi-nested, multiplex polymerase chain reaction for detection of human malaria parasites and evidence of Plasmodium vivax infection in Equatorial Guinea.
A semi-nested, multiplex polymerase chain reaction (PCR) based on the amplification of the sequences of the 18S small subunit ribosomal RNA (ssrRNA) gene was tested in a field trial in Equatorial Guinea (a hyperendemic focus of malaria in west central Africa). The method uses a primary PCR amplification reaction with a universal reverse primer and two forward primers specific for the genus Plasmodium and to mammals (the mammalian-specific primer was included as a positive control to distinguish uninfected cases from inhibition of the PCR). The second amplification is carried out with the same Plasmodium genus-specific forward primer and four specific reverse primers for each human Plasmodium species. The PCR amplified products are differentiated by fragment size after electrophoresis on a 2% agarose gel. Four villages from three regions of the island of Bioko (Equatorial Guinea) and two suspected Plasmodium vivax-P. ovale infections from the hospital of Malabo were tested by microscopy and PCR. The PCR method showed greater sensitivity and specificity than microscopic examination and confirmed the existence of a focus of P. vivax infections in Equatorial Guinea suspected by microscopic examination. It also provided evidence of several mixed infections, mainly P. falciparum and P. malariae, the two predominant species causing malaria in Equatorial Guinea.


Client Desires and the Price of Seduction: Exploring the Relationship Between Independent Escorts' Marketing and Rates.
This article explores Web site content and differences in advertised rates among a sample of 839 independent female online escorts operating their own Web sites in major metropolitan areas in the United States. Statistical analyses of escorts' rates indicate pricing variation across cities in which escorts advertise; the number of cities and Websites in which they advertise; whether they travel to areas beyond their primary locality to meet clients; their age and stated racial/ethnic/sexual identity; the Internet platforms on which they advertise; and how they present themselves and their services on their Web pages. These relationships between business strategies of independent escorts and their published rates shed light on client preferences and market demand. Our findings provide important new insights into independent online escorts' business strategies and financial tactics and identify factors impacting perceived market value for escort services. This research supports emerging literature indicating that clients of independent online escorts will pay more for particular provider characteristics, dispositions, and services, and they most highly value erotic services that are seductive and mirror the qualities of nonremunerative sexual exchange, often described as the "girlfriend experience" (GFE).


The role of size-specific predation in the evolution and diversification of prey life histories.
Some of the best empirical examples of life-history evolution involve responses to predation. Nevertheless, most life-history theory dealing with responses to predation has not been formulated within an explicit dynamic food-web context. In particular, most previous theory does not explicitly consider the coupled population dynamics of the focal species and its predators and resources. Here we present a model of life-history evolution that explores the evolutionary consequences of size-specific predation on small individuals when there is a trade-off between growth and reproduction. The model explicitly describes the population dynamics of a predator, the prey of interest, and its resource. The selective forces that cause life-history evolution in the prey species emerge from the ecological interactions embodied by this model and can involve important elements of frequency dependence. Our results demonstrate that the strength of the coupling between predator and prey in the community determines many aspects of life-history evolution. If the coupling is weak (as is implicitly assumed in many previous models), differences in resource productivity have no effect on the nature of life-history evolution. A single life-history strategy is favored that minimizes the equilibrium resource density (if possible). If the coupling is strong, then higher resource productivities select for faster growth into the predation size refuge. Moreover, under strong coupling it is also possible for natural selection to favor an evolutionary diversification of life histories, possibly resulting in two coexisting species with divergent life-history strategies.


Enhanced calorigenesis in brown adipose tissue in physically trained rats.
The calorigenesis occurring in brown adipose tissues (BAT) in response to infused norepinephrine [NE: 4 micrograms/(kg . min)] was estimated from the arteriovenous O2 difference across the interscapular brown adipose tissue and the rate of blood flow to BAT in physically trained (TR) and control (CT) rats. TR rats were trained by 2-hr daily swimming in agitated water at 36 degrees C for 18 weeks. The colonic temperature was maintained at approximately 37.5 degrees C throughout the training period. With NE infusion, the O2 content of arterial blood was unchanged, but that from Sulzer's vein significantly decreased from 12.5 to 2.5 vol% in TR and from 15.7 to 4.3 vol% in CT rats. The increase in O2 consumption in BAT with NE was estimated as 1.60 ml/min in TR and 0.83 ml/min in CT rats. The increase in the whole body O2 consumption with NE was 3.19 ml/min in TR and 2.29 ml/min in CT rats. The contribution of calorigenesis in BAT to the whole body calorigenic response to NE was estimated at 50% in TR and 36% in CT rats. These results directly demonstrated that physical training per se causes an enhancement of the calorigenic response of brown adipose tissues to norepinephrine in rats.


Fatal intracranial hemorrhage as the initial presentation of acute lymphocytic leukemia: a case report.
Hemorrhagic complications of acute leukemia are well described and are a common cause of mortality in these patients. However, to our knowledge, fatal intracerebral hemorrhage (ICH) as an initial presentation of acute lymphocytic leukemia (ALL) has only been reported once. We report a case of previously undiagnosed ALL presenting with ICH. Our patient is a 17-year old male who was found unresponsive several hours after complaining of headache. Initial emergency room evaluation found the patient to have anisocoria with a fixed and dilated right pupil and demonstrated evidence of decorticate posturing. Imaging revealed a large right-sided intraparenchymal hemorrhage, intraventricular hemorrhage, midline shift, and uncal herniation. Laboratory evaluation showed marked leukocytosis with blastic predominance and evidence of disseminated intravascular coagulopathy. Emergent surgical intervention was performed. However, despite evacuation of the hematoma, the patient eventually progressed to clinical brain death. Usually, ICH is seen in ALL patients after the diagnosis has been made. We report a unique case of fatal intracranial hemorrhage as the initial presentation of ALL and discuss the possible management dilemmas to treat such entities. ALL should be kept in the broad differential diagnosis of spontaneous ICH, especially in a young patient with evidence of severe coagulopathy.


Effects of gamma-irradiation on trehalose-hydroxyethylcellulose microspheres loaded with vancomycin.
Ionizing radiation can be used as a drug sterilization technique, provided that the drug itself is not modified and that no toxic products are produced; moreover, if the irradiated product is a drug delivery system, the drug release characteristics must not be significantly altered by radiation. The aim of this work was to study the effects of sterilization by ionizing radiation on hydroxyethylcellulose/trehalose spherical micromatrices, containing the antibiotic vancomycin. Our experimental results showed that gamma-rays did not alter the chromophore groups of vancomycin (UV measurements), and did not modify the kinetic behavior of drug release from microspheres. Moreover, no significant changes in the shape and in the size distribution of microspheres were found after irradiation. The electron spin resonance (ESR) spectroscopy was proven to be a valid identification method of the executed radiation treatment, even after 5 years. The experimental results showed that the therapeutic application of the pharmacological system investigated was not compromised by irradiation, and that ESR spectroscopy can be used to distinguish irradiated from non-irradiated products.


Oral Targeted Delivery by Nanoparticles Enhances Efficacy of an Hsp90 Inhibitor by Reducing Systemic Exposure in Murine Models of Colitis and Colitis-Associated Cancer.
Heat shock protein 90 [Hsp90]-targeted therapy has been proposed as a promising strategy for the treatment of ulcerative colitis [UC] and colitis-associated cancer [CAC]. Systemic administration of the Hsp90 inhibitor, 17-AAG, was found to be profoundly protective in preclinical mouse models of inflammatory bowel disease [IBD]. However, the therapeutic potential of 17-AAG is limited by potential side effects associated with its systemic exposure and the modest bioavailability afforded by its oral administration. To address these issues, we used a versatile single-step surface-functionalizing technique to prepare a 17-AAG oral delivery system using PLGA/PLA-PEG-FA nanoparticles [NP-PEG-FA/17-AAG]. NP-PEG-FA could be efficiently taken up by mouse Colon-26 cells and activated Raw 264.7 cells in vitro and by inflamed mouse colitis tissues in vivo. The therapeutic efficacy of orally administrated NP-PEG-FA/17-AAG was evaluated in in vivo models using dextran sulphate sodium [DSS]-induced UC and azoxymethane [AOM]/DSS-induced CAC, and the results indicated that NP-PEG-FA/17-AAG significantly alleviated the symptoms of UC and CAC. More importantly, our inflamed colitis-targeted 17-AAG nano-formulation reduced systemic exposure and provided a degree of therapeutic response similar to that obtained by systemic administration [intraperitoneal] of 17-AAG, but at a ten-fold lower dose. We describe a convenient, orally administrated 17-AAG delivery system that exhibits enhanced efficacy in UC and CAC therapy while reducing systemic exposure. This system may represent a promising therapeutic approach for treating UC and CAC.


Experimental Infection of Domestic Pigs with African Swine Fever Virus Isolated in 2019 in Mongolia.
African swine fever (ASF) is an infectious viral disease caused by African swine fever virus (ASFV), that causes high mortality in domestic swine and wild boar (Sus scrofa). Currently, outbreaks are mitigated through strict quarantine measures and the culling of affected herds, resulting in massive economic losses to the global pork industry. In 2019, an ASFV outbreak was reported in Mongolia, describing a rapidly progressing clinical disease and gross lesions consistent with the acute form of ASF; the virus was identified as a genotype II virus. Due to the limited information on clinical disease and viral dynamics within hosts available from field observations of the Mongolian isolates, we conducted the present study to further evaluate the progression of clinical disease, virulence, and pathology of an ASFV Mongolia/2019 field isolate (ASFV-MNG19), by experimental infection of domestic pigs. Intramuscular inoculation of domestic pigs with ASFV-MNG19 resulted in clinical signs and viremia at 3 days post challenge (DPC). Clinical disease rapidly progressed, resulting in the humane euthanasia of all pigs by 7 DPC. ASFV-MNG19 infected pigs had viremic titers of 108 TCID50/mL by 5 DPC and shed virus in oral secretions late in disease, as determined from oropharyngeal swabs. Whole-genome sequencing confirmed that the ASFV-MNG19 strain used in this study was a genotype II strain highly similar to other regional strains. In conclusion, we demonstrate that ASFV-MNG19 is a virulent genotype II ASFV strain that causes acute ASF in domestic swine.


A radiomics based method for prediction of prostate cancer Gleason score using enlarged region of interest.
Prostate cancer (PCa) is one of the most common cancers in men worldwide, and its timely diagnosis and treatment are becoming increasingly important. MRI is in increasing use to diagnose cancer and to distinguish between non-clinically significant and clinically significant PCa, leading to more precise diagnosis and treatment. The purpose of this study is to present a radiomics-based method for determining the Gleason score (GS) for PCa using tumour heterogeneity on multiparametric MRI (mp-MRI). Twenty-six patients with biopsy-proven PCa were included in this study. The quantitative T2 values, apparent diffusion coefficient (ADC) and signal enhancement rates (α) were calculated using multi-echo T2 images, diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE-MRI), for the annotated region of interests (ROI). After texture feature analysis, ROI range expansion and feature filtering was performed. Then obtained data were put into support vector machine (SVM), K-Nearest Neighbor (KNN) and other classifiers for binary classification. The highest classification accuracy was 73.96% for distinguishing between clinically significant (Gleason 3 + 4 and above) and non-significant cancers (Gleason 3 + 3) and 83.72% for distinguishing between Gleason 3 + 4 from Gleason 4 + 3 and above, which was achieved using initial ROIs drawn by the radiologists. The accuracy improved when using expanded ROIs to 80.67% using SVM and 88.42% using Bayesian classification for distinguishing between clinically significant and non-significant cancers and Gleason 3 + 4 from Gleason 4 + 3 and above, respectively. Our results indicate the research significance and value of this study for determining the GS for prostate cancer using the expansion of the ROI region.


The synergistic regulation of sewage sludge biodrying and greenhouse gas reduction by additives.
As a dewatering method of high moisture solid waste sludge, biodrying still faces environmental problems such as material loss and greenhouse gas emission in the process of treatment. In this study, biochar and magnesium chloride were used to explore the synergistic effect of enhancing sludge biodrying and reducing greenhouse gas emissions. The highest temperature of biodrying was raised to 68.2 °C within 3 days, extending the longest high-temperature period to 5 days, which reduced the water content to 28.8 % in the single addition of biochar treatment. The complex addition increased the NH4+-N content of materials by 57.49 % and decreased the NO3--N content of materials by 40.62 %. The use of additives significantly reduced the emissions of CO2, CH4, and N2O compared to the no-addition treatment. The increase in dominant Actinomycetes and Chloroflexibacter was the main reason for the reduction in gas emissions.


Psychedelics as a Treatment for Alzheimer's Disease Dementia.
Currently, there are no disease-modifying treatments for Alzheimer's disease (AD) or any other dementia subtype. The renaissance in psychedelic research in recent years, in particular studies involving psilocybin and lysergic acid diethylamide (LSD), coupled with anecdotal reports of cognitive benefits from micro-dosing, suggests that they may have a therapeutic role in a range of psychiatric and neurological conditions due to their potential to stimulate neurogenesis, provoke neuroplastic changes and reduce neuroinflammation. This inevitably makes them interesting candidates for therapeutics in dementia. This mini-review will look at the basic science and current clinical evidence for the role of psychedelics in treating dementia, especially early AD, with a particular focus on micro-dosing of the classical psychedelics LSD and psilocybin.


Shock-induced stress induces loss of microvascular endothelial Tie2 in the kidney which is not associated with reduced glomerular barrier function.
Both hemorrhagic shock and endotoxemia induce a pronounced vascular activation in the kidney which coincides with albuminuria and glomerular barrier dysfunction. We hypothesized that changes in Tie2, a vascular restricted receptor tyrosine kinase shown to control microvascular integrity and endothelial inflammation, underlie this loss of glomerular barrier function. In healthy murine and human kidney, Tie2 is heterogeneously expressed in all microvascular beds, although to different extents. In mice subjected to hemorrhagic and septic shock, Tie2 mRNA and protein were rapidly, and temporarily, lost from the renal microvasculature, and normalized within 24 h after initiation of the shock insult. The loss of Tie2 protein could not be attributed to shedding as both in mice and healthy volunteers subjected to endotoxemia, sTie2 levels in the systemic circulation did not change. In an attempt to identify the molecular control of Tie2, we activated glomerular endothelial cell cultures and human kidney slices in vitro with LPS or TNF-alpha, but did not observe a change in Tie2 mRNA levels. In parallel to the loss of Tie2 in vivo, an overt influx of neutrophils in the glomerular compartment, which coincided with proteinuria, was seen. As neutrophil-endothelial cell interactions may play a role in endothelial adaptation to shock, and these effects cannot be mimicked in vitro, we depleted neutrophils before shock induction. While this neutrophil depletion abolished proteinuria, Tie2 was not rescued, implying that Tie2 may not be a major factor controlling maintenance of the glomerular filtration barrier in this model.


Endoscopic Lateral Osteotomy in Rhinoplasty.
The purpose of this study was to investigate the advantages of endoscopic lateral osteotomy, to evaluate the effects of the periosteal elevation on ecchymosis and to search the reasons for the ecchymosis and the intranasal mucosal tears. On a randomly chosen side a subperiosteal tunnel was elevated, on the other side a subperiosteal tunnel was not elevated. Bilateral lateral osteotomies were performed. Internal nasal packing was not used. The post-operative care was similar for all patients. The patients were evaluated on the third post-operative day. The intranasal mucosal tears, the lateral osteotomy cut on the periosteal elevation side were examined using endoscopes. The degree of ecchymosis was determined by 2 other surgeons, who were unaware of the elevated side, using the grading system adapted from Hoffman et al. The intranasal mucosal injury was seen in 16 of non-elevated side whereas it was 14 on the periosteal elevated side. Endoscopy showed the perforating arteries and elevation of the periosteum caused rupture and oozing from these arteries which might be a cause for ecchymosis. Ecchymosis was more severe on the side with subperiosteal tunnel in 6 patients; whereas only in 2 patients it was more severe on the side with no subperiosteal tunnel elevation while in 12 patients the degree of ecchymosis was the same on both sides. Endoscopy gives a great opportunity to visualize the lateral osteotomy site. Besides the lateral osteotomy cut, the arteries and the intranasal mucosal injury can be visualized. Periost elevation increases the severity of ecchymosis due to the rupture of the perforating arteries, not due to the trauma of the angular artery. Intramucosal tears do not increase the severity of the ecchymosis.


The interplay of obesity, microbiome dynamics, and innovative anti-obesity strategies in the context of endometrial cancer progression and therapeutic approaches.
Endometrial cancer (EC) is the most common gynecologic malignancy in the United States, and its incidence and mortality are rising. Obesity is more tightly associated with EC than any other cancer. Thus, the rising prevalence of obesity and associated risk factors, including diabetes and insulin resistance, cause alarm. The metabolic derangements of obesity increase the bioavailability of estrogen, hyperinsulinemia, and inflammation in a complex system with direct and indirect effects on the endometrium, resulting in proliferation and, ultimately, carcinogenesis. In addition, the gut dysbiosis associated with obesity helps contribute to these metabolic derangements, priming an individual for developing EC and perhaps affecting treatment efficacy. More recent studies are beginning to explore obesity's effect on the local tumor microbiome of EC and its role in carcinogenesis. Significant and sustained weight loss in individuals can considerably decrease the risk of EC, likely through reversal of the altered metabolism and dysbiosis resulting obesity. Bariatric surgery is the gold standard for successful weight loss and highlights how reversing of the systemic effects of obesity can reduce EC risk. However, the current limited availability, knowledge, and imposed stigma of bariatric surgery prohibits population-level reductions in EC. Therefore, effective and maintainable non-surgical dietary and pharmacologic interventions are needed.


Oestradiol-17beta inhibits tamoxifen-induced LHRH self-priming blocking hormone-dependent and ligand-independent activation of the gonadotrope progesterone receptor in the rat.
In the rat, administration of tamoxifen (TX) in the absence of oestrogen (E) induces LHRH self-priming, the progesterone receptor (PR)-dependent property of LHRH that increases gonadotrope responsiveness to itself. The oestrogen-dependent PR can be phosphorylated/activated by progesterone (P4) and, in the absence of the cognate ligand, by intracellular LHRH signals, particularly cAMP/protein kinase A. We have recently found that oestradiol-17beta (E2), acting on a putative membrane estrogen receptor-alpha in the gonadotrope, inhibits this agonist action of TX. This study investigated the mechanism by which E2 inhibits TX-elicited LHRH self-priming using both incubated pituitaries from TX-treated ovariectomized (OVX) rats and anterior pituitary cells from OVX rats cultured with TX. It was found that (1) in addition to the inhibitory effect on TX-elicited LHRH self-priming, E2 blocked P4 and adenylyl cyclase activator forskolin augmentation of LHRH-stimulated LH secretion, and (2) E2 did not affect the increasing action of TX on gonadotrope PR expression or pituitary cAMP content. Furthermore, inhibition of protein phosphatases with okadaic acid suppressed E2 inhibition of TX-elicited LHRH-induced LH secretion, while stimulation of protein phosphatases with ceramide blocked TX-induced LHRH self-priming. Together, these results indicated that membrane ER-mediated E2 inhibition of the TX-stimulated LHRH self-priming pathway involves a blockade of gonadotrope PR phosphorylation/activation, but not a deficient response of PR to phosphorylases. Results also suggested that the inhibitory effect of E2 on TX-induced LHRH self-priming is exerted through modulation of cellular protein phosphatase activity in the gonadotrope.


Long-term adefovir dipivoxil monotherapy for up to 5 years in lamivudine-resistant chronic hepatitis B.
Large clinical studies assessing long-term adefovir dipivoxil salvage monotherapy in patients with lamivudine-resistant chronic hepatitis B (CHB) are lacking, particularly in patients positive for hepatitis B e antigen (HBeAg). We assessed the efficacy and resistance profile of adefovir dipivoxil monotherapy for up to 5 years in a large cohort of Korean patients with lamivudine-resistant CHB. A total of 320 patients (81.3% HBeAg-positive; 100% genotype C) with confirmed genotypic lamivudine-resistant CHB were switched to adefovir dipivoxil 10 mg once daily. Liver function tests and HBV DNA were monitored every 3 months. Genotypic resistance to adefovir dipivoxil was performed in patients with detectable HBV DNA. The overall cumulative virological response rate at 5 years of adefovir dipivoxil therapy was 48.8%. The virological response rate was significantly higher in HBeAg-negative patients (62.0% versus 45.9%; P=0.010). Most cases of virological response (131/134, 97.8%) occurred within the first 36 months of therapy. The 5-year cumulative probability of genotypic resistance and virological breakthrough was 65.6% and 61.8%, respectively. Predictive factors for a virological response included baseline HBeAg seronegativity, HBV DNA< or =8 log(10) copies/ml and achievement of an on-treatment initial virological response. Adefovir dipivoxil salvage monotherapy for lamivudine-resistant CHB resulted in a modest cumulative virological response rate at 5 years, which was associated with progressive antiviral resistance. Consequently, adefovir monotherapy is not preferable as a first-line strategy for lamivudine resistance where combination lamivudine plus adefovir dipivoxil therapy is available.


Genetic variation of human neutrophil Fcγ receptors and SIRPα in antibody-dependent cellular cytotoxicity towards cancer cells.
The efficacy of cancer therapeutic antibodies varies considerably among patients. Anti-cancer antibodies act through different mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) triggered via Fcγ receptors (FcγR). This phagocyte ADCC can be promoted by interference with CD47-SIRPα interactions, but the magnitude of this enhancement also varies among individuals. Both FcγR and SIRPα display considerable genetic variation, and we investigated whether this explains some of the variability in ADCC. Because of linkage disequilibrium between FcγR variants the interpretation of previous reports suggesting a potential link between FcγR polymorphisms and ADCC has been troublesome. We performed an integrated genetic analysis that enables stratification. ADCC by activated human neutrophils towards Trastuzumab-coated breast cancer cells was predominantly dependent on FcγRIIa. Neutrophils from individuals with the FcγRIIa-131H polymorphic variant displayed significantly higher killing capacity relative to those with FcγRIIa-131R. Furthermore, ADCC was consistently enhanced by targeting CD47-SIRPα interactions, and there were no significant functional differences between the two most prevalent SIRPα polymorphic variants. Thus, neutrophil ADCC capacity is directly related to the FcγRIIa polymorphism, and targeting CD47-SIRPα interactions enhances ADCC independently of FcγR and SIRPα genotype, thereby further suggesting that CD47-SIRPα interference might be a generic strategy for potentiating the efficacy of antibody therapy in cancer.


Inpatient Hospitalization Costs: A Comparative Study of Micronesians, Native Hawaiians, Japanese, and Whites in Hawai'i.
Considerable interest exists in health care costs for the growing Micronesian population in the United States (US) due to their significant health care needs, poor average socioeconomic status, and unique immigration status, which impacts their access to public health care coverage. Using Hawai'i statewide impatient data from 2010 to 2012 for Micronesians, whites, Japanese, and Native Hawaiians (N = 162,152 hospitalizations), we compared inpatient hospital costs across racial/ethnic groups using multivariable models including age, gender, payer, residence location, and severity of illness (SOI). We also examined total inpatient hospital costs of Micronesians generally and for Medicaid specifically. Costs were estimated using standard cost-to-charge metrics overall and within nine major disease categories determined by All Patient Refined Diagnosis Related Groups. Micronesians had higher unadjusted hospitalization costs overall and specifically within several disease categories (including infectious and heart diseases). Higher SOI in Micronesians explained some, but not all, of these higher costs. The total cost of the 3486 Micronesian hospitalizations in the three-year study period was $58.1 million and 75% was covered by Medicaid; 23% of Native Hawaiian, 3% of Japanese, and 15% of white hospitalizations costs were covered by Medicaid. These findings may be of particular interests to hospitals, Medicaid programs, and policy makers.


Daily interactions with aging parents and adult children: Associations with negative affect and diurnal cortisol.
Midlife adults report greater investment in their children than in their parents, and these ties have important implications for well-being. To date, little research has addressed daily experiences in these ties. The present study examines daily experiences (negative and positive) with aging parents and adult children and their associations with daily negative affect and diurnal cortisol rhythms. Participants were middle-aged adults (N = 156; 56% women) from Wave 2 of the Family Exchanges Study, conducted in 2013, who completed a 7-day daily diary study, which included assessments of daily negative and positive social encounters and negative affect, and 4 days of saliva collection, which was collected 3 times a day (upon waking, 30 min after waking, and at bedtime) and assayed for cortisol. Multilevel models revealed that individuals were more likely to have contact with adult children than with parents but more likely to have negative experiences (negative interactions, avoidance, negative thoughts) with parents than with adult children. Nevertheless, contact and negative experiences with adult children were more consistently associated with negative affect and daily cortisol patterns than were interactions with parents. Findings are consistent with the intergenerational stake hypothesis, which suggests that individuals have a greater stake in their children than in their parents. Indeed, negative experiences with adult children may be more salient because tensions with adult children occur less frequently than do tensions with parents. (PsycINFO Database Record


[Immunohistochemical study of mucins in chronic pancreatitis and ductal adenocarcinoma of the pancreas].
Based on the results of an immunohistological study of MUC1, MUC2, MUC4, MUC5AC, and MUC6 in pancreatic tissue from 50 patients with chronic pancreatitis (CP) and 50 patients with ductal adenocarcinoma (DAC), the authors showed altered mucin immunological responsiveness in severe forms of CP, in the foci of PanIN and DAC. They also revealed that determination of mucin expression may be used in the differential diagnosis of pancreatic cancer.


Somatic reversion of pathogenic DOCK8 variants alters lymphocyte differentiation and function to effectively cure DOCK8 deficiency.
Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.