Childhood trauma and risk for chronic fatigue syndrome: association with neuroendocrine dysfunction.
Childhood trauma appears to be a potent risk factor for chronic fatigue syndrome (CFS). Evidence from developmental neuroscience suggests that early experience programs the development of regulatory systems that are implicated in the pathophysiology of CFS, including the hypothalamic-pituitary-adrenal axis. However, the contribution of childhood trauma to neuroendocrine dysfunction in CFS remains obscure. To replicate findings on the relationship between childhood trauma and risk for CFS and to evaluate the association between childhood trauma and neuroendocrine dysfunction in CFS. A case-control study of 113 persons with CFS and 124 well control subjects identified from a general population sample of 19 381 adult residents of Georgia. Self-reported childhood trauma (sexual, physical, and emotional abuse; emotional and physical neglect), psychopathology (depression, anxiety, and posttraumatic stress disorder), and salivary cortisol response to awakening. Individuals with CFS reported significantly higher levels of childhood trauma and psychopathological symptoms than control subjects. Exposure to childhood trauma was associated with a 6-fold increased risk of CFS. Sexual abuse, emotional abuse, and emotional neglect were most effective in discriminating CFS cases from controls. There was a graded relationship between exposure level and CFS risk. The risk of CFS conveyed by childhood trauma further increased with the presence of posttraumatic stress disorder symptoms. Only individuals with CFS and with childhood trauma exposure, but not individuals with CFS without exposure, exhibited decreased salivary cortisol concentrations after awakening compared with control subjects. Our results confirm childhood trauma as an important risk factor of CFS. In addition, neuroendocrine dysfunction, a hallmark feature of CFS, appears to be associated with childhood trauma. This possibly reflects a biological correlate of vulnerability due to early developmental insults. Our findings are critical to inform pathophysiological research and to devise targets for the prevention of CFS.


The jaw functional limitation scale: development, reliability, and validity of 8-item and 20-item versions.
To develop the Jaw Functional Limitation Scale (JFLS), comprising 3 constructs and a global scale, based on a preliminary instrument, and to investigate content validity of the overall functional limitation construct, reliability, and generalizability. A temporomandibular disorders (TMD) patient group, compared to other diagnostic groups, was hypothesized to report further limitation in each of the 3 new proposed constructs. One hundred thirty-two consecutive patients from 5 diagnostic groups (TMD, primary Sjogren syndrome, burning mouth syndrome, skeletal malocclusion, and healthy controls) participated in a known-groups validity design. Fifty-two jaw functional limitation items were identified by an expert panel for content validity. Rasch methodology was used for item reduction and assessment of model fit. The instrument was retested 1 to 2 weeks later. Three constructs (mastication, vertical jaw mobility, and emotional and verbal expression) comprising a total of 20 items were identified along with a global scale (the JFLS-20), and each exhibited excellent psychometric properties with respect to modeled variance, item fit, reliability, and internal consistency. The psychometric properties of each construct remained satisfactory when analyzed separately among the 5 diagnostic groups. Temporal stability was satisfactory. A shorter 8-item form (JFLS-8) also proved useful for assessing global functional jaw limitation. The JFLS-20 is an organ-specific instrument comprising 3 constructs for assessing functional status of the masticatory system; the 3 scales exhibit properties that are ideal for both research and patient evaluation in patient groups with a range of functional limitations of the jaw. The JFLS-8 emerged as a short form for measuring global functional limitation of the jaw.


Microsurgical denervation of rat spermatic cord: safety and efficacy data.
To describe a microsurgical technique for denervation of the spermatic cord and use of multiphoton microscopy (MPM) laser to identify and ablate residual nerves after microsurgical denervation. To evaluate structural and functional changes in the rat testis and vas deferens after denervation. Nine Sprague-Dawley rats were divided into three experimental groups: sham, microsurgical denervation of the spermatic cord (MDSC), and MDSC immediately followed by laser ablation with MPM. At 2 months after surgery, we assessed testicular volume, functional circulation of the testicular artery with Doppler, patency of the vas deferens, and histology of the testis and vas deferens. There was a significant decrease in the median number of nerves remaining around the vas deferens with MDSC alone (3.5 nerves) or MDSC with MPM (1.5 nerves) compared with sham rats (15.5 nerves) (P = 0.003). Although, MDSC with MPM resulted in the fewest remaining nerves, this result was similar to MDSC alone (P = 0.29). No deleterious effects on spermatogenesis or vas patency were seen in the experimental groups when compared with the sham rats. A microsurgical approach can be used to effectively and safely denervate the rat spermatic cord with minimal changes to structure and function of the testis and vas deferens. MPM can be used as an adjunct to identify and ablate residual nerves after MDSC.


Resurrecting Darwin's Niata - anatomical, biomechanical, genetic, and morphometric studies of morphological novelty in cattle.
The Niata was a cattle variety from South America that figured prominently in writings on evolution by Charles Darwin. Its shortened head and other aspects of its unusual morphology have been subject of unsettled discussions since Darwin's time. Here, we examine the anatomy, cranial shape, skull biomechanics, and population genetics of the Niata. Our results show that the Niata was a viable variety of cattle and exhibited anatomical differences to known chondrodysplastic forms. In cranial shape and genetic analysis, the Niata occupies an isolated position clearly separated from other cattle. Computational biomechanical model comparison reveals that the shorter face of the Niata resulted in a restricted distribution and lower magnitude of stress during biting. Morphological and genetic data illustrate the acquisition of novelty in the domestication process and confirm the distinct nature of the Niata cattle, validating Darwin's view that it was a true breed.


Acyl-homoserine lactone recognition and response hindering the quorum-sensing regulator EsaR.
During quorum sensing in the plant pathogen Pantoea stewartii subsp. stewartii, EsaI, an acyl-homoserine lactone (AHL) synthase, and the transcription factor EsaR coordinately control capsular polysaccharide production. The capsule is expressed only at high cell density when AHL levels are high, leading to inactivation of EsaR. In lieu of detailed structural information, the precise mechanism whereby EsaR recognizes AHL and is hindered by it, in a response opposite to that of most other LuxR homologues, remains unresolved. Hence, a random mutagenesis genetic approach was designed to isolate EsaR* variants that are immune to the effects of AHL. Error-prone PCR was used to generate the desired mutants, which were subsequently screened for their ability to repress transcription in the presence of AHL. Following sequencing, site-directed mutagenesis was used to generate all possible mutations of interest as single, rather than multiple amino acid substitutions. Eight individual amino acids playing a critical role in the AHL-insensitive phenotype have been identified. The ability of EsaR* variants to bind AHL and the effect of individual substitutions on the overall conformation of the protein were examined through in vitro assays. Six EsaR* variants had a decreased ability to bind AHL. Fluorescence anisotropy was used to examine the relative DNA binding affinity of the final two EsaR* variants, which retained some AHL binding capability but remained unresponsive to it, perhaps due to an inability of the N-terminal domain to transduce information to the C-terminal domain.


Geographic Factors and Human Papillomavirus (HPV) Vaccination Initiation among Adolescent Girls in the United States.
This study is among the first to explore geographic factors that may be associated with human papillomavirus (HPV) vaccine uptake in the United States. Data from the 2011 and 2012 National Immunization Survey-Teen for 20,565 female adolescents aged 13 to 17 years were analyzed to examine associations of HPV vaccine initiation (receipt of at least one dose) with ZIP code-level geographic factors. Logistic regression including individual and geographic factors was used to estimate the odds of HPV vaccine initiation. Approximately 53% of girls initiated the HPV vaccine in both years. Girls in high poverty communities had higher HPV vaccine initiation compared with those in low poverty communities [61.1% vs. 52.4%; adjusted OR (AOR), 1.18; 95% confidence intervals (CI), 1.04-1.33]. Initiation was higher among girls in communities where the majority of the population was Hispanic (69.0% vs. 49.9%; AOR, 1.64; 95% CI, 1.43-1.87) or non-Hispanic mixed race (60.4% vs. 49.9%; AOR, 1.30; 95% CI, 1.17-1.44) compared with majority non-Hispanic white communities. Interactions between individual-level race/ethnicity and community racial-ethnic composition indicated significantly higher odds of initiation among Hispanic girls living in Hispanic communities compared with Hispanic girls living in predominantly non-Hispanic White (NHW) (AOR, 2.23; 95% CI, 1.87-2.65) or non-Hispanic Black (NHB) (AOR, 1.90; 95% CI, 1.20-3.04) communities, respectively. Initiation rates of HPV vaccination among teen girls were highest in the poorest communities and among Hispanics living in communities where the racial-ethnic composition was predominantly Hispanic or mixed race. Given low HPV vaccination rates in the United States, these results provide important evidence to inform public health interventions to increase HPV vaccination.


Dynamic blastomere behaviour reflects human embryo ploidy by the four-cell stage.
Previous studies have demonstrated that aneuploidy in human embryos is surprisingly frequent with 50-80% of cleavage-stage human embryos carrying an abnormal chromosome number. Here we combine non-invasive time-lapse imaging with karyotypic reconstruction of all blastomeres in four-cell human embryos to address the hypothesis that blastomere behaviour may reflect ploidy during the first two cleavage divisions. We demonstrate that precise cell cycle parameter timing is observed in all euploid embryos to the four-cell stage, whereas only 30% of aneuploid embryos exhibit parameter values within normal timing windows. Further, we observe that the generation of human embryonic aneuploidy is complex with contribution from chromosome-containing fragments/micronuclei that frequently emerge and may persist or become reabsorbed during interphase. These findings suggest that cell cycle and fragmentation parameters of individual blastomeres are diagnostic of ploidy, amenable to automated tracking algorithms, and likely of clinical relevance in reducing transfer of embryos prone to miscarriage.


[Pathology of intracerebral hemorrhage in ruptured aneurysms of the posterior communicating artery at its origin from the internal carotid artery].
There were thirty-two autopsied cases of ruptured aneurysms at the junction of the internal carotid and posterior communicating arteries in the file of Montefiore Medical Center from 1948 to 1983 (Table 1). The age range of the patients was 11-83 years. Seven were men and twenty-five were women. Fifteen had previous surgery; either clipping of the neck of the aneurysm or ligation of the common carotid artery. Analysis of the hemorrhage associated with the ruptured aneurysms revealed two distinct patterns. One is subarachnoid hemorrhage alone (18 cases) and another is subarachnoid hemorrhage and intraventricular rupture through the temporal horn (14 cases). These aneurysms did not produce a large intracerebral hematoma in the temporal lobe because they ruptured into the temporal horn. Among the post-operative cases (14 cases), only 3 cases had intraventricular hemorrhage. Correlation of these autopsy findings with CT Scans revealed that an intraventricular hematoma in the temporal horn could be interpreted as a large intracerebral hematoma in the temporal lobe.


Enhancing transparency in reporting the synthesis of qualitative research: ENTREQ.
The syntheses of multiple qualitative studies can pull together data across different contexts, generate new theoretical or conceptual models, identify research gaps, and provide evidence for the development, implementation and evaluation of health interventions. This study aims to develop a framework for reporting the synthesis of qualitative health research. We conducted a comprehensive search for guidance and reviews relevant to the synthesis of qualitative research, methodology papers, and published syntheses of qualitative health research in MEDLINE, Embase, CINAHL and relevant organisational websites to May 2011. Initial items were generated inductively from guides to synthesizing qualitative health research. The preliminary checklist was piloted against forty published syntheses of qualitative research, purposively selected to capture a range of year of publication, methods and methodologies, and health topics. We removed items that were duplicated, impractical to assess, and rephrased items for clarity. The Enhancing transparency in reporting the synthesis of qualitative research (ENTREQ) statement consists of 21 items grouped into five main domains: introduction, methods and methodology, literature search and selection, appraisal, and synthesis of findings. The ENTREQ statement can help researchers to report the stages most commonly associated with the synthesis of qualitative health research: searching and selecting qualitative research, quality appraisal, and methods for synthesising qualitative findings. The synthesis of qualitative research is an expanding and evolving methodological area and we would value feedback from all stakeholders for the continued development and extension of the ENTREQ statement.


Glucose transport and glucose transporters in muscle and their metabolic regulation.
Skeletal muscle is the primary tissue responsible for insulin-dependent glucose uptake in vivo; therefore, glucose uptake by this tissue plays an important role in determining glycemia. Glucose uptake in muscle occurs by a system of facilitated diffusion involving at least two distinct glucose transporters, GLUT-1 and GLUT-4. Both bind the fungal metabolite and inhibitor of glucose transport cytochalasin B. In human skeletal muscle, both types of transporters are detected immunologically, and corresponding mRNA transcripts of both transporter forms are detected. In human skeletal muscle cells in culture, in which contamination by other tissues is ruled out, a 50,000-Mr polypeptide is photolabeled with cytochalasin B. In rat skeletal muscle, acute treatment with insulin in vivo increases glucose-transport activity and the number of specific cytochalasin B-binding sites at the plasma membrane. In mildly diabetic (streptozocin-induced) rats, the number of cytochalasin B-binding sites is decreased in total membranes, and preferentially in the plasma membrane. In response to acute insulin treatment, however, there is still recruitment of glucose transporters to the plasma membrane from an intracellular membrane store. Hence, migration of transporters does occur in this form of diabetes. In L6 muscle cells in culture, acute treatment (1 h) with insulin causes recruitment of glucose transporters to the plasma membrane, and prolonged exposure to insulin or to glucose-deprived medium causes increased expression of GLUT-1 mRNA and GLUT-1 protein. Prolonged exposure (24 h) to high glucose in the medium causes a decrease in the number of glucose transporters in the plasma membrane. Hence, in those cells the expression of the GLUT-1 glucose transporter is modulated by insulin.


Long-term outcomes after repair of symptomatic abdominal aortic aneurysms.
Previous studies have reported increased perioperative mortality of nonruptured symptomatic abdominal aortic aneurysms (Sx-AAA) compared with asymptomatic elective AAA (E-AAA) repairs, but no long-term-outcomes have been reported. We sought to compare long-term outcomes of Sx-AAA and E-AAA after repair at a single academic institution. Patients receiving AAA repair for Sx-AAA and E-AAA from 1995 through 2015 were included. Ruptured AAA and suprarenal or thoracoabdominal AAA were excluded. Demographics, comorbidities, and operative approach were collected. Long-term mortality was the primary outcome, determined by chart review or link to Social Security Death Index. Additionally, long-term mortality and reinterventions were compared after groups were matched with nearest neighbor propensity to reduce bias. AAA repair was performed for 1054 E-AAA (383 open repair [36%], 671 endovascular aneurysm repair [EVAR] [64%]), and 139 symptomatic aneurysms (60 open repair [43%], 79 EVAR [57%]). Age (73 years vs 74 years; P = .13) and aneurysm diameter were similar between Sx-AAA and E-AAA (6.0 cm vs 5.8 cm; P = .5). The proportion of women was higher for Sx-AAA (26% vs 16%; P = .003), as was the proportion of non-Caucasians (40% vs 29%; P = .009). After propensity matching, there were no differences between groups for patient characteristics, AAA diameter, treatment modality, or comorbidities, including hypertension, coronary artery disease, congestive heart failure, diabetes, hyperlipidemia, lung disease, diabetes, renal disease, and smoking history. Women were treated for Sx-AAA at significantly smaller aortic diameters; however, compared with men (5.1 cm vs 6.3 cm; P < .001). Perioperative mortality was 5.0% for Sx-AAA and 2.3% for E-AAA (P = .055). By life-table analysis, Sx-AAA had lower 5-year (62% vs 71%) and 10-year (39% vs 51%) survivals (P = .01) compared with E-AAA for the entire cohort. Similar trends were observed for 5-year and 10-year mortality after propensity matching (63% and 40% vs 71% and 52%; P = .05). When stratified by repair type 5-year and 10-year survivals trended lower after open surgery (68% and 42% Sx-AAA vs 84% and 59% E-AAA; P = .08) but not EVAR (59% and 40% Sx-AAA vs 61% and 49% E-AAA; P = .4). Aneurysm-related reinterventions were similar for Sx-AAA and E-AAA (15% vs 14%; P = .8). Reinterventions were more common after EVAR compared with open repair (22% vs 7%, Sx-AAA P = .015; 20% vs 4% E-AAA; P = .007). Patients with Sx-AAA had lower long-term survival and similar aneurysm-related reinterventions compared with patients with E-AAA undergoing repair. Women also underwent repair for Sx-AAA at a significantly smaller size when compared with men, which emphasizes the role of gender in AAA symptomatology. Differences in long-term survival may be only partially explained by measured patient, aneurysm, and operative factors, and may reflect unmeasured social factors or suggest inherent differences in pathophysiology of Sx-AAAs.


Sustaining containment of COVID-19: global sharing for pandemic response.
The coronavirus disease 2019 (COVID-19) outbreak, caused by SARS-CoV-2, has rapidly escalated into a global pandemic. One of our significant concerns is that we have no data as to whether people, who acquired immunity against this deadly virus and recovered from COVID-19, are protected from further infections with the same virus. Moreover, we have no data as to whether this pandemic will persist in our societies and continue vexing us for long periods of time. Implementing science-based response strategy is essential to sustain containment of COVID-19 globally. Rapidly sharing scientific information means providing real-time research data and relevant findings. As an international academic journal, Global Health & Medicine publishes this special issue entitled "GHM Special Topic: COVID-19". It includes a range of articles describing COVID-19 based on frontline data from Japan, China, the United States, Italy, the United Kingdom, and other countries and areas worldwide. Our hope is that the rapid publication and sharing of information contribute, in whichever possible way, to this global fight against COVID-19.


Mortality experience of Tsimane Amerindians of Bolivia: regional variation and temporal trends.
This paper examines regional and temporal trends in mortality patterns among the Tsimane, a population of small-scale forager-horticulturalists in lowland Bolivia. We compare age-specific mortality in remote forest and riverine regions with that in more acculturated villages and examine mortality changes among all age groups over the past 50 years. Discrete-time logistic regression is used to examine impacts of region, period, sex, and age on mortality hazard. Villages in the remote forest and riverine regions show 2-4 times higher mortality rates from infancy until middle adulthood than in the acculturated region. While there was little change in mortality for most of the life course over the period 1950-1989, overall life expectancy at birth improved by 10 years from 45 to 53 after 1990. In both periods, over half of all deaths were due to infectious disease, especially respiratory and gastrointestinal infections. Accidents and violence accounted for a quarter of all deaths. Unlike typical patterns described by epidemiologic transition theory, we find a much larger period reduction of death rates during middle and late adulthood than during infancy or childhood. In the remote villages, infant death rates changed little, whereas death rates among older adults decreased sharply. We hypothesize that this pattern is due to a combination of differential access to medical interventions, a continued lack of public health infrastructure and Tsimane cultural beliefs concerning sickness and dying.


Cancer and the microbiota.
A host's microbiota may increase, diminish, or have no effect at all on cancer susceptibility. Assigning causal roles in cancer to specific microbes and microbiotas, unraveling host-microbiota interactions with environmental factors in carcinogenesis, and exploiting such knowledge for cancer diagnosis and treatment are areas of intensive interest. This Review considers how microbes and the microbiota may amplify or mitigate carcinogenesis, responsiveness to cancer therapeutics, and cancer-associated complications.


Rhizobium sp. strain NGR234 and R. fredii USDA257 share exceptionally broad, nested host ranges.
Genetically, Rhizobium sp. strain NGR234 and R. fredii USDA257 are closely related. Small differences in their nodulation genes result in NGR234 secreting larger amounts of more diverse lipo-oligosaccharidic Nod factors than USDA257. What effects these differences have on nodulation were analyzed by inoculating 452 species of legumes, representing all three subfamilies of the Leguminosae, as well as the nonlegume Parasponia andersonii, with both strains. The two bacteria nodulated P. andersonii, induced ineffective outgrowths on Delonix regia, and nodulated Chamaecrista fasciculata, a member of the only nodulating genus of the Caesalpinieae tested. Both strains nodulated a range of mimosoid legumes, especially the Australian species of Acacia, and the tribe Ingeae. Highest compatibilities were found with the papilionoid tribes Phaseoleae and Desmodieae. On Vigna spp. (Phaseoleae), both bacteria formed more effective symbioses than rhizobia of the "cowpea" (V. unguiculata) miscellany. USDA257 nodulated an exact subset (79 genera) of the NGR234 hosts (112 genera). If only one of the bacteria formed effective, nitrogen-fixing nodules it was usually NGR234. The only exceptions were with Apios americana, Glycine max, and G. soja. Few correlations can be drawn between Nod-factor substituents and the ability to nodulate specific legumes. Relationships between the ability to nodulate and the origin of the host were not apparent. As both P. andersonii and NGR234 originate from Indonesia/Malaysia/Papua New Guinea, and NGR234's preferred hosts (Desmodiinae/Phaseoleae) are largely Asian, we suggest that broad host range originated in Southeast Asia and spread outward.


Terahertz emission by diffusion of carriers and metal-mask dipole inhibition of radiation.
Terahertz (THz) radiation can be generated by ultrafast photo-excitation of carriers in a semiconductor partly masked by a gold surface. A simulation of the effect taking into account the diffusion of carriers and the electric field shows that the total net current is approximately zero and cannot account for the THz radiation. Finite element modelling and analytic calculations indicate that the THz emission arises because the metal inhibits the radiation from part of the dipole population, thus creating an asymmetry and therefore a net current. Experimental investigations confirm the simulations and show that metal-mask dipole inhibition can be used to create THz emitters.


Effect of Morning Light Glasses and Night Short-Wavelength Filter Glasses on Sleep-Wake Rhythmicity in Medical Inpatients.
Sleep and circadian rhythm disorders are common amongst medical inpatients. They are caused by a mixture of factors, including noise, loss of habitual daily routines, and abnormal exposure to light, which tends to be insufficient in the day and too high at night. The aim of the present study was to test the efficacy of morning light therapy plus night short-wavelength filter glasses on sleep quality/timing, and sleepiness/mood over the daytime hours, in a group of well-characterized medical inpatients. Thirty-three inpatients were enrolled and randomized (2:1) to either treatment (n = 22; 13 males, 48.3 ± 13.3 years) or standard of care (n = 11; 8 males, 56.9 ± 12.9 years). On admission, all underwent a baseline assessment of sleep quality/timing and diurnal preference. During hospitalization they underwent monitoring of sleep quality/timing (sleep diaries and actigraphy), plus hourly assessment of sleepiness/mood during the daytime hours on one, standard day of hospitalization. Patients in the treatment arm were administered bright light through glasses immediately after awakening, and wore short-wavelength filter glasses in the evening hours. Treated and untreated patients were comparable in terms of demographics, disease severity/comorbidity, diurnal preference and pre-admission sleep quality/timing. During hospitalization, sleep diaries documented a trend for a lower number of night awakenings in treated compared to untreated patients (1.6 ± 0.8 vs. 2.4 ± 1.3, p = 0.057). Actigraphy documented significantly earlier day mode in treated compared to untreated patients (06:39 ± 00:35 vs. 07:44 ± 00:40, p = 0.008). Sleepiness during a standard day of hospitalization, recorded between 09:30 and 21:30, showed physiological variation in treated compared to untreated patients, who exhibited a more blunted profile. The level of sleepiness reported by treated patients was lower over the 09:30-14:30 interval, i.e., soon after light administration (interaction effect: F = 2.661; p = 0.026). Mood levels were generally higher in treated patients, with statistically significant differences over the 09:30-14:30 time interval, i.e., soon after light administration (treatment: F = 5.692, p = 0.026). In conclusion, treatment with morning bright light and short-wavelength filter glasses in the evening, which was well tolerated, showed positive results in terms of sleepiness/mood over the morning hours and a trend for decreased night awakenings.


Salinity monitoring in Western Australia using remotely sensed and other spatial data.
The southwest of Western Australia is affected by dryland salinity that results in the loss of previously productive agricultural land, damage to buildings, roads, and other infrastructure, decline in pockets of remnant vegetation and biodiversity, and reduction in water quality. Accurate information on the location and rate of change of the extent of saline land over the region is required by resource managers. For the first time, comprehensive, spatially explicit maps of dryland salinity and its change over approximately 10 yr for the southwest agricultural region of Western Australia have been produced operationally in the 'Land Monitor' project. The methods rely on an integrated analysis of long-term sequences of Landsat TM satellite image data together with variables derived from digital elevation models (DEMs). Understanding of the physical process and surface expression of salinity provided by experts was used to guide the analyses. Ground data-the delineation of salt-affected land by field experts-was collected for training and validation. The results indicate that the land area currently affected by salinity in Western Australia's southwest is about 1 million hectares (in 1996) and the annual rate of increase is about 14,000 ha. This is a lesser extent than many previous estimates and lower rate of change than generally predicted from limited hydrological data. The results are widely distributed and publicly available. The key to providing accurate mapping and monitoring information was the incorporation of time series classification of a sequence of images over several years combined with landform information.


Identifying anomalous nuclear radioactive sources using Poisson kriging and mobile sensor networks.
Nuclear security is a critical concept for public health, counter-terrorism efforts, and national security. Nuclear radioactive materials should be monitored and secured in near real-time to reduce potential danger of malicious usage. However, several challenges have arose to detect the anomalous radioactive source in a large geographical area. Radiation naturally occurs in the environment. Therefore, a non-zero level of radiation will always exist with or without an anomalous radioactive source present. Additionally, radiation data contain high levels of uncertainty, meaning that the measured radiation value is significantly affected by the velocity of the detector and background noise. In this article, we propose an innovative approach to detect anomalous radiation source using mobile sensor networks combined with a Poisson kriging technique. We validate our results using several experiments with simulated radioactive sources. As results, the accuracy of the model is extremely high when the source intensity is high or the anomalous source is close enough to the detector.


The frequency of bacterial contamination and diversity of drug resistance patterns in devices and staff of endoscopy and colonoscopy units.
Background: This study aimed at analyzing microbial contamination in medical equipment, environment, and staff of a gastroenterology unit. Methods: Samples of gastrointestinal imaging devices, the environment, and staff were collected using standard swab-rinse technique and biochemical or molecular characteristics of the isolates, their susceptibility to antibiotics, and similarity of the resistance patterns were investigated. Results: Out of 107 samples, bacterial contamination was detected in the hands of staff (54.1%), imaging devices (56.7%), and in the environment (54.5%). While Pseudomonas spp. were detected only in the imaging devices (13.5%), Bacillus spp. (32.4% and 31.5%), Enterococcus spp. (14.3% and 5.9%), Clostridium difficile (10.8% and 10.5%), and Staphylococcus epidermidis (5.4% and 15.9%) were orderly the most common isolates from samples of the imaging devices and the environment. Nearly, 40% of P. aeruginosa strains were resistant to cefepime, while resistance to cephalosporins and β-lactamase inhibitor was detected in 33% and 75% of S. aureus strains, respectively. Homology of resistance patterns was detected between the imaging devices and hands of the staff. Conclusion: Our results proposed biofilm and spore forming bacteria as main contaminants of imaging devices in this hospital. Homology of the resistance patterns proposed involvement of staff in contamination of the equipment.


Sudden hearing loss as an early detector of multiple sclerosis: a systematic review.
To evaluate whether Sudden Sensorineural Hearing Loss (S-SNHL) may be an early symptom of Multiple Sclerosis (MS). A systematic review was conducted using the following keywords: "Multiple sclerosis, hearing loss, sudden hearing loss, vertigo, tinnitus, magnetic resonance imaging, otoacoustic emission, auditory brainstem responses, white matter lesions, sensorineural hearing loss, symptoms of MS and otolaryngology, nerve disease and MS". Only the articles that included results of at least one auditory test and MRI were considered. We evaluated the prevalence of SNHL in patients with MS, the presence of different forms of SNHL (S-SNHL and Progressive SNHL (P-SNHL)) and their correlation with the stage of MS, the results of electrophysiological tests, and the location (if any) of MS lesions as detected by white matter hyperintensities in the MRI. We reviewed a total of 47 articles, which included 29 case reports, 6 prospective studies, 6 cohort studies, 4 case-control studies, and 2 retrospective studies. 25% of patients suffered from SNHL. S-SNHL typically occurred in the early stage of the disease (92% of patients) and was the only presenting symptom in 43% of female subjects. Instead, P-SNHL occurred in the late stage of MS (88% of patients). Auditory Brainstem Responses (ABR) were abnormal in all MS patients with S-SNHL. When S-SNHL appeared during the early stage of the disease, MS lesions were found in the brain in 60% of patients and in the Internal Auditory Canal in 40% of patients. ABR remained abnormal after recovery. S-SNHL can be an early manifestation of MS and should always be considered in the differential diagnosis of this condition, especially in women. The pathophysiology can be explained by the involvement of microglia attacking the central and/or peripheral auditory pathways as indicated by WMHs.


First Report of Iris yellow spot virus on Onion in New York.
Iris yellow spot virus (IYSV [family Bunyaviridae, genus Tospovirus]), a potentially devastating disease of onion vectored by onion thrips (Thrips tabaci Lindeman), has been reported from most states in the western United States where significant onion production occurs, with the most recent report from Texas (1). In June 2006, volunteer onion (Allium cepa) plants in Orleans County, New York (Elba muckland) were found to have symptoms indicative of IYSV infection. The scapes (seed stalks) of the volunteer onions found at the edge of a cull pile from a 2005 onion crop exhibited diamond-shaped lesions, each with a distinct green center and a double yellow border. Approximately 25 of 100 plants of red and yellow onion cultivars exhibited characteristic IYSV lesions. The cull pile was composed primarily of locally grown onions, although a few of the bulbs were grown from imported bare-root transplants imported from Arizona. Symptomatic plants tested positive for IYSV using IYSV-specific antiserum from Agdia Inc. (Elkhart, IN) in a double-antibody sandwich-ELISA. The presence of IYSV was verified by reverse transcription (RT)-PCR using primers derived from the small RNA of IYSV (S-RNA). The primers flanked the IYSV nucleocapsid (N) gene (5'-TAA AAC AAA CAT TCA AAC AA-3' and 5'-CTC TTA AAC ACA TTT AAC AAG CAC-3' (3). RT-PCR assays produced a PCR amplicon of expected size (approximately 1.2 kb) and the product was cloned and sequenced. Nucleotide sequence analysis confirmed the identity of the amplicon as that of the IYSV S-RNA. Sequence comparisons showed 95 to 98% identity with known IYSV N gene sequences available in GenBank. The virus is poorly transmitted to onion by mechanical inoculation and we did not have access to a noninfested colony of the onion thrips vector to transfer the virus from these samples to noninfected onions. No asymptomatic plants were tested. Among the onion-growing states in the eastern United States, IYSV has previously only been reported from Georgia (2). To our knowledge, this is the first report of IYSV in New York and the greater northeastern United States. The finding of this disease in New York confirms further spread of the virus within North America and the need for research to develop more effective management options to reduce the impact of IYSV on onion crops. References: (1) M. Miller et al. Plant Dis. 90:1359, 2006. (2) S. W. Mullis et al. Plant Dis. 90:377, 2006. (3) H. R. Pappu et al. Arch. Virol. 151:1015, 2006.


Adjuvant radiotherapy after curative surgery for oral cavity squamous cell carcinoma and treatment effect of timing and duration on outcome-A Taiwan Cancer Registry national database analysis.
Conduct an accurate risk assessment of resected oral cavity squamous cell carcinoma (OSCC) patients by accessing a nationwide systemic investigation is pivotal to improve treatment outcomes. In this article, we tried to determine the impact of different prognostic factors for OSCC patients who received adjuvant radiotherapy (RT) after curative surgery, using Taiwan's national cancer registry database (TCR). A nationwide, large population-based study was conducted using TCR with patients identified from 2007 to 2015. The study variables included age, gender, cancer subsites, stage, histology grade, margin and extra-nodal extension (ENE) status, treatment type, surgery to RT interval (ORI), total RT treatment time (RTT), and RT dose. Univariate and multivariate analysis were performed to identify predictors of the variables associated with overall survival (OS), cause-specific survival (CSS), local-regional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). 8986 OSCC patients treated with surgery and adjuvant RT were analyzed. In multivariate analysis, worse outcomes were associated with males, older age, subsite in the oral tongue, advanced stage, higher histologic grade, involved margin, and positive ENE. ORI only showed an adverse trend in LRFS, when exceeding 7 weeks (P = .06). RTT >8 weeks was a significant poor predictor in OS, CSS and LRFS (P < .001). Extreme RT dose (>70 Gy or ≤50 Gy) also demonstrated an adverse impact on the outcomes. Prolonged RT treatment time and extreme RT doses were identified as significantly poor prognostic predictors in OSCC patients who received adjuvant RT after curative surgery.


Greater stem growth, woody allocation, and aboveground biomass in Paleotropical forests than in Neotropical forests.
Forest dynamics and tree species composition vary substantially between Paleotropical and Neotropical forests, but these broad biogeographic regions are treated uniformly in many land models. To assess whether these regional differences translate into variation in productivity and carbon (C) storage, we compiled a database of climate, tree stem growth, litterfall, aboveground net primary production (ANPP), and aboveground biomass across tropical rainforest sites spanning 33 countries throughout Central and South America, Asia, and Australasia, but excluding Africa due to a paucity of available data. Though the sum of litterfall and stem growth (ANPP) did not differ between regions, both stem growth and the ratio of stem growth to litterfall were higher in Paleotropical forests compared to Neotropical forests across the full observed range of ANPP. Greater C allocation to woody growth likely explains the much larger aboveground biomass estimates in Paleotropical forests (~29%, or ~80 Mg DW/ha, greater than in the Neotropics). Climate was similar in Paleo- and Neotropical forests, thus the observed differences in C likely reflect differences in the evolutionary history of species and forest structure and function between regions. Our analysis suggests that Paleotropical forests, which can be dominated by tall-statured Dipterocarpaceae species, may be disproportionate hotspots for aboveground C storage. Land models typically treat these distinct tropical forests with differential structures as a single functional unit, but our findings suggest that this may overlook critical biogeographic variation in C storage potential among regions.


Fountain streaming contributes to fast tip-growth through regulating the gradients of turgor pressure and concentration in pollen tubes.
Fountain streaming is a typical microfluidic pattern in plant cells, especially for cells with a high aspect ratio such as pollen tubes. Although it has been found that fountain streaming plays crucial roles in the transport of nutrients and metabolites, the positioning of organelles and the mixing of cytoplasms, its implications for the fast tip growth of pollen tubes remain a mystery. To address this, based on the observations of asiatic lily Lilium Casablanca, we developed physical models for reverse fountain streaming in pollen tubes and solved the hydrodynamics and advection-diffusion dynamics of viscous Stokes flow in the shank and apical region of pollen tubes. Theoretical and numerical results demonstrated that the gradients of turgor pressure and concentration of wall materials along the length of pollen tubes provide undamped driving force and high-efficiency materials supply, which are supposed to contribute to the fast tip-growth of pollen tubes. The sample experimental results show that the tip-growth will be abnormal when the gradients of turgor pressure change under osmotic stress induced by different concentrations of PEG-6000 (a dehydrant).


Evidence for gene-smoking interactions for hearing loss and deafness in Japanese American families.
This study investigated the relationship between smoking and hearing loss and deafness (HLD) and whether the relationship is modified by genetic variation. Data for these analyses was from the subset of Japanese American families collected as part of the American Diabetes Association Genetics of Non-insulin Dependent Diabetes Mellitus study. Logistic regression with generalized estimating equations assessed the relationship between HLD and smoking. Nonparametric linkage analysis identified genetic regions harboring HLD susceptibility genes and ordered subset analysis was used to identify regions showing evidence for gene-smoking interactions. Genetic variants within these candidate regions were then each tested for interaction with smoking using logistic regression models. After adjusting for age, sex, diabetes status and smoking duration, for each pack of cigarettes smoked per day, risk of HLD increased 4.58 times (odds ratio (OR) = 4.58; 95% Confidence Interval (CI): (1.40,15.03)), and ever smokers were over 5 times more likely than nonsmokers to report HLD (OR = 5.22; 95% CI: (1.24, 22.03)). Suggestive evidence for linkage for HLD was observed in multiple genomic regions (Chromosomes 5p15, 8p23 and 17q21), and additional suggestive regions were identified when considering interactions with smoking status (Chromosomes 7p21, 11q23, 12q32, 15q26, and 20q13) and packs-per-day (Chromosome 8q21). To our knowledge this was the first report of possible gene-by-smoking interactions in HLD using family data. Additional work, including independent replication, is needed to understand the basis of these findings. HLD are important public health issues and understanding the contributions of genetic and environmental factors may inform public health messages and policies.


Electroencephalogram Theta/Beta Ratio and Spectral Power Correlates of Executive Functions in Children and Adolescents With AD/HD.
The electroencephalogram (EEG) has been widely used in AD/HD research. The current study firstly aimed to replicate a recent trend related to EEG theta/beta ratio (TBR) in children and adolescents. Also, the study aimed to examine the value of resting EEG activity as biomarkers for executive function (EF) in participants with AD/HD. Fifty-three participants with AD/HD and 37 healthy controls were recruited. Resting EEG was recorded with eyes closed. Participants with AD/HD additionally completed EF tasks via the Cambridge Neuropsychological Test Automated Battery. TBR did not differ between groups; however, TBR was positively correlated with inattentive symptoms in AD/HD. Other correlations were found between EEG activity and neuropsychological functions including spatial planning and decision making in the AD/HD group. The results do not support the diagnostic value of TBR. Instead, given the heterogeneous features, the results support the prognostic value of EEG in AD/HD.


AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity.
AMP-activated protein kinase (AMPK) is a metabolic fuel gauge conserved along the evolutionary scale in eukaryotes that senses changes in the intracellular AMP/ATP ratio. Recent evidence indicated an important role for AMPK in the therapeutic benefits of metformin, thiazolidinediones and exercise, which form the cornerstones of the clinical management of type 2 diabetes and associated metabolic disorders. In general, activation of AMPK acts to maintain cellular energy stores, switching on catabolic pathways that produce ATP, mostly by enhancing oxidative metabolism and mitochondrial biogenesis, while switching off anabolic pathways that consume ATP. This regulation can take place acutely, through the regulation of fast post-translational events, but also by transcriptionally reprogramming the cell to meet energetic needs. Here we demonstrate that AMPK controls the expression of genes involved in energy metabolism in mouse skeletal muscle by acting in coordination with another metabolic sensor, the NAD+-dependent type III deacetylase SIRT1. AMPK enhances SIRT1 activity by increasing cellular NAD+ levels, resulting in the deacetylation and modulation of the activity of downstream SIRT1 targets that include the peroxisome proliferator-activated receptor-gamma coactivator 1alpha and the forkhead box O1 (FOXO1) and O3 (FOXO3a) transcription factors. The AMPK-induced SIRT1-mediated deacetylation of these targets explains many of the convergent biological effects of AMPK and SIRT1 on energy metabolism.


Wiskott-Aldrich syndrome protein is needed for vaccinia virus pathogenesis.
Smallpox, caused by variola virus, was a devastating disease in humans, but how the virus evolved a strategy to spread to tissue remains unknown. Through the use of microarrays, we identified the gene encoding the Wiskott-Aldrich syndrome protein (WASP), one of the five known WASP family members, which has been induced in the course of infection of human cells with different strains of vaccinia virus (VV) (S. Guerra, L. A. Lopez-Fernandez, A. Pascual-Montano, M. Munoz, K. Harshman, and M. Esteban, J. Virol. 77:6493-6506, 2003; S. Guerra, L. A. Lopez-Fernandez, R. Conde, A. Pascual-Montano, K. Harshman, and M. Esteban, J. Virol. 78:5820-5834, 2004). In a mouse model, we evaluated the role of WASP in infection with VV, a close relative of variola virus. WASP(-/-) (KO) mice infected intranasally and intraperitoneally with VV showed reduced weight loss and mortality compared to wild-type (WT) mice. WASP expression correlated with VV replication in the ovaries but not in the liver or spleen. WT mouse macrophages express WASP but not N-WASP; after VV infection, WASP levels increase threefold. KO macrophages lack N-WASP expression and, when VV infected, are incapable of inducing actin tails and producing extracellular virus. These functions were rescued in KO macrophages after ectopic WASP expression. Overall, our findings demonstrate that WASP has a role in orthopoxvirus infections. Use of WASP proteins for virus spread via the actin tail provides a selective advantage for VV, and probably variola virus, dissemination to distant tissues.


Mutant KRAS is a druggable target for pancreatic cancer.
Pancreatic ductal adenocarcinoma (PDA) represents an unmet therapeutic challenge. PDA is addicted to the activity of the mutated KRAS oncogene which is considered so far an undruggable therapeutic target. We propose an approach to target KRAS effectively in patients using RNA interference. To meet this challenge, we have developed a local prolonged siRNA delivery system (Local Drug EluteR, LODER) shedding siRNA against the mutated KRAS (siG12D LODER). The siG12D LODER was assessed for its structural, release, and delivery properties in vitro and in vivo. The effect of the siG12D LODER on tumor growth was assessed in s.c. and orthotopic mouse models. KRAS silencing effect was further assessed on the KRAS downstream signaling pathway. The LODER-encapsulated siRNA was stable and active in vivo for 155 d. Treatment of PDA cells with siG12D LODER resulted in a significant decrease in KRAS levels, leading to inhibition of proliferation and epithelial-mesenchymal transition. In vivo, siG12D LODER impeded the growth of human pancreatic tumor cells and prolonged mouse survival. We report a reproducible and safe delivery platform based on a miniature biodegradable polymeric matrix, for the controlled and prolonged delivery of siRNA. This technology provides the following advantages: (i) siRNA is protected from degradation; (ii) the siRNA is slowly released locally within the tumor for prolonged periods; and (iii) the siG12D LODER elicits a therapeutic effect, thereby demonstrating that mutated KRAS is indeed a druggable target.


The clinical benefit of adjunctive dexamethasone in tuberculous meningitis is not associated with measurable attenuation of peripheral or local immune responses.
Outcome from tuberculous meningitis (TBM) is believed to be dependent on the severity of the intracerebral inflammatory response. We have recently shown that dexamethasone improved survival in adults with TBM and postulated that the clinical effect would be associated with a measurable systemic and intracerebral impact on immunological markers of inflammation. Prolonged inflammatory responses were detected in all TBM patients irrespective of treatment assignment (placebo or dexamethasone). The inflammatory response in the cerebrospinal fluid was characterized by a leukocytosis (predominantly CD3(+)CD4(+) T lymphocytes, phenotypically distinct from those in the peripheral blood), elevated concentrations of inflammatory and anti-inflammatory cytokines, chemokines, and evidence of prolonged blood-brain barrier dysfunction. Dexamethasone significantly modulated acute cerebrospinal fluid protein concentrations and marginally reduced IFN-gamma concentrations; other immunological and routine biochemical indices of inflammation were unaffected. Peripheral blood monocyte and T cell responses to Mycobacterium tuberculosis Ags were also unaffected. Dexamethasone does not appear to improve survival from TBM by attenuating immunological mediators of inflammation in the subarachnoid space or by suppressing peripheral T cell responses to mycobacterial Ags. These findings challenge previously held theories of corticosteroid action in this disease. An understanding of how dexamethasone acts in TBM may suggest novel and more effective treatment strategies.


Ginkgo biloba for cerebral insufficiency.
1. By means of a critical review we tried to establish whether there is evidence from controlled trials in humans on the efficacy of Ginkgo biloba extracts in cerebral insufficiency. 2. The methodological quality of 40 trials on Ginkgo and cerebral insufficiency was assessed using a list of predefined criteria of good methodology, and the outcome of the trials was interpreted in relation to their quality. A comparison of the quality was made with trials of co-dergocrine, which is registered for the same indication. 3. There were eight well performed trials out of a total of 40. Shortcomings were limited numbers of patients included, and incomplete description of randomization procedures, patient characteristics, effect measurement and data presentation. In no trial was double-blindness checked. Virtually all trials reported positive results, in most trials the dosage was 120 mg Ginkgo extract a day, given for at least 4-6 weeks. For the best trials, there were no marked differences in the quality of the evidence of the efficacy of Ginkgo in cerebral insufficiency compared with co-dergocrine. The results of the review may be complicated by a combination of publication bias and other biases, because there were no negative results reported in many trials of low methodological quality. 4. Positive results have been reported for Ginkgo biloba extracts in the treatment of cerebral insufficiency. The clinical evidence is similar to that of a registered product which is prescribed for the same indication. However, further studies should be conducted for a more detailed assessment of the efficacy.


Hybrid resection of duodenal tumors.
The aim of this study was to review our experience with the hand-assisted laparoscopic management of duodenal tumors with no or low malignant potential and to compare this approach with published case reports of purely laparoscopic local duodenal resection. Eight cases of hand-assisted laparoscopic local duodenal resection performed from 2000 to 2008 were retrospectively reviewed. Hand-assistance was utilized for complete duodenal mobilization, and local duodenal resection was accomplished extracorporeally through the hand-access incision. Patient and tumor characteristics, operative time, length of stay, and complications were compared with 18 cases of totally laparoscopic local excision of duodenal tumors published since 1997. Patients with ampullary tumors were excluded. Compared with the purely laparoscopic approach, the hand-assisted technique was associated with shorter operative time (179 versus 131 minutes, P=.03) and was more commonly used for lesions located in the third portion of the duodenum (0% versus 37.5%, P=.02). Tumor size (2.9 cm versus 3.2 cm, P=.61) and length of hospital stay (5.9 versus 5.9 days, P=.96) were similar between the two groups. The rate of complications was also comparable (0% versus 12.5%, P=.31); 1 of 8 patients in the hand-assisted group developed an incisional hernia at the hand-access site. Hand-assisted laparoscopic local duodenal resection is a feasible, safe, and effective alternative to the totally laparoscopic approach. In addition to being associated with comparable length of hospital stay, hand-assistance can shorten operative time by facilitating duodenal mobilization as well as extracorporeal duodenal resection and closure.


Intraindividual variation of running economy in highly trained and moderately trained males.
Previous studies of intraindividual variation in running economy have not compared within-subject variability between groups of runners differing in training level, nor have they considered the workload of the submaximal but relative to the lactate breakpoint. Therefore, the purpose of the present study was to assess intraindividual variation in submaximal oxygen consumption (VO2) during steady rate treadmill running below the lactate breakpoint in highly trained (n = 7) and moderately trained (n = 8) male runners. Subjects completed a discontinuous VO2 max protocol with blood sampling to determine the lactate breakpoint. Three 15 minute level treadmill bouts at approximately 88% of the lactate breakpoint were then performed. Time of day, day of the week, diet, and and footwear were controlled within each subject across the three tests. Statistically significant differences were found between groups in VO2 max, relative fat, training mileage, and 10 km race time (p < 0.01), while the lactate breakpoint was similar between groups (integral of 80% of VO2 max). The difference in treadmill speed between highly trained and moderately trained runners for the submaximal bouts was statistically significant (p < 0.01) and correlated with reported training paces (r = 0.82). Although the mean coefficient of variation for steady rate VO2 was smaller for the highly trained group, the difference was not statistically significant (highly trained = 1.77%, moderately trained = 2.00%; p > 0.05). The mean coefficient of variation for all 15 subjects was 1.90%. After accounting for technological error, biological variation was found to comprise approximately 94% of the intraindividual variation in running economy. In comparison to other studies, these results suggest that workloads below the lactate breakpoint may allow more stable measures of running economy to be obtained.


Determination of Zn-citrate in human milk by CIM monolithic chromatography with atomic and mass spectrometry detection.
In human milk zinc (Zn) is bound to proteins and low molecular mass (LMM) ligands. Numerous investigations demonstrated that Zn bioavailability in human milk is for infant much higher than in cow's milk. It was presumed that in the LMM human milk fraction highly bioavailable Zn-citrate prevails. However, literature data are controversial regarding the amount of Zn-citrate in human milk since analytical procedures reported were not quantitative. So, complex investigation was carried out to develop analytical method for quantitative determination of this biologically important molecule. Studies were performed within the pH range 5-7 by the use of synthetic solutions of Zn-citrate prepared in HEPES, MOPS and MES buffers. Zn-citrate was separated on weak anion-exchange convective interaction media (CIM) diethylaminoethyl (DEAE) monolithic chromatographic column using NH(4)NO(3) as an eluent. Separated Zn species were determined by flame atomic absorption spectrometry (FAAS) or inductively coupled plasma mass spectrometry (ICP-MS). Quantitative separation of Zn-citrate complexes ([Zn(Cit)](-) and [Zn(Cit)(2)](4-); column recoveries 94-102%) and good repeatability and reproducibility of results with relative standard deviation (RSD±3.0%) were obtained. In fractions under the chromatographic peaks Zn-binding ligand was identified by electrospray ionization tandem mass spectrometry (ESI-MS-MS). Limits of detection (LOD) for determination of Zn-citrate species by CIM DEAE-FAAS and CIM DEAE-ICP-MS were 0.01 μg Zn mL(-1) and 0.0005 μg Zn mL(-1), respectively. Both techniques were sensitive enough for quantification of Zn-citrate in human milk. Results demonstrated that about 23% of total Zn was present in the LMM milk fraction and that LMM-Zn corresponded to Zn-citrate. The developed speciation method represents a reliable analytical tool for investigation of the percentage and the amount of Zn-citrate in human milk.


On the thermotropic and magnetotropic phase behavior of lipid liquid crystals containing magnetic nanoparticles.
The inclusion of superparamagnetic iron oxide nanoparticles (SPIONs) in lipid mesophases is a promising strategy for drug-delivery applications, combining the innate biocompatibility of lipid architectures with SPIONs' response to external magnetic fields. Moreover, the organization of SPIONs within the lipid scaffold can lead to locally enhanced SPIONs concentration and improved magnetic response, which is key to overcome the current limitations of hyperthermic treatments. Here we present a Small-Angle X-ray Scattering (SAXS) structural investigation of the thermotropic and magnetotropic behavior of glyceryl monooleate (GMO)/water mesophases, loaded with hydrophobic SPIONs. We prove that even very low amounts of SPIONs deeply alter the phase behavior and thermotropic properties of the mesophases, promoting a cubic to hexagonal phase transition, which is similarly induced upon application of an Alternating Magnetic Field (AMF). Moreover, in the hexagonal phase SPIONs spontaneously self-assemble within the lipid scaffold into a linear supraparticle. This phase behavior is interpreted in the framework of the Helfrich's theory, which shows that SPIONs affect the mesophase both from a viscoelastic and from a structural standpoint. Finally, the dispersion of these cubic phases into stable magnetic colloidal particles, which retain their liquid crystalline internal structure, is addressed as a promising route towards magneto-responsive drug-delivery systems (DDS).


Quality improvement study on early recognition and intervention of caregiver burden in a tertiary hospital.
Caregivers play a crucial role in taking over the important task of looking after patients post-hospitalisation. Caregivers who are unfamiliar with patients' post-discharge care often experience caregiver stress, while patients may see deterioration in their condition. As caregivers are our core partners in healthcare, it is therefore necessary for patient navigators to recognise, assess and address caregivers' needs or burden as early as on admission to hospital. Patient navigators are trained registered nurses whose main role is to provide patients and caregivers with personalised guidance through the complex healthcare system. This quality improvement study examined the efficacy of using the Zarit Burden Interview as a tool in helping patient navigators recognise caregiver burden early and the effectiveness of targeted interventions on caregiver burden. Various quality improvement tools were used. Eighty-six patient-caregiver dyads who met the inclusion criteria were enrolled. Informal caregivers were assessed for caregiver burden using the Zarit Burden Interview during hospital admission (T0) and again at 30 days postdischarge (T1), post-intervention. There was significant improvement in the Zarit Burden mean scores from T0 to T1 reported for the 80 dyads who completed the study, even after adjusting for covariates (T0 mean=11.08, SD=7.64; T1 mean=2.48, SD=3.36, positive ranks, p<0.001). Highest burden identified by most caregivers were the personal strain; trying to meet other responsibilities and uncertain about what to do in caring for their loved one. By recognising the different aspects of caregiver burden early, patient navigators were able to focus their interventions. Early recognition of caregiver burden and targeted interventions were found to be effective at reducing caregiver burden in a tertiary hospital.


New androgen receptor genomic targets show an interaction with the ETS1 transcription factor.
The androgen receptor (AR) initiates important developmental and oncogenic transcriptional pathways. The AR is known to bind as a homodimer to 15-base pair bipartite palindromic androgen-response elements; however, few direct AR gene targets are known. To identify AR promoter targets, we used chromatin immunoprecipitation with on-chip detection of genomic fragments. We identified 1,532 potential AR-binding sites, including previously known AR gene targets. Many of the new AR target genes show altered expression in prostate cancer. Analysis of sequences underlying AR-binding sites showed that more than 50% of AR-binding sites did not contain the established 15 bp AR-binding element. Unbiased sequence analysis showed 6-bp motifs, which were significantly enriched and were bound directly by the AR in vitro. Binding sequences for the avian erythroblastosis virus E26 homologue (ETS) transcription factor family were also highly enriched, and we uncovered an interaction between the AR and ETS1 at a subset of AR promoter targets.


Absolute linearity characterization of lock-in amplifiers.
In applications where low signal-to-noise ratios are encountered, the use of phase-sensitive detection (PSD) is highly advantageous and is applied widely. However, the characteristics of lock-in amplifiers that utilize the PSD technique, such as the linearity of the output and the gain of these instruments, have not been extensively evaluated. The author proposes a method for measuring the linearity characteristics of lock-in amplifiers and describes how this method was used to measure the linearity factor of three nominally identical commercially available digital lock-in amplifiers. The results of this study show that the linearity factor of these lock-in amplifiers can deviate from unity by more than 0.1% over a factor of 2 change in output. Moreover, the linearity characteristics of these lock-in amplifiers vary from one instrument to the next. The linearity characteristics were shown to be independent of the reference frequency, the time constant, and the temporal profile of the signal being analyzed. However, they were found to be dependent on the sensitivity settings of these instruments. The linearity characteristics of these instruments were observed not to change with time. This implies that, where the uncertainty contribution due to the nonlinearity of a lock-in amplifier is significant, the nonlinearity can be evaluated by using the method described in this article and can be used to apply corrections.


Optical transmission of corrugated metal films on a two-dimensional hetero-colloidal crystal.
The near infrared transmission of corrugated metal films deposited on hetero-colloidal crystals is investigated. The transmission response of the quasi-three-dimensional (quasi-3D) metal film is modified by controlling the nominal thickness of a dielectric layer pre-deposited on the top surface of the colloidal crystal to form a new hetero-colloidal crystal. An extraordinary optical transmission (EOT) phenomenon could be presented in such metallodielectric (MD) architectures. We have found that the main transmission peak is suppressed as the thickness of the intercalated dielectric layer is increased. We propose that the observed EOT is a result of constructive interference between a localized sphere-like plasmon mode and an index-guided eigen mode mainly confined in the colloidal crystal, which is confirmed by our numerical simulations. Based on the MD microstructures, a distinct plasmon sensitivity response difference is achieved, which indicates potential applications for biochemical sensing.


St John's wort (Hypericum perforatum)-induced psychosis: a case report.
St John's wort (Hypericum perforatum) has been known for centuries for its therapeutic properties and its efficacy as an antidepressant has been confirmed by a growing body of evidence. During the last two decades it has also come to prominence with a wider public, due to advertising efforts across Europe and United States of America. However, its availability without prescription, as an over-the-counter medication, raises some concern regarding its clinical management and unsupervised administration to individuals with psychopathological risks. To date, the evidence available regarding the administration of Hypericum in people with severe mental health problems is still meager and refers mainly to affective disorder spectrum or psychotic relapse in people with established diagnoses. To the best of our knowledge, this is the first report regarding the onset of psychotic features in a patient presenting with psychotic diathesis. The case discussed in this report is a 25-year-old white man, not known to the psychiatric services, with a history of brief and self-remitting drug-induced psychosis and a positive family history of psychotic depression. He was admitted to hospital due to the onset of florid psychotic symptoms concomitant with self-administration of Hypericum perforatum. The aim of this report is to promote further systematic research, draw the attention of clinicians to the potential risks of Hypericum precipitating psychosis, and raise awareness among health professionals to investigate and caution their patients on the haphazard use of phytotherapeutics such as Hypericum.


Toward the Replacement of Animal Experiments through the Bioinformatics-driven Analysis of 'Omics' Data from Human Cell Cultures.
This paper outlines the work for which Roland Grafström and Pekka Kohonen were awarded the 2014 Lush Science Prize. The research activities of the Grafström laboratory have, for many years, covered cancer biology studies, as well as the development and application of toxicity-predictive in vitro models to determine chemical safety. Through the integration of in silico analyses of diverse types of genomics data (transcriptomic and proteomic), their efforts have proved to fit well into the recently-developed Adverse Outcome Pathway paradigm. Genomics analysis within state-of-the-art cancer biology research and Toxicology in the 21st Century concepts share many technological tools. A key category within the Three Rs paradigm is the Replacement of animals in toxicity testing with alternative methods, such as bioinformatics-driven analyses of data obtained from human cell cultures exposed to diverse toxicants. This work was recently expanded within the pan-European SEURAT-1 project (Safety Evaluation Ultimately Replacing Animal Testing), to replace repeat-dose toxicity testing with data-rich analyses of sophisticated cell culture models. The aims and objectives of the SEURAT project have been to guide the application, analysis, interpretation and storage of 'omics' technology-derived data within the service-oriented sub-project, ToxBank. Particularly addressing the Lush Science Prize focus on the relevance of toxicity pathways, a 'data warehouse' that is under continuous expansion, coupled with the development of novel data storage and management methods for toxicology, serve to address data integration across multiple 'omics' technologies. The prize winners' guiding principles and concepts for modern knowledge management of toxicological data are summarised. The translation of basic discovery results ranged from chemical-testing and material-testing data, to information relevant to human health and environmental safety.


Great tits (Parus major) reduce caterpillar damage in commercial apple orchards.
Alternative ways to control caterpillar pests and reduce the use of pesticides in apple orchards are in the interest of the environment, farmers and the public. Great tits have already been shown to reduce damage under high caterpillar density when breeding in nest boxes in an experimental apple orchard. We tested whether this reduction also occurs under practical conditions of Integrated Pest Management (IPM), as well as Organic Farming (OF), by setting up an area with nest boxes while leaving a comparable area as a control within 12 commercial orchards. We showed that in IPM orchards, but not in OF orchards, in the areas with breeding great tits, apples had 50% of the caterpillar damage of the control areas. Offering nest boxes to attract insectivorous passerines in orchards can thus lead to more limited pesticide use, thereby adding to the natural biological diversity in an agricultural landscape, while also being economically profitable to the fruit growers.


Influence of degree correlations on network structure and stability in protein-protein interaction networks.
The existence of negative correlations between degrees of interacting proteins is being discussed since such negative degree correlations were found for the large-scale yeast protein-protein interaction (PPI) network of Ito et al. More recent studies observed no such negative correlations for high-confidence interaction sets. In this article, we analyzed a range of experimentally derived interaction networks to understand the role and prevalence of degree correlations in PPI networks. We investigated how degree correlations influence the structure of networks and their tolerance against perturbations such as the targeted deletion of hubs. For each PPI network, we simulated uncorrelated, positively and negatively correlated reference networks. Here, a simple model was developed which can create different types of degree correlations in a network without changing the degree distribution. Differences in static properties associated with degree correlations were compared by analyzing the network characteristics of the original PPI and reference networks. Dynamics were compared by simulating the effect of a selective deletion of hubs in all networks. Considerable differences between the network types were found for the number of components in the original networks. Negatively correlated networks are fragmented into significantly less components than observed for positively correlated networks. On the other hand, the selective deletion of hubs showed an increased structural tolerance to these deletions for the positively correlated networks. This results in a lower rate of interaction loss in these networks compared to the negatively correlated networks and a decreased disintegration rate. Interestingly, real PPI networks are most similar to the randomly correlated references with respect to all properties analyzed. Thus, although structural properties of networks can be modified considerably by degree correlations, biological PPI networks do not actually seem to make use of this possibility.


Botulinum A toxin improves life quality in severe primary focal hyperhidrosis.
Focal hyperhidrosis is a condition that may disturb emotional, social and professional life. Treatment options for severe cases are surgical sympathectomy and local chemical sweat gland denervation by intradermal injections of botulinum toxin A (Btx A). The Dermatology Life Quality Index (DLQI) is a simple validated questionnaire designed to measure and compare disability in different skin diseases. The aim of this study was to assess quality of life with the DLQI before and after treatment with botulinum toxin injections in a group of patients with severe hyperhidrosis. DLQI was administered to 58 randomly chosen patients before and after treatment. All patients answered the DLQI questionnaire prior to treatment and 53/58 at mean 5.2 months after treatment. The mean DLQI score in the 58 patients before treatment was 10.3 (2-23). In the group of 16/53 patients who had a relapse of sweating when answering the DLQI a second time, no significant improvement was seen [score 10.6 before and 8.8 after treatment (P = 0.21)]. In patients without relapse, a 76% improvement was obtained (DLQI was reduced from 9.9 to 2.4; P < 0.0001). The study showed that focal hyperhidrosis may considerably reduce life quality and the disability experienced by the patients can be largely reversed by botulinum toxin injections.


Genomic organization and reproductive regulation of a large lipid transfer protein in the varroa mite, Varroa destructor (Anderson & Trueman).
The complete genomic region and corresponding transcript of the most abundant protein in phoretic varroa mites, Varroa destructor (Anderson & Trueman), were sequenced and have homology with acarine hemelipoglycoproteins and the large lipid transfer protein (LLTP) super family. The genomic sequence of VdLLTP included 14 introns and the mature transcript coded for a predicted polypeptide of 1575 amino acid residues. VdLLTP shared a minimum of 25% sequence identity with acarine LLTPs. Phylogenetic assessment showed VdLLTP was most closely related to Metaseiulus occidentalis vitellogenin and LLTP proteins of ticks; however, no heme binding by VdLLTP was detected. Analysis of lipids associated with VdLLTP showed that it was a carrier for free and esterified C12 -C22 fatty acids from triglycerides, diacylglycerides and monoacylglycerides. Additionally, cholesterol and β-sitosterol were found as cholesterol esters linked to common fatty acids. Transcript levels of VdLLTP were 42 and 310 times higher in phoretic female mites when compared with males and quiescent deutonymphs, respectively. Coincident with initiation of the reproductive phase, VdLLTP transcript levels declined to a third of those in phoretic female mites. VdLLTP functions as an important lipid transporter and should provide a significant RNA interference target for assessing the control of varroa mites.


Optimizing personalized normative feedback: the use of gender-specific referents.
Many brief interventions include personalized normative feedback (PNF) using gender-specific or gender-neutral referents. Several theories suggest that information pertaining to more socially proximal referents should have greater influence on one's behavior compared with more socially distal referents. The current research evaluated whether gender specificity of the normative referent employed in PNF related to intervention efficacy. Following baseline assessment, 185 college students (45.2% women) were randomly assigned to one of three intervention conditions: gender-specific feedback, gender-neutral feedback, or assessment-only control. Immediately after completing measures of perceived norms, alcohol consumption, and gender identity, participants in the gender-neutral and gender-specific intervention conditions were provided with computerized information detailing their own drinking behavior, their perceptions of student drinking, and actual student drinking. After a 1-month follow-up, the results indicated that normative feedback was effective in changing perceived norms and reducing alcohol consumption for both intervention groups for women and men. The results provide support, however, for changes in perceived gender-specific norms as a mediator of the effects of normative feedback on reduced drinking behavior for women only. Additionally, gender-specific feedback was found to be more effective for women higher in gender identity, relative to the gender-neutral feedback. A post-assessment follow-up telephone survey administered to assess potential demand characteristics corroborated the intervention effects. Results extend previous research documenting efficacy of computer delivered PNF. Gender specificity and gender identity appear to be important elements to consider for PNF intervention efficacy for women.


Impact of Ocean Acidification and Warming on the bioenergetics of developing eggs of Atlantic herring Clupea harengus.
Atlantic herring (Clupea harengus) is a benthic spawner, therefore its eggs are prone to encounter different water conditions during embryonic development, with bottom waters often depleted of oxygen and enriched in CO2. Some Atlantic herring spawning grounds are predicted to be highly affected by ongoing Ocean Acidification and Warming with water temperature increasing by up to +3°C and CO2 levels reaching ca. 1000 μatm (RCP 8.5). Although many studies investigated the effects of high levels of CO2 on the embryonic development of Atlantic herring, little is known about the combination of temperature and ecologically relevant levels of CO2. In this study, we investigated the effects of Ocean Acidification and Warming on embryonic metabolic and developmental performance such as mitochondrial function, respiration, hatching success (HS) and growth in Atlantic herring from the Oslo Fjord, one of the spawning grounds predicted to be greatly affected by climate change. Fertilized eggs were incubated under combinations of two PCO2 conditions (400 μatm and 1100 μatm) and three temperatures (6, 10 and 14°C), which correspond to current and end-of-the-century conditions. We analysed HS, oxygen consumption (MO2) and mitochondrial function of embryos as well as larval length at hatch. The capacity of the electron transport system (ETS) increased with temperature, reaching a plateau at 14°C, where the contribution of Complex I to the ETS declined in favour of Complex II. This relative shift was coupled with a dramatic increase in MO2 at 14°C. HS was high under ambient spawning conditions (6-10°C), but decreased at 14°C and hatched larvae at this temperature were smaller. Elevated PCO2 increased larval malformations, indicating sub-lethal effects. These results indicate that energetic limitations due to thermally affected mitochondria and higher energy demand for maintenance occur at the expense of embryonic development and growth.


MicroRNA let-7-TGFBR3 signalling regulates cardiomyocyte apoptosis after infarction.
Myocardial infarction (MI) is a life-threatening disease, often leading to heart failure. Defining therapeutic targets at an early time point is important to prevent heart failure. MicroRNA screening was performed at early time points after MI using paired samples isolated from the infarcted and remote myocardium of pigs. We also examined the microRNA expression in plasma of MI patients and pigs. For mechanistic studies, AAV9-mediated microRNA knockdown and overexpression were administrated in mice undergoing MI. MicroRNAs let-7a and let-7f were significantly downregulated in the infarct area within 24 h post-MI in pigs. We also observed a reduction of let-7a and let-7f in plasma of MI patients and pigs. Inhibition of let-7 exacerbated cardiomyocyte apoptosis, induced a cardiac hypertrophic phenotype, and resulted in worsened left ventricular ejection fraction. In contrast, ectopic let-7 overexpression significantly reduced those phenotypes and improved heart function. We then identified TGFBR3 as a target of let-7, and found that induction of Tgfbr3 in cardiomyocytes caused apoptosis, likely through p38 MAPK activation. Finally, we showed that the plasma TGFBR3 level was elevated after MI in plasma of MI patients and pigs. Together, we conclude that the let-7-Tgfbr3-p38 MAPK signalling plays an important role in cardiomyocyte apoptosis after MI. Furthermore, microRNA let-7 and Tgfbr3 may serve as therapeutic targets and biomarkers for myocardial damage. FUND: Ministry of Science and Technology, National Health Research Institutes, Academia Sinica Program for Translational Innovation of Biopharmaceutical Development-Technology Supporting Platform Axis, Thematic Research Program and the Summit Research Program, Taiwan.


Complement facilitates early prion pathogenesis.
New-variant Creutzfeldt-Jakob disease and scrapie are typically initiated by extracerebral exposure to the causative agent, and exhibit early prion replication in lymphoid organs. In mouse scrapie, depletion of B-lymphocytes prevents neuropathogenesis after intraperitoneal inoculation, probably due to impaired lymphotoxin-dependent maturation of follicular dendritic cells (FDCs), which are a major extracerebral prion reservoir. FDCs trap immune complexes with Fc-gamma receptors and C3d/C4b-opsonized antigens with CD21/CD35 complement receptors. We examined whether these mechanisms participate in peripheral prion pathogenesis. Depletion of circulating immunoglobulins or of individual Fc-gamma receptors had no effect on scrapie pathogenesis if B-cell maturation was unaffected. However, mice deficient in C3, C1q, Bf/C2, combinations thereof or complement receptors were partially or fully protected against spongiform encephalopathy upon intraperitoneal exposure to limiting amounts of prions. Splenic accumulation of prion infectivity and PrPSc was delayed, indicating that activation of specific complement components is involved in the initial trapping of prions in lymphoreticular organs early after infection.


Direct Measurement of the Nickel Spectrum in Cosmic Rays in the Energy Range from 8.8 GeV/n to 240 GeV/n with CALET on the International Space Station.
The relative abundance of cosmic ray nickel nuclei with respect to iron is by far larger than for all other transiron elements; therefore it provides a favorable opportunity for a low background measurement of its spectrum. Since nickel, as well as iron, is one of the most stable nuclei, the nickel energy spectrum and its relative abundance with respect to iron provide important information to estimate the abundances at the cosmic ray source and to model the Galactic propagation of heavy nuclei. However, only a few direct measurements of cosmic-ray nickel at energy larger than ∼3 GeV/n are available at present in the literature, and they are affected by strong limitations in both energy reach and statistics. In this Letter, we present a measurement of the differential energy spectrum of nickel in the energy range from 8.8 to 240 GeV/n, carried out with unprecedented precision by the Calorimetric Electron Telescope (CALET) in operation on the International Space Station since 2015. The CALET instrument can identify individual nuclear species via a measurement of their electric charge with a dynamic range extending far beyond iron (up to atomic number Z=40). The particle's energy is measured by a homogeneous calorimeter (1.2 proton interaction lengths, 27 radiation lengths) preceded by a thin imaging section (3 radiation lengths) providing tracking and energy sampling. This Letter follows our previous measurement of the iron spectrum [1O. Adriani et al. (CALET Collaboration), Phys. Rev. Lett. 126, 241101 (2021).PRLTAO0031-900710.1103/PhysRevLett.126.241101], and it extends our investigation on the energy dependence of the spectral index of heavy elements. It reports the analysis of nickel data collected from November 2015 to May 2021 and a detailed assessment of the systematic uncertainties. In the region from 20 to 240 GeV/n our present data are compatible within the errors with a single power law with spectral index -2.51±0.07.


FOX-GA: a genetic algorithm for generating and analyzing battlefield courses of action.
This paper describes FOX-GA, a genetic algorithm (GA) that generates and evaluates plans in the complex domain of military maneuver planning. FOX-GA's contributions are to demonstrate an effective application of GA technology to a complex real world planning problem, and to provide an understanding of the properties needed in a GA solution to meet the challenges of decision support in complex domains. Previous obstacles to applying GA technology to maneuver planning include the lack of efficient algorithms for determining the fitness of plans. Detailed simulations would ideally be used to evaluate these plans, but most such simulations typically require several hours to assess a single plan. Since a GA needs to quickly generate and evaluate thousands of plans, these methods are too slow. To solve this problem we developed an efficient evaluator (wargamer) that uses course-grained representations of this problem domain to allow appropriate yet intelligent trade-offs between computational efficiency and accuracy. An additional challenge was that users needed a diverse set of significantly different plan options from which to choose. Typical GA's tend to develop a group of "best" solutions that may be very similar (or identical) to each other. This may not provide users with sufficient choice. We addressed this problem by adding a niching strategy to the selection mechanism to insure diversity in the solution set, providing users with a more satisfactory range of choices. FOX-GA's impact will be in providing decision support to time constrained and cognitively overloaded battlestaff to help them rapidly explore options, create plans, and better cope with the information demands of modern warfare.


miR-9-5p regulates immunometabolic and epigenetic pathways in β-glucan-trained immunity via IDH3α.
Trained immunity, induced by β-glucan in monocytes, is mediated by activating metabolic pathways that result in epigenetic rewiring of cellular functional programs; however, molecular mechanisms underlying these changes remain unclear. Here, we report a key immunometabolic and epigenetic pathway mediated by the miR-9-5p-isocitrate dehydrogenase 3α (IDH3α) axis in trained immunity. We found that β-glucan-trained miR-9-5p-/- monocytes showed decreased IL-1β, IL-6, and TNF-α production after LPS stimulation. Trained miR-9-5p-/- mice produced decreased levels of proinflammatory cytokines upon rechallenge in vivo and had worse protection against Candida albicans infection. miR-9-5p targeted IDH3α and reduced α-ketoglutarate (α-KG) levels to stabilize HIF-1α, which promoted glycolysis. Accumulating succinate and fumarate via miR-9-5p action integrated immunometabolic circuits to induce histone modifications by inhibiting KDM5 demethylases. β-Glucan-trained monocytes exhibited low IDH3α levels, and IDH3α overexpression blocked the induction of trained immunity by monocytes. Monocytes with IDH3α variants from autosomal recessive retinitis pigmentosa patients showed a trained immunity phenotype at immunometabolic and epigenetic levels. These findings suggest that miR-9-5p and IDH3α act as critical metabolic and epigenetic switches in trained immunity.


The third-dimensional structure of the complex between an Fv antibody fragment and an analogue of the main immunogenic region of the acetylcholine receptor: a combined two-dimensional NMR, homology, and molecular modeling approach.
Binding of autoantibodies to the acetylcholine receptor (AChR) plays a major role in the autoimmune disease Myasthenia gravis (MG). In this paper, we propose a structure model of a putative immunocomplex that gives rise to the reduction of functional AChR molecules during the course of MG. The model complex consists of the [G(70), Nle(76)] decapeptide analogue of the main immunogenic region (MIR), representing the major antigenic epitope of AChR, and the single chain Fv fragment of monoclonal antibody 198, a potent MG autoantibody. The structure of the complexed decapeptide antigen [G(70), Nle(76)]MIR was determined using two-dimensional nmr, whereas the antibody structure was derived by means of homology modeling. The final complex was constructed using calculational docking and molecular dynamics. We termed this approach "directed modeling," since the known peptide structure directs the prestructured antibody binding site to its final conformation. The independently derived structures of the peptide antigen and antibody binding site already showed a high degree of surface complementarity after the initial docking calculation, during which the peptide was conformationally restrained. The docking routine was a soft algorithm, applying a combination of Monte Carlo simulation and energy minimization. The observed shape complementarity in the docking process suggested that the structure assessments already led to anti-idiotypic conformations of peptide antigen and antibody fragment. Refinement of the complex by dynamic simulation yielded improved surface adaptation by small rearrangements within antibody and antigen. The complex presented herein was analyzed in terms of antibody-antigen interactions, properties of contacting surfaces, and segmental mobility. The structural requirements for AChR complexation by autoantibodies were explored and compared with experimental data from alanine scans of the MIR peptides. The analysis revealed that the N-terminal loop of the peptide structure, which is indispensable for antibody recognition, aligns three hydrophobic groups in a favorable arrangement leading to the burial of 40% of the peptide surface in the binding cleft upon complexation. These data should be valuable in the rational design of an Fv mutant with much improved affinity for the MIR and AChR to be used in therapeutic approaches in MG.


The effect of underwater gait training on balance ability of stroke patients.
[Purpose] The purpose of this study was to investigate the effects of underwater treadmill gait training on the balance ability of stroke patients. [Subjects] Twenty-two patients with stroke were randomly assigned to an underwater treadmill group (n =11) or a control group (n =11). [Methods] Both groups received general rehabilitation for 30 min per session, 5 times per week, over a 4-week period. The underwater treadmill group received additional underwater gait training for 30 min per session, 5 times per week, over the same 4-week period. Static and dynamic balances were evaluated before and after the intervention. [Results] The means of static and dynamic balance ability increased significantly in both groups, but there was no significant difference between the two groups. [Conclusion] Compared to the general rehabilitation program, underwater treadmill gait training was not more effective at improving the balance ability of stroke patients than land-based training.


International assistance and cooperation for access to essential medicines.
Access to essential medicines is a critical problem that plagues many developing countries. With a daunting number of domestic constraints - technologically, economically, and otherwise - developing countries are faced with a steep uphill battle to meet the human rights obligation of providing essential medicines immediately. To meet these challenges, the international human rights obligations of international assistance and cooperation can play a key role to help developing countries fulfill the need for access to essential medicines. This article seeks to highlight and expand upon the current understanding of international assistance and cooperation for access to essential medicines through a review of obligations identified in international human rights law and a synthesis of official guidance provided on the matter.


Chemoradionuclide therapy with 186re-labeled liposomal doxorubicin: toxicity, dosimetry, and therapeutic response.
This study was performed to determine the maximum tolerated dose (MTD) and therapeutic effects of rhenium-186 ((186)Re)-labeled liposomal doxorubicin (Doxil), investigate associated toxicities, and calculate radiation absorbed dose in head and neck tumor xenografts and normal organs. Doxil and control polyethylene glycol (PEG)-liposomes were labeled using (186)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA) method. Tumor-bearing rats received either no therapy (n=6), intravenous Doxil (n=4), or escalating radioactivity of (186)Re-Doxil (185-925 MBq/kg) or (186)Re-PEG-liposomes (1110-1665 MBq/kg) and were monitored for 28 days. Based on body weight loss and systemic toxicity, MTD for (186)Re-Doxil and (186)Re-PEG-liposomes were established at injected radioactivity/body weight of 740 and 1480 MBq/kg, respectively. (186)Re-injected radioactivity/body weight for therapy studies was determined to be 555 MBq/kg for (186)Re-Doxil and 1295 MBq/kg for (186)Re-PEG-liposomes. All groups recovered from their body weight loss, leucopenia, and thrombocytopenia by 28 days postinjection. Normalized radiation absorbed dose to tumor was significantly higher for (186)Re-Doxil (0.299±0.109 Gy/MBq) compared with (186)Re-PEG-liposomes (0.096±0.120 Gy/MBq) (p<0.05). In a separate therapy study, tumor volumes were significantly smaller for (186)Re-Doxil (555 MBq/kg) compared with (186)Re-PEG-liposomes (1295 MBq/kg) (p<0.01) at 42 days postinjection. In conclusion, combination chemoradionuclide therapy with (186)Re-Doxil has promising potential, because good tumor control was achieved with limited associated toxicity.


Voltage-gated K+ channels contain multiple intersubunit association sites.
A domain in the cytoplasmic NH2 terminus of voltage-gated K+ channels supervises the proper assembly of specific tetrameric channels (Li, M., Jan, J. M., and Jan, L. Y.(1992) Science 257, 1225-1230; Shen, N. V., Chen X., Boyer, M. M., and Pfaffinger, P. (1993) Neuron 11, 67-76). It is referred to as a first tetramerization domain, or T1 (Shen, N. V., Chen X., Boyer, M. M., and Pfaffinger, P.(1993) Neuron 11, 67-76). However, a deletion mutant of Kv1.3 that lacks the first 141 amino acids, Kv1.3 (T1(-)) forms functional channels, suggesting that additional association sites in the central core of Kv1.3 mediate oligomerization. To characterize these sites, we have tested the abilities of cRNA Kv1.3 (T1(-)) fragments co-injected with Kv1.3 (T1(-)) to suppress current in Xenopus oocytes. The fragments include portions of the six putative transmembrane segments, S1 through S6, specifically: S1, S1-S2, S1-S2-S3, S2-S3, S2-S3-S4, S3-S4, S3-S4-S5, S2 through COOH, S3 through COOH, S4 through COOH, and S5-S6-COOH. Electrophysiologic experiments show that the fragments S1-S2-S3, S3-S4-S5, S2 through COOH, and S3 through COOH strongly suppress Kv1.3 (T1(-)) current, while others do not. Suppression of expressed current is due to specific effects of the translated peptide Kv1.3 fragments, as validated by in vivo immunoprecipitation studies of a strong suppressor and a nonsuppressor. Pulse-chase experiments indicate that translation of truncated peptide fragments neither prevents translation of Kv1.3 (T1(-)) nor increases its rate of degradation. Co-immunoprecipitation experiments suggest that suppression involves direct association of a peptide fragment with Kv1.3 (T1(-)). Fragments that strongly suppress Kv1.3 (T1(-)) also suppress an analogous NH2-terminal deletion mutant of Kv2.1 (Kv2.1 (DeltaN139)), an isoform belonging to a different subfamily. Our results indicate that sites in the central core of Kv1.3 facilitate intersubunit association and that there are suppression sites in the central core, which are promiscuous across voltage-gated K+ channel subfamilies.


Resting state brain oscillations and symptom profiles in attention deficit/hyperactivity disorder.
Our perspective on resting-state electroencephalogram (EEG) is that it provides a window into the substrate of cognitive and perceptual processing, reflecting the dynamic potential of the brain's current functional state. In an extended research program into the electrophysiology of attention deficit/hyperactivity disorder (AD/HD), we have examined resting-state EEG power and coherence, and event-related potentials (ERPs), in children, adolescents, and adults with the disorder. We sought initially to identify consistent AD/HD anomalies in these measures, relative to normal control subjects, and then to understand how these differences related to existing models of AD/HD. An emergent strand in this program has been to clarify the EEG correlates of "arousal" and to understand the role of arousal dysfunction as a core anomaly in AD/HD. To date, findings in this strand serve to rule out a commonly held dictum in the AD/HD field: that elevated theta/beta ratio is an indicator of hypo-arousal. In turn, this requires further work to elucidate the ratio's functional significance in the disorder. Our brain dynamics studies relating prestimulus EEG amplitude and phase states to ERP outcomes are expected to help in this regard, but we are still at a relatively early stage, currently examining these relationships in control children, in order to better understand normal aspects of brain dynamics before turning to children with AD/HD. This range of studies provides a framework for our recent work relating resting-state EEG anomalies, in individuals with AD/HD, to their symptom profile. This has had promising results, indicating links between increased inattention scores and reduced resting EEG gamma power. With resting-state EEG coherence, reduced left lateralized coherences across several bands have correlated negatively with inattention scores, while reduced frontal interhemispheric coherence has been correlated negatively with hyperactivity/impulsivity scores. Such linkages appear to provide encouraging leads for future EEG research in AD/HD.