Release of autonomic neuromediators by local ventricular electrical stimulation.
Trains of electrical stimuli were applied to the ventricular epicardium in pentobarbital-anesthetized dogs. The trains, delivered during the absolute refractory period via Walton-Brodie strain gauge arches, resulted in a highly localized potentiation of ventricular contractile force. The magnitude of the potentiation was directly related to the intensity of the trains. The positive inotropic response of either ventricle to trains of stimuli was abolished following chronic cardiac denervation or beta-adrenergic blockade with tolamolol, indicating that the response was probably mediated by the excitation of local sympathetic nerve fibers. Following the elimination of adrenergic influences, a slight negative inotropic response to trains of stimuli was observed in some animals. Administration of atropine blocked the negative inotropic response. When the adrenergic system was intact the administration of atropine resulted in a significant augmentation of the positive inotropic response of both ventricles to trains of stimuli. Thus in addition to norepinephrine release, it also appeared that electrical stimulation of the ventricles resulted in activation of local parasympathetic fibers with subsequent release of acetylcholine.


[Carbohydrate metabolism abnormalities in patients with cancer of major duodenal papilla before and after pancreaticoduodenal resections].
56 Patients with cancer of major duodenal papilla were examined before and after pylorus-saving pancreaticoduodenal resection. Carbohydrate metabolism was estimated before and after the operation, impact of the operation on diabetes mellitus progression was detected. If there were no carbohydrate metabolism abnormalities in 75% before the operation, then there were 55% of such patients after the operation. After the pylorus-saving pancreaticoduodenal resection the impaired glucose tolerance was detected in 4 (7%) of patients whose carbohydrate metabolism had corresponded to norms before the operation. 7 (13%) of 17 (31%) patients had diabetes mellitus of mild severity after the pylorus-saving pancreaticoduodenal resection, the rest 10 (18%) had diabetes mellitus of moderate severity. In 7 (13%) patients after the pylorus-saving pancreaticoduodenal resection the diabetes mellitus of moderate severity was detected for the first time, at that in 4 patients diabetes mellitus of mild severity was detected, and in 3 patients--diabetes mellitus of moderate severity (everyone received insulin therapy in the long-term postoperative period) was detected. Checking protocol of the patients' carbohydrate metabolism in the perioperative period was described in detail. The possibility of prognostication of carbohydrate metabolism abnormalities in the long-term postoperative period by indications of carbohydrate metabolism before the operation and in early postoperative period was studied. Middle blood glucose level in early postoperative period is an informative indication for prognostication of carbohydrate metabolism state in the long-term postoperative period. An algorithm of patients' examination with cancer of major duodenal papilla before the operation and after it was offered; also checking protocol of carbohydrate metabolism indices and correction of the detected abnormalities in the early postoperative period were offered.


A questionnaire survey of family practice physicians' perceptions of bereavement care.
Survey responses were obtained from 113 family physicians in an exploratory investigation of bereavement care by family physicians. Respondents generally indicated that they believed that bereavement presented significant health risks to their patients and that the identification and treatment of bereaved patients was an important part of their role. However, physicians were highly variable in how they reported identifying and responding to bereaved patients in terms of counseling, addressing spiritual concerns, and medically treating symptoms. The "grief-responsive" physician is described based on these data. We document the interest and need for training in bereavement care.


Association between proton pump inhibitors and hepatic encephalopathy: A meta-analysis.
Several studies have shown that proton pump inhibitors (PPIs) use can increase the risk of developing hepatic encephalopathy (HE) in patients with liver dysfunction. However, no definite conclusion is drawn because of study design limitations. Therefore, we conducted a meta-analysis to explore the association between PPIs and HE. We searched PubMed, EMBASE, and the Cochrane Library from inception until November 2016. Data from the identified studies were combined using a random effects model, and odds ratios (ORs) were calculated. Three case-control studies were included. Compared with nonusers, hepatic insufficiency patients receiving PPIs therapy had a significantly increased risk of developing HE (OR = 1.76, 95% CI: 1.15-2.69), with notable heterogeneity (I = 61.4%, P = .075) and publication bias. No relevance was found between PPIs and HE after using the trim and fill method (OR = 1.360, 95%CI: 0.909-2.035, P = .135). PPIs are associated with a higher risk of HE among patients with chronic and acute liver dysfunction. A final conclusion cannot be drawn because of the limited number of studies and a lack of prospective studies.


Vascular surgery triage during the coronavirus disease 2019 pandemic.
The coronavirus disease 2019 (COVID-19) pandemic has resulted in a marked increase in hospital usage, medical resource scarcity, and rationing of surgical procedures. This has created the need for strategies to triage surgical patients. We have described our experience using the American College of Surgeons (ACS) COVID-19 guidelines for triage of vascular surgery patients in an academic surgery practice. We used the ACS guidelines as a framework to direct the triage of vascular surgery patients during the COVID-19 pandemic. We retrospectively analyzed the results of this triage during the first month of surgical restriction at our hospital. Patients undergoing surgery were identified by reviewing the operating room schedule. We reviewed the electronic medical records (EMRs) and assigned an ACS category, condition, and tier class to each completed surgery. Surgeries that were postponed during the same period were identified from a prospectively maintained list. We reviewed the EMRs for all postponed surgeries and assigned an ACS category, condition, and tier class to each surgery. We reviewed the EMRs for all postponed procedures to identify any adverse events related to the treatment delay. We performed 69 surgeries in 52 patients during the study period. All surgeries were performed to treat emergent, urgent, or time-sensitive elective diagnoses. Of the 69 surgeries, 47 (68%) were from tier 3 and 22 (32%) from tier 2b. We did not perform any surgeries from tier 1 or 2a. We postponed surgery for 66 patients during the same period, of which 36 (55%) were from tier 1, 22 (33%) from tier 2a, 5 (8%) from tier 2b, and 3 (5%) could not be assigned a tier class. No tier 3 surgeries were postponed. Of the 66 patients, 3 (4.5%) experienced an adverse event that could be attributed to the treatment delay. The ACS triage guidelines provided an effective method to decrease vascular surgical volumes during the COVID-19 pandemic without an increase in patient morbidity. We believe the clinical utility of the guidelines would be strengthened by incorporating the SURGCON/VASCCON (surgical activity condition/vascular activity condition) threat level alert system.


Rapid fluorescence ratio assay for detecting changes in radiosensitivity.
To test modifications in sensitization to radiation or drugs in preclinical studies of cancer therapy, the colony-forming assay is regarded as the gold standard. Because this assay is time consuming, somewhat laborious, and unsuitable for rapid screening, development of other assays is desirable. We describe here an assay based on the detection of enhanced green fluorescence protein (EGFP) with flow cytometry that is particularly suitable for genetic manipulation studies in which the gene of interest is introduced together with EGFP as reporter. It is easily adaptable to other reporters, however, whether naturally fluorescent or requiring immunochemical staining. Cells are irradiated as mixed populations of a known standard cell line (nonfluorescent) together with the genetically manipulated cell line expressing EGFP. Ratios of fluorescent and nonfluorescent cells are measured before treatment and several days after treatment. If the cell populations have equal radiosensitivities, the ratio remains unchanged. Changes in the ratio indicate changes in radiosensitivity. The assay was validated for two situations in which dominant negative peptides inhibiting DNA repair were expressed in A549 human lung cells and affected radiosensitivity.


Telomere length and telomerase activity in osteoporosis and osteoarthritis.
Osteoarthritis (OA) and osteoporosis (OP) are associated skeletal pathologies and have as a distinct feature the abnormal reconstruction of the subchondral bone. OA and OP have been characterized as age-related diseases and have been associated with telomere shortening and altered telomerase activity (TA). This review discusses the role of telomeres and telomerase in OA and OP pathologies and focuses on the usability of telomere length (TL) and the rate of telomere shortening as potential disease biomarkers. A number of studies have demonstrated that telomere shortening may contribute to OA and OP as an epigenetic factor. Therefore, it has been claimed that the measurement of TL of chondrocytes and/or peripheral blood cells may be an appropriate marker for the evaluation of the progression of these diseases. However, there is a need to be perform further studies with larger cohorts, with the aim of obtaining objective results and a better understanding of the association between TL, inflammation and aging, in order to provide further insight into the pathophysiology of degenerative joint diseases.


Cervical Lymph Nodes as a Selective Niche for Brucella during Oral Infections.
Cervical lymph nodes (CLN) are the first lymph nodes encountered by material taking the oral route. To study their role in orally acquired infections, we analyzed 307 patients of up to 14 years treated in the university clinic of Skopje, Macedonia, for brucellosis, a zoonotic bacterial disease frequently acquired by ingestion of contaminated dairy products. From these children, 36% had lymphadenopathy. Among orally infected children, lymphadenopathy with CLN being the only lymph nodes affected was significantly more frequent as compared to those infected by contact with animals (83% vs. 63%), suggesting a possible involvement of CLN during orally acquired human brucellosis. Using a murine model where bacteria are delivered into the oral cavity, we show that Brucella quickly and selectively colonize the CLN where they proliferate and persist over long periods of time for up to 50 days post-infection. A similar efficient though less specific drainage to CLN was found for Brucella, Salmonella typhimurium and fluorescent microspheres delivered by gavage, a pathway likely representing a mixed infection mode of intragastric and oral infection, suggesting a central pathway of drained material. Microspheres as well as bacteria drained to CLN predominately reside in cells expressing CD68 and no or low levels of CD11c. Even though no systemic response could be detected, Brucella induced a locally restricted inflammatory reaction with increased expression levels of interferon γ, interleukin (IL)-6, IL-12, granzyme B and a delayed induction of Nos2. Inflammation led to pronounced lymphadenopathy, infiltration of macrophages/monocytes expressing high levels of major histocompatibility complex II and to formation of epitheloid granulomas. Together, these results highlight the role of CLN in oral infections as both, an initial and efficient trap for bacterial invaders and as possible reservoir for chronic pathogens. They likewise cast a new light on the significance of oral routes for means of vaccination.


Impaired subjective self-control in alcohol use: An ecological momentary assessment study.
While both theory and empirical findings have supported impaired self-control as a crucial factor in understanding problem drinking, little is known about the relationship of self-control and drinking in naturalistic settings. The present study uses Ecological Momentary Assessment (EMA) to examine the predictive relationships between impaired subjective self-control, craving and alcohol use in everyday life. A sample of 172 regular drinkers responded on their smartphone to three random prompts each day for seven days in which amount of perceived self-control and craving were measured with self-report. In the meantime, participants were instructed to initiate an EMA report when they started drinking alcohol. Findings supported the hypotheses that impaired self-control and higher craving levels were prospectively related to the likelihood that people will drink. That is, on random assessments that preceded drinking (i.e., were within two hours of drinking), perceived self-control was lower and craving was higher compared to random assessments that were not followed by drinking. Additionally, during drink consumption, impaired self-control and craving were associated with a higher amount of expected alcohol consumption. Findings further indicated that subjective self-control acted as a moderator of the relationship between craving and alcohol consumption during drinking occasions. By using a smartphone mobile application, this study showed that impaired subjective self-control and craving are prospectively related to alcohol use in the real-world. Furthermore, findings are consistent with theories of addiction that substance use might be associated with the interplay of control processes and increased motivation.


Identification and distribution of type VI collagen in tendon fibrocartilages.
Structural and compositional variations are marked in tendon fibrocartilages, which appear at the insertion to bone and in areas subjected to compressive plus frictional loading regime. We are interested in characterizing the extracellular matrix adaptations in these areas, in an attempt to understand cellular responses to biomechanics. In this work, we have applied immunocytochemistry and an ATP treatment for the ultrastructural identification of type VI collagen, to tendons subjected to compressive forces in different species. Immunocytochemistry, after testicular hyaluronidase or pepsin digestion, revealed the presence of type VI collagen in tensional and compressive areas of the plantaris longus tendon of the bullfrog, in the deep flexor tendon of dogs and rabbits, in the calcanear tendon and the suprapatela of rats and in the gastrocnemius tendon of chickens. In each tendon, the tensional region showed a weak reaction, restricted to the collagen fiber surface. However, the compression region was especially rich in type VI collagen, which accumulates in the interfibrillar spaces and is concentrated around the fibrochondrocytes. Intense reaction was also found in the paratenon. The ATP treatment not only allowed for the detection of the typical ladder-like aggregates of type VI collagen in the same areas identified by immunocytochemistry, but also demonstrated that type VI collagen forms a microfibrillar network around the fibrochondrocytes. Besides the function of organizing groups of collagen fibrils, type VI collagen seems to assemble the pericellular matrix in tendon fibrocartilages, perhaps through physical interactions with the large proteoglycans that concentrate in the same area.


Development of a high-throughput screen to detect inhibitors of TRPS1 sumoylation.
Small ubiquitin-like modifier (SUMO) belongs to the family of ubiquitin-like proteins (Ubls) that can be reversibly conjugated to target-specific lysines on substrate proteins. Although covalently sumoylated products are readily detectible in gel-based assays, there has been little progress toward the development of robust quantitative sumoylation assay formats for the evaluation of large compound libraries. In an effort to identify inhibitors of ubiquitin carrier protein 9 (Ubc9)-dependent sumoylation, a high-throughput fluorescence polarization assay was developed, which allows detection of Lys-1201 sumoylation, corresponding to the major site of functional sumoylation within the transcriptional repressor trichorhino-phalangeal syndrome type I protein (TRPS1). A minimal hexapeptide substrate peptide, TMR-VVK₁₂₀₁TEK, was used in this assay format to afford high-throughput screening of the GlaxoSmithKline diversity compound collection. A total of 728 hits were confirmed but no specific noncovalent inhibitors of Ubc9 dependent trans-sumoylation were found. However, several diaminopyrimidine compounds were identified as inhibitors in the assay with IC₅₀ values of 12.5 μM. These were further characterized to be competent substrates which were subject to sumoylation by SUMO-Ubc9 and which were competitive with the sumoylation of the TRPS1 peptide substrates.


Report of the Skin Research Workgroups from the GRAPPA 2018 Annual Meeting.
At the 2018 annual meeting of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), the International Dermatology Outcome Measures (IDEOM) Psoriasis Working Group presented an overview of its efforts to enhance clinical care and research in both the clinical setting as well as in clinical trials for psoriasis. First, the group discussed the results of a Delphi survey conducted in collaboration with the American Academy of Dermatology to agree on a unique physician-reported global assessment to measure the quality of care delivered to patients with psoriasis and other chronic inflammatory dermatoses. Second, the group summarized its efforts to select outcome measures for "PsA symptoms" and "treatment satisfaction," 2 of the domains of the psoriasis core domain set that were established by IDEOM. Finally, the Psoriasis and Psoriatic Arthritis Clinics Multicenter Advancement Network (PPACMAN) presented an update on its clinical, educational, and research missions to foster the development of combined clinics for psoriatic disease, increase disease awareness, and accelerate management.


The impact of pathogen-reduced platelets in acute leukaemia treatment on the total blood product requirement: a subgroup analysis of an EFFIPAP randomised trial.
To evaluate the impact of pathogen-reduced (PR) platelet transfusions on blood products requirement for clinical practice. PR platelets are increasing in use as standard blood products. However, few randomised trials have evaluated their impact on bleeding control or prevention. Furthermore, PR platelets recirculate less than untreated platelets. A subgroup study of the randomised clinical trial EFFIPAP compared three arms of platelet preparations (PR: P-PRP/PAS, additive solution: P-PAS and plasma P-P arms respectively). The subgroup of acute leukaemia patients, in their chemotherapy induction phase, included 392 patients (133 P-PRP/PAS arm, 132 P-PAS arm and 130 P-P arm). Blood requirements were analysed across over periods of 7 days. The number of platelet transfusions per week was significantly higher in the P-PRP/PAS group 2.3 [1.6-3.3] compared to the control groups 1.9 [1.3-2.8] and 2.0 [1.3-3.0] for P-P and P-PAS groups respectively (p < 0.0001). However, the total number of platelets transfused per week was not different. The number of red blood cell concentrates (RBC) transfusion per week did not differ either. In a homogeneous group of patients, platelet pathogen reduction resulted in an increased number of platelet units transfused per week while having no impact on the total number of platelets transfused or the number of RBC transfusion; resulting to an average requirement of 2 RBC and 2-3 platelets transfusions per week of marrow aplasia.


Identification of a chemokine network that recruits FoxP3(+) regulatory T cells into chronically inflamed intestine.
It has been unclear which chemokine network is involved in migration of T-cell subsets to chronically inflamed lesions of the intestine. SAMP1/YP mice develop a spontaneous chronic transmural intestinal lesion specifically in the ileum. Using these mice, we investigated the gut chemokine network involved in specific migration of T-cell subsets to the inflamed lesion of the intestine. We performed expression analyses of chemokines and their receptors, chemokine receptor blocking studies, and migration studies in vitro and in vivo to identify the gut chemokine network induced in intestinal inflammation and to determine its role in migration of conventional and FoxP3(+) suppressor T cells to the inflamed intestine. The expression of homeostatic chemokines was largely unchanged in the inflamed lesion of SAMP1/YP mice compared with control mice. However, an additional chemokine axis (CCL5-CCR5) was up-regulated in the inflamed intestine of SAMP1/YP mice compared with control mice. Activated T cells of SAMP1/YP mice compared with control mice were hyperresponsive to CCL5 in chemotaxis. CCR5(+) T cells preferentially migrated to the inflamed lesion, which can be blocked by a CCR5 antagonist. Importantly, the FoxP3(+) regulatory T cells of the inflamed lesion of SAMP1/YP mice highly expressed CCR5. CCR5 blockade suppressed the migration of FoxP3(+) T cells into the inflamed intestine and significantly exacerbated the intestinal inflammation. The CCL5-CCR5 chemokine axis is involved in preferential recruitment of FoxP3(+) regulatory T cells, which prevents further exacerbation of chronic inflammation in the intestine.


Nemorosone blocks proliferation and induces apoptosis in leukemia cells.
This work is aimed at characterizing nemorosone, isolated from Clusia rosea, as a potential antileukemic agent. In addition, we analyzed its influence on hematopoiesis in a mouse model. The isolation of nemorosone was carried out employing the RP-HPLC (reversed phase high-performance liquid chromatography) technique. Cytotoxicity was assessed in human leukemia cell lines including parental and chemotherapy-refractory sublines based on the MTT compound. Its effects on the cell cycle were analyzed using FACS (fluorescence-activated cell sorting) and Western blot techniques. Studies on the drug-induced early apoptotic process were carried out by means of fluorescence microscopy. Major signal transducers and the enzymatic inhibition of immunoprecipitated Akt/PKB were detected by Western blot. Hematopoiesis was analyzed in NMRI nu/nu mice after chronic nemorosone treatment, measuring hematological parameters by conventional laboratory techniques. Nemorosone proved cytotoxic in both parental and chemoresistant leukemia cell lines with IC50 values between 2.10 and 3.10 mg/ml. No cross-resistances could be detected. Cell cycle studies showed apoptosis induction accompanied by an increase in the G0/G1 population in both cell lines studied, whereas a significant decrease in the S-phase was found in Jurkat cells. Nemorosone induced a down-regulation of cyclins A, B1, D1, and E as well as a dephosphorylation of cdc2. Major signal transduction elements such as ERK1/2 and p38 MAPK, as well as important oncoproteins such as c-Myb and BCR/ABL were also found down-regulated. The enzymatic activity of immunoprecipitated Akt/PKB was substantially inhibited in vitro. Moreover, subchronic nemorosone treatment induced reversible monocytosis and thrombocytosis in the mouse model examined. Here, we demonstrate for the first time that nemorosone exerts cytotoxicity in leukemia cells, partly by targeting the Akt/PKB signal transducer, affecting protein levels and cell cycle progression. Finally, in vivo studies suggest that nemorosone significantly affects hematopoiesis in mice.


Structure and Function of Kdac1, a Class II Deacetylase from the Multidrug-Resistant Pathogen Acinetobacter baumannii.
Proteomics studies indicate that 10% of proteins in the opportunistic pathogen Acinetobacter baumannii are acetylated, suggesting that lysine acetyltransferases and deacetylases function to maintain and regulate a robust bacterial acetylome. As the first step in exploring these fascinating prokaryotic enzymes, we now report the preparation and characterization of the lysine deacetylase Kdac1. We show that Kdac1 catalyzes the deacetylation of free acetyllysine and acetyllysine tetrapeptide assay substrates, and we also report the X-ray crystal structures of unliganded Kdac1 as well as its complex with the hydroxamate inhibitor Citarinostat. Kdac1 is a tetramer in solution and in the crystal; the crystal structure reveals that the L1 loop functions to stabilize quaternary structure, forming inter-subunit hydrogen bonds and salt bridges around a central arginine residue (R30). Surprisingly, the L1 loop partially blocks entry to the active site, but it is sufficiently flexible to allow for the binding of two Citarinostat molecules in the active site. The L12 loop is also important for maintaining quaternary structure; here, a conserved arginine (R278) accepts hydrogen bonds from the backbone carbonyl groups of residues in an adjacent monomer. Structural comparisons with two other prokaryotic lysine deacetylases reveal conserved residues in the L1 and L12 loops that similarly support tetramer assembly. These studies provide a structural foundation for understanding enzymes that regulate protein function in bacteria through reversible lysine acetylation, serving as a first step in the exploration of these enzymes as possible targets for the development of new antibiotics.


Enhanced intergrain tunneling magnetoresistance in half-metallic CrO2 films
Low-field tunneling magnetoresistance was observed in films of half-metallic CrO2 that were grown by high-pressure thermal decomposition of CrO3. High-temperature annealing treatments modified the intergrain barriers of the as-grown films through surface decomposition of CrO2 into insulating Cr2O3, which led to a threefold enhancement of the low-field magnetoresistance. This enhancement indicates the potential of this simple method to directly control the interface barrier characteristics that determine the magnetotransport properties.


Objective and Subjective Perspectives on Implementation of a Violence Risk Screening Program in an Emergency Department.
The objective of this study was to use quantitative and qualitative data to gather information about emergency medicine and psychiatric provider perspectives regarding the evolution of a violence risk screening process including the simultaneous implementation of a universal suicide screening program. A retrospective review of violence risk screening data for 496 patient encounters over a 2-year period and across 4 phases of implementation and improvement was completed. Four focus groups were conducted with emergency medicine and psychiatric providers using nondirective facilitation methods to gather data regarding provider perspectives about violence and suicide risk screening. The focus groups were recorded, transcribed, and analyzed for thematic content. Four of the 6 violence risk screening items were most strongly associated with high-risk stratification across all phases. There were no changes in proportions of positive responses for 3 of the items. The proportion of positive responses for the other items changed significantly after expert feedback and clarification of item wording. Only 3% of the focus group passages included discussion of the universal suicide screening program. The providers indicated that they believed the violence risk screening and suicide screening procedures helped improve clinical thoroughness and documentation. Ongoing feedback between providers and program developers was beneficial. The implementation of the universal suicide screening process was relatively seamless for these providers.


Fertility control as a means of controlling bovine tuberculosis in badger (Meles meles) populations in south-west England: predictions from a spatial stochastic simulation model.
A spatial stochastic simulation model was used to assess the potential of fertility control, based on a yet-to-be-developed oral bait-delivered contraceptive directed at females, for the control of bovine tuberculosis in badger populations in south-west England. The contraceptive had a lifelong effect so that females rendered sterile in any particular year remained so for the rest of their lives. The efficacy of fertility control alone repeated annually for varying periods of time was compared with a single culling operation and integrated control involving an initial single cull followed by annually repeated fertility control. With fertility control alone, in no instance was the disease eradicated completely while a viable badger population (mean group size of at least one individual) was still maintained. Near eradication of the disease (less than 1% prevalence) combined with the survival of a minimum viable badger population was only achieved under a very limited set of conditions, either with high efficiency of control (95%) over a short time period (1-3 years) or a low efficiency of control (20%) over an intermediate time period (10-20 years). Under these conditions, it took more than 20 years for the disease to decline to such low levels. A single cull of 80% efficiency succeeded in near eradication of the disease (below 1% prevalence) after a period of 6-8 years, while still maintaining a viable badger population. Integrated strategies reduced disease prevalence more rapidly and to lower levels than culling alone, although the mean badger group size following the onset of control was smaller. Under certain integrated strategies, principally where a high initial cull (80%) was followed by fertility control over a short (1-3 year) time period, the disease could be completely eradicated while a viable badger population was maintained. However, even under the most favourable conditions of integrated control, it took on average more than 12 years following the onset of control for the disease to disappear completely from the badger population. These results show that whilst fertility control would not be a successful strategy for the control of bovine tuberculosis in badgers if used alone, it could be effective if used with culling as part of an integrated strategy. This type of integrated strategy is likely to be more effective in terms of disease eradication than a strategy employing culling alone. However, the high cost of developing a suitable fertility control agent, combined with the welfare and conservation implications, are significant factors which should be taken into account when considering its possible use as a means of controlling bovine tuberculosis in badger populations in the UK.


Associations of long-chain polyunsaturated fatty acid concentrations with birth outcome in term Indian mothers and their neonates.
The purpose of this study was to examine the maternal and cord long-chain polyunsaturated fatty acid (LCPUFA) concentrations and their associations with birth outcome in term deliveries. Pregnant women (n = 253) delivering at term were divided into two groups based on their babies' birth weights (1) normal birth weight (NBW), that is, ≥2.5 kg (n = 190) and (2) low-birth weight (LBW), that is, <2.5 kg (n = 63). Each group is further divided into two groups according to the baby's sex, that is, male NBW (M-NBW), female NBW (F-NBW), male LBW (M-LBW), and female LBW (F-LBW) groups. Maternal plasma docosahexaenoic acid and erythrocyte arachidonic acid (AA) levels were lower (P < 0.05 for both), while cord plasma docosahexaenoic acid and erythrocyte AA levels were higher (P < 0.05 for both) in LBW group when compared to the NBW group. Maternal erythrocyte AA levels were positively associated with birth weight (P = 0.001), while cord plasma docosahexaenoic acid levels were negatively (P = 0.05) associated with birth weight. Reduced maternal and increased cord LCPUFA levels exist in mothers delivering LBW babies, especially in mothers delivering female babies, indicative of sex-specific effects.


The structure of social relationships among captive female giraffe (Giraffa camelopardalis).
Giraffe herds have been characterized as random associations of individuals, but recent evidence suggests giraffe have a more complex social structure. The authors formulated 3 hypotheses designed to evaluate whether a herd of captive giraffe (Giraffa camelopardalis) associated randomly or patterned their behavior and proximity in a manner indicative of social relationships. Affiliative interaction, proximity, and nearest neighbors for 6 captive female giraffe living in a large outdoor enclosure were analyzed, and all three measures were nonrandomly distributed, indicating female giraffe had social preferences. Furthermore, preferences were consistent across measures and time, suggesting that adult female giraffe maintain relationships. Mother-daughter pairs and pairs with large age differences between members interacted and associated most often. The social structure of this captive herd is influenced by social relationships between individual adult females, and the social behavior of individual females should be examined more closely in the wild.


A parametric approach to relaxing the independence assumption in relative survival analysis.
With known cause of death (CoD), competing risk survival methods are applicable in estimating disease-specific survival. Relative survival analysis may be used to estimate disease-specific survival when cause of death is either unknown or subject to misspecification and not reliable for practical usage. This method is popular for population-based cancer survival studies using registry data and does not require CoD information. The standard estimator is the ratio of all-cause survival in the cancer cohort group to the known expected survival from a general reference population. Disease-specific death competes with other causes of mortality, potentially creating dependence among the CoD. The standard ratio estimate is only valid when death from disease and death from other causes are independent. To relax the independence assumption, we formulate dependence using a copula-based model. Likelihood-based parametric method is used to fit the distribution of disease-specific death without CoD information, where the copula is assumed known and the distribution of other cause of mortality is derived from the reference population. We propose a sensitivity analysis, where the analysis is conducted across a range of assumed dependence structures. We demonstrate the utility of our method through simulation studies and an application to French breast cancer data.


A retrospective study of eating and psychosocial problems in patients with hepatic glycogen storage diseases and idiopathic ketotic hypoglycemia: Towards a standard set of patient-reported outcome measures.
There is a paucity in literature on eating and psychosocial problems in patients with hepatic glycogen storage disease (GSD) and idiopathic ketotic hypoglycemia (IKH), problems that can greatly affect quality of life. This is a monocentre, retrospective, observational mixed method study of patients with hepatic GSD or IKH treated at the Beatrix Children's Hospital Groningen, who had been referred to SeysCentra, a specialist centre for the treatment of eating problems. Additionally, a systematic literature review has been performed to identify instruments to quantify patient-reported outcome measures of psychosocial problems in hepatic GSD patients. Sixteen patients from 12 families were included with ages ranging between 3 and 24 years. Five out of sixteen patients were diagnosed with Avoidant/Restrictive Food Intake Disorder and six patients showed characteristics of this disorder. Fourteen patients experienced sleeping problems, and 11 out of 12 parent couples experienced stress about the illness of their child. We subsequently identified 26 instruments to quantify patient-reported outcome measures for GSD patients. This study demonstrates that GSD patients can develop Avoidant/Restrictive Food Intake Disorder influencing quality of life at multiple domains. The identification of instruments to assess psychosocial wellbeing is an important step towards a standard set of patient-reported outcome measures.


VirtMRI: A Tool for Teaching MRI.
Magnetic resonance image formation is not trivial and remains a difficult subject for teaching. Therefore, we saw an urgent need to facilitate teaching by developing a practical and easily accessible MR image generator. Due to the increasing interest in X-nuclei MRI, sodium image generation is also offered. The tool is implemented as a web application that is compatible with all standard desktop browsers and is open source. The user interface focuses on the parameters needed for the creation and display of the resulting images. Available MR sequences range from the standard Spin Echo and Inversion Recovery over steady-state to conventional sodium and more advanced single and triple quantum sequences. Additionally, the user interface has parameters to alter the resolution, the noise, and the k-space sampling. Our software is free to use and specifically suited for teaching purposes.


Partial sequence analyses of exon 7 of the ABO locus of cynomolgus (Macaca fascicularis) and rhesus (M. mulatta) macaques: Indeterminate phenotypes show the presence of the O blood group.
Compatibility tests to identify A, B, and O alleles are critical for establishing suitable donor-recipient matches among experimental animals. Using a qPCR-based SNP probe assay, we have identified A, B, AB, and indeterminate blood group phenotypes in cynomolgus and rhesus macaques. We have hypothesized, albeit without molecular confirmation, that the indeterminate phenotype represents homozygosity for the null O allele at the macaque ABO locus. The indeterminate phenotype represents the unsuccessful detection of either A or B alleles using primers targeting the A-specific and B-specific single nucleotide polymorphisms (SNPs) in a variable region of exon 7 of the ABO locus. These SNPs are associated with two functional sites, detected using two allele-specific probes in the qPCR assay where the codons leucine and methionine (at codon 266) and glycine and alanine (at codon 268) are required for the synthesis of the A and B transferases, respectively. While reference sequences for the A and B alleles exhibited no novel mutations in the functional exon, plasmid Sanger sequence analyses showed unique mutations within the diagnostic target sites in 10 macaques exhibiting the indeterminate phenotype. Eight of these indeterminate individuals exhibited SNPs at codon 268 that should prevent the syntheses of an A or B transferase. While the two other indeterminate samples had functional codons that were consistent with A or B alleles, mutations in either their probe- or primer-binding sites that altered their peptide sequences probably impeded their detection by our assay.


Dual targeting of Nur77 and AMPKα by isoalantolactone inhibits adipogenesis in vitro and decreases body fat mass in vivo.
Suppression of adipogenesis has been considered as a potential target for the prevention and treatment of obesity and associated metabolic disorders, and the nuclear receptor 4A1 (NR4A1/Nur77) and AMPKα are known to play important roles during early and intermediate stages of adipogenesis. Therefore, we hypothesized that dual targeting Nur77 and AMPKα would show strong inhibitory effect on adipogenesis. We screened a herbal medicine-based small molecule library to identify novel natural compounds dual targeting Nur77 and AMPKα, and the antiadipogenic effects and mechanisms of action of a "hit" compound were studied in 3T3-L1 cells. In vivo antiobesity effects of the compound were also investigated in high-fat diet (HFD)-induced obese mice. We identified isoalantolactone (ISO) as a new NR4A1 inactivator that also activates AMPKα in 3T3-L1 cells. ISO, as expected, inhibited adipogenic differentiation of 3T3-L1 preadipocytes, accompanied by reduced mitotic clonal expansion (MCE) which occurs in the early stage of adipogenesis and decreased expression of genes required for MCE and cell cycle markers including cyclin A, cyclin D1. Furthermore, ISO reduced body weight gain and fat mass (epididymal, subcutaneous, perirenal, and inguinal white adipose tissues) in the high-fat diet-fed C57BL/6 N mice. Serum levels of triglycerides, aspartate transaminase, and alanine transaminase and hepatic steatosis were also significantly improved in the ISO-treated group compared to the high-fat diet control group. These results suggest that ISO dual targeting Nur77 and AMPKα during adipogenesis represents a novel class of mechanism-based antiadipogenic agents for treatment of obesity and associated metabolic disorders, including hyperlipidemia and fatty liver.


European Master's Program in Gerontology (EuMaG): goals, curriculum, and students.
The European Master's Program in Gerontology (EuMaG) started in September 2003 with support from the European Commission. The EuMaG is a modular, 2-year, part-time international training program about the aging process and its societal implications. The multidisciplinary curriculum comprises four domains of gerontology (i.e., social gerontology, psychogerontology, health gerontology, and biogerontology). Recently, a module on research and academic writing has been added to the core program. EuMaG emphasizes international comparison, focusing on current European debates concerning-among other things-policy and care for older adults. Members of several gerontology programs deliver the program across Europe. Guest lecturers from the wider EuMaG consortium are invited during the core modules. All institutes are involved in aging research, which provides ample opportunities to inform students about the latest research. Part of the standard curriculum is the Summer School, which is a collaborative endeavor of the VU-University Amsterdam and one of the partner universities of the larger European network. Since the start of EuMaG in 2003, a mix of participants with respect to age, nationality, and background has entered EuMaG. More than 100 students subscribed for (parts) of the EuMaG program. Students evaluate the EuMaG as highly informative and inspiring and appreciate the possibility to build an international network of gerontologists.


[Comparative cytochemical study of the central nervous system in Wistar and August rats in dopamine system hyperfunction].
Peculiarities of the CNS response to chronic treatment with L-DOPA were revealed by quantitative cytochemical methods in August (stress-sensitive) and Wistar (emotionally resistant) rats. In August rats L-DOPA administration caused aminopeptidase activity increase in sensomotor cortex layer 3 and nucleus accumbens, glutamate dehydrogenase activity growth in nucleus accumbens as well as the elevation of monoaminoxidase (MAO) activity in nucleus caudatus and nucleus accumbens (serotonin as substrate) and in nucleus caudatus and hippocampus (tryptamine as substrate), while acetyl cholinesterase activity did not change at all. At the same time in Wistar rats only glutamate dehydrogenase activity increase was observed in nucleus caudatus and nucleus accumbens.


[Overview of standardised diagnostic instruments of dementia].
The symptoms of dementia refer to a decline in intellectual abilities and to an impairment of general and instrumental activities of daily living (ADL). Beside cognitive decline and loss of ADL's the diagnosis of dementia requires the documentation of changes in social adaptation, psychopathology and behaviour. There are a large number of scales used in the assessment of the various manifestations of the disease. Some scales focus on a particular aspect of the symptomatology, others prefer a comprehensive approach in the detection of dementia symptoms. We present a list of assessment procedures and scales which seem appropriate to detect different aspects of dementia and which are widely accepted in the scientific community. We describe these scales in detail including their methodology and source of informations, psychometric properties regarding validity and reliability as well as time taken to complete the scales. Our synopsis may serve as an orientation mark in the selection of adequate instruments for the assessment of different symptom domains during the process of diagnosis, the observation of the course of dementia and the efficacy of treatment interventions.


Leelamine Is a Novel Lipogenesis Inhibitor in Prostate Cancer Cells In Vitro and In Vivo.
Increased de novo synthesis of fatty acids is implicated in the pathogenesis of human prostate cancer, but a safe and effective clinical inhibitor of this metabolic pathway is still lacking. We have shown previously that leelamine (LLM) suppresses transcriptional activity of androgen receptor, which is known to regulate fatty acid synthesis. Therefore, the current study was designed to investigate the effect of LLM on fatty acid synthesis. Exposure of 22Rv1, LNCaP, and PC-3 prostate cancer cells, but not RWPE-1 normal prostate epithelial cell line, to LLM resulted in a decrease in intracellular levels of neutral lipids or total free fatty acids. LLM was superior to another fatty acid synthesis inhibitor (cerulenin) for suppression of total free fatty acid levels. LLM treatment downregulated protein and/or mRNA expression of key fatty acid synthesis enzymes, including ATP citrate lyase, acetyl-CoA carboxylase 1, fatty acid synthase, and sterol regulatory element-binding protein 1 (SREBP1) in each cell line. Consistent with these in vitro findings, we also observed a significant decrease in ATP citrate lyase and SREBP1 protein expression as well as number of neutral lipid droplets in vivo in 22Rv1 tumor sections of LLM-treated mice when compared with that of controls. LLM-mediated suppression of intracellular levels of total free fatty acids and neutral lipids was partly attenuated by overexpression of SREBP1. In conclusion, these results indicate that LLM is a novel inhibitor of SREBP1-regulated fatty acid/lipid synthesis in prostate cancer cells that is not affected by androgen receptor status.


The popliteal surface axis may define hip anteversion.
This study aims to investigate the usability and reliability of our new axis in a three-dimensional modelling work and demonstrate if it is a reproducible method for anteversion measurement that sufficiently correlates with other computed tomography (CT)-derived gold standards including trans- epicondylar axis (TEA) and posterior condylar axis (PCA). Three-dimensional solid models were derived from left femoral CT data of 100 participants (50 males, 50 females; mean age 57 years; range, 21 to 86). The newly proposed popliteal surface axis (PSA) was compared with TEA and PCA in terms of anteversion measurement on these solid models. Popliteal surface axis was found as a reproducible reference axis in our study as it could be measured in 99% of our sample. The mean value of PSA based anteversion was (-) 1.8° which was 10.7° and 4.4° for PCA and TEA, respectively. Popliteal surface axis was perfectly correlated with PCA and TEA for anteversion measurements (p<0.001, r=0.92 for both). Our findings suggest that the newly defined PSA may be used as an alternative method for determination of anteversion.


Transcription factor-induced activation of cardiac gene expression in human c-kit+ cardiac progenitor cells.
Although transplantation of c-kit+ cardiac progenitor cells (CPCs) significantly alleviates post-myocardial infarction left ventricular dysfunction, generation of cardiomyocytes by exogenous CPCs in the recipient heart has often been limited. Inducing robust differentiation would be necessary for improving the efficacy of the regenerative cardiac cell therapy. We assessed the hypothesis that differentiation of human c-kit+ CPCs can be enhanced by priming them with cardiac transcription factors (TFs). We introduced five different TFs (Gata4, MEF2C, NKX2.5, TBX5, and BAF60C) into CPCs, either alone or in combination, and then examined the expression of marker genes associated with the major cardiac cell types using quantitative RT-PCR. When introduced individually, Gata4 and TBX5 induced a subset of myocyte markers. Moreover, Gata4 alone significantly induced smooth muscle cell and fibroblast markers. Interestingly, these gene expression changes brought by Gata4 were also accompanied by morphological changes. In contrast, MEF2C and NKX2.5 were largely ineffective in initiating cardiac gene expression in CPCs. Surprisingly, introduction of multiple TFs in different combinations mostly failed to act synergistically. Likewise, addition of BAF60C to Gata4 and/or TBX5 did not further potentiate their effects on cardiac gene expression. Based on our results, it appears that GATA4 is able to potentiate gene expression programs associated with multiple cardiovascular lineages in CPCs, suggesting that GATA4 may be effective in priming CPCs for enhanced differentiation in the setting of stem cell therapy.


Dietary Supplementation of Hericium erinaceus Increases Mossy Fiber-CA3 Hippocampal Neurotransmission and Recognition Memory in Wild-Type Mice.
Hericium erinaceus (Bull.) Pers. is a medicinal mushroom capable of inducing a large number of modulatory effects on human physiology ranging from the strengthening of the immune system to the improvement of cognitive functions. In mice, dietary supplementation with H. erinaceus prevents the impairment of spatial short-term and visual recognition memory in an Alzheimer model. Intriguingly other neurobiological effects have recently been reported like the effect on neurite outgrowth and differentiation in PC12 cells. Until now no investigations have been conducted to assess the impact of this dietary supplementation on brain function in healthy subjects. Therefore, we have faced the problem by considering the effect on cognitive skills and on hippocampal neurotransmission in wild-type mice. In wild-type mice the oral supplementation with H. erinaceus induces, in behaviour test, a significant improvement in the recognition memory and, in hippocampal slices, an increase in spontaneous and evoked excitatory synaptic current in mossy fiber-CA3 synapse. In conclusion, we have produced a series of findings in support of the concept that H. erinaceus induces a boost effect onto neuronal functions also in nonpathological conditions.


The fate of pro-TNF-alpha following inhibition of metalloprotease-dependent processing to soluble TNF-alpha in human monocytes.
Human monocytes rapidly produce TNF-alpha following activation by bacterial LPS. The message for TNF-alpha encodes a 26-kDa protein that is proteolytically processed to the secreted 17-kDa form. Sequencing of the N terminus of the protein secreted by monocytes shows processing of the 26-kDa pro-TNF-alpha to a mature form at the projected metalloprotease cleavage site to generate 17-kDa TNF-alpha with the N terminus VRSSSR-. The addition of hydroxamic acid-based metalloprotease inhibitors to the cell culture is capable of blocking >95% of the production of soluble TNF-alpha and leads to a transient, but reproducible, increase in cell surface TNF-alpha as measured by FACS analysis. The cell surface TNF-alpha was demonstrated to increase the cell's ability to kill L929 tumor targets and induce PG production from human gingival fibroblasts. The buildup of cell surface TNF-alpha is unable to account for the TNF-alpha that is not secreted when inhibitor is present. Pulse-chase analysis of the cells demonstrates rapid degradation of the pro-TNF-alpha that remains unprocessed in the monocytes. Through inhibition of processing and secretion by brefeldin A, processing was shown to occur at a postendoplasmic reticulum site and is closely associated with movement to the cell surface.


Angular asymmetries of the human face.
The determination of an acceptable occlusal plane is essential for the development of esthetic prosthodontic restorations. However, since most faces are not symmetric, a method was developed for measuring facial angular asymmetry, i.e., the divergence from the vertical or horizontal of the line joining the midpoint of the intercanthal line and the philtrum of the lip, the interpupillary line, the intermeatal line, the lip commissure line, and the intercuspid line. Standardized frontal images (mouth closed, smiling, and biting on a wooden spatula) of 100 subjects were taken using a digital camera. These images were downloaded into a computer, and the angles between the various facial lines and the horizontal were measured. The subjects were grouped by sex, age, and history of trauma and orthodontic treatment. No statistically significant differences were found between the mean values for each group. Asymmetry of the face can be measured using digital camera imaging and computer analysis. A range of facial asymmetries that can influence the choice of occlusal plane during prosthodontic treatment exists. Thus, the use of an occlusal plane parallel to the ala tragus and interpupillary lines, as often advocated by prosthodontists, may result in less than ideal esthetics in the final restoration.


Strain structure analysis of Mycobacterium tuberculosis circulating among HIV negative, positive and drug resistant TB patients attending chest clinics in Western Kenya.
Despite global tuberculosis (TB) interventions, the disease remains one of the major public health concerns. Kenya is ranked 15th among 22 high burden TB countries globally. A cross-sectional study was conducted in Western Kenya, which comprises 10 counties. A multistage sampling method was used where a single sub-county was randomly selected followed by sampling two high volume health facility from each sub-county. Identification of spoligotype profiles and their family distribution and lineage level were achieved by comparison with SITVIT database. Lineage distribution pattern revealed that the most predominant lineage was CAS 220 (39.8%) followed by Beijing 128 (23.1%). The other lineages identified were T, LAM, H, X, S and MANU which were quantified as 87 (15.7%), 67 (12.1%), 16 (2.8%), 10 (1.8%), 8 (1.4%) and 5 (0.9%) respectively. CAS and Beijing strains were the most predominant lineage in both HIV negative and positive TB patients. The Beijing lineage was also the most predominant in resistant M. tuberculosis strains as compared to wild type. A total of 12 (2.0%) were orphaned M. tuberculosis strains which were spread across all the 10 counties of the study site. In multivariate logistic regression adjusting for potential cofounders three potential risk factors were significant. HIV status (OR = 1.52, CI = 0.29-3.68 and P value of 0.001), Alcohol use (OR = 0.59, CI = 0.43-3.12 and P-value =0.001) and cross border travel (OR = 0.61, CI = 0.49-3.87 and P value = 0.026). Most M. tuberculosis clinical isolates showed genetic clustering with multivariate logistic regression indicating three potential risk factors to clustering. HIV status (OR = 1.52, CI = 0.29-3.68 and P value of 0.001), Alcohol use (OR = 0.59, CI = 0.43-3.12 and P-value =0.001) and cross border travel (OR = 0.61, CI = 0.49-3.87 and P value = 0.026). There exist diverse strains of M. tuberculosis across the 10 counties of Western Kenya. Predominant distribution of clustered genotype points to the fact that most TB cases in this region are as a result of resent transmission other than activation of latent TB.


[Computed tomography in studying the surgical anatomy of the posterior cranial fossa].
To determine the individual roentgenometric parameters of the posterior cranial fossa and the specific features of the location of brain structures on computed tomography scans in terms of their possible use on planning surgical approaches. The computed tomography scans of the bony base of the posterior cranial fossa and the projection variants of the location of brain structures relative to the osseous landmarks were roentgenometrically studied in 116 patients without pathology of the cranial bones and brain. The main linear (length, width, depth) and angular (a pyramidal convergence angle, a pyramidal occipital angle, a slope angle, and occipital squama inclination) roentgenometric parameters determining the shape of the posterior cranial fossa were determined. The most commonly encountered (long narrow deep, long wide fine, long narrow fine, long wide deep, and short narrow fine) shapes were identified according to the combination of the extrema of these parameters. The variants of the location of brain structures were determined within the projection planes. There were the roentgenometric parameters and craniocerebral ratios, which are of value in the individual planning of surgical approaches to the structures of the posterior cranial fossa.


[Effect of retinol deficiency on the activity and solubility of various enzymes of the endoplasmic reticulum membranes in the rat liver].
Solubilization by sodium deoxycholate and trypsin of some metabolic enzymes of unrelated compounds associated with endoplasmic reticulum membranes was carried out. The effects of urea, butanol and detergents on the retinol content in the membranes were studied. It was shown that retinol deficiency causes changes in the interactions of NADH-arylesterase with microsomal membrane components that are manifested in the decrease of the activating effect of butanol and low detergent concentrations on the NADH-reductase activity as well as in the increase in the damaging effect of urea and high detergent concentrations on the enzyme activity. Under conditions of retinol deficiency, the degree of solubilization of NADH-reductase, hydroxylase and arylesterase in the presence of sodium deoxycholate is enhanced. After treatment of liver microsomes of retinol-deficient animals with trypsin or with a trypsin-sodium cholate mixture, the content of these enzymes in the supernatant becomes much greater than that in liver microsomes of vitamin A-deficient rats. It is assumed that retinol deficiency causes of weakening of hydrophobic interactions within the membrane as well as partial translocation of the enzymes from the hydrophobic to the hydrophilic layer.


Lessons learned in public health emergency management: personal reflections.
Multiple environmental, ecological, and socio-political forces are converging to increase the occurrence of both natural and technological disasters. Ten forces are of most concern in this regard. These are: 1) global warming, with its consequent weather extremes and climate changes; 2) continued rapid human population growth and concomitant increased urbanization; 3) decreased bio-diversity and consequent ecological fragility; 4) deforestation and loss of natural habitat for animal species, with resultant greater overlap of human and animal habitats, human exposure to animal pathogens, and other ecological perturbations; 5) increased technological development throughout the world (especially in developing countries with their typically immature safety programs); 6) globalization and increased population mobility; 7) sub-national religious and ethnic conflicts, and their potential for conflict escalation and large scale displacement of populations; 8) the collapse of several major countries and consequent unraveling of national identity and social order; 9) the rise of terrorism; and 10) dramatic advances in the science and technology of computing, communications, biotechnology, and genomics. This paper describes 10 lessons learned relative to the public health aspects of emergency management, especially as they pertain to disasters. 1) Planning pays; 2) A bad situation can be made worse by inappropriate responses; 3) Most life saving interventions will occur before the disaster happens and immediately afterwards by local action; 4) Public health emergency management is not a democratic process; 5) Psychological impacts are usually greater than anticipated; 6) Communications and information management are vital, but often are the weak link in the response chain; 7) Collaboration and partnerships are essential; 8) Unsolicited volunteers and aid are inevitable and must be planned for and managed; 9) Never assume anything, and always expect the unexpected; and 10) Post-event evaluation is important, and must be coordinated. The paramount lesson learned from past emergencies is that the untoward impact of these events can be anticipated and significantly ameliorated by appropriate planning and preparation. On the other hand, preparation for emergency events has deteriorated because of health-care financial constraints, and resources to support planning and needed infrastructure have diminished. Given these realities, the major unresolved challenge is how to ensure that planning for the common good is supported and, in fact, gets done.


Children's liver chemistries vary with age and gender and require customized pediatric reference ranges.
Used to detect liver disease and injury, baseline liver chemistry distributions were evaluated by age and gender in children without known liver disease. Baseline liver chemistries [alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin (TBIL)] were analyzed from 24 randomized controlled pediatric clinical trials. Using quantile regression, liver chemistry distributions were examined by age and gender; upper limit normal (ULN) ranges were compared to the 97.5th percentiles of the distributions for the specified ages and genders. 5410 subjects without known liver disease (0-18 years; 60% male) were studied. The median ALT varied little with age. In males age 5-18, the ALT 97.5th percentile increased from 34 to 63 IU/L. In both genders, the median and 97.5th percentile AST decreased with age. After age 9, ALP decreased. TBIL increased with age. Despite most liver chemistry 97.5th percentiles changing substantively with age and gender, the reference lab ULN generally changed minimally and did not correlate with the 97.5th percentile. Gender and age specific 97.5th percentile data should therefore be considered for the reference laboratory ULN in children to more accurately detect liver injury and disease.


Frontal lobe epilepsy with atypical seizure semiology resembling shuddering attacks or wet dog shake seizures.
We report a girl with a drug-resistant frontal lobe epilepsy caused by focal cortical dysplasia, who exhibited uncommon seizures. The seizures consisted of shoulder or whole body shuddering after a short psychic aura and face grimacing. Consciousness was fully preserved. The seizures resembled "wet dog shake" seizures described in rat models of epilepsy or shuddering attacks in infants. EEG findings were inconclusive, however, MRI showed a clear dysplastic lesion in the right frontal mesial and polar structures. The patient underwent an extended lesionectomy guided by neuronavigation and intraoperative electrocorticography. Focal cortical dysplasia type Ib was histologically confirmed and the patient has been seizure-free for the three years following resection. [Published with video sequences].


Acute exercise and gender alter cardiac autonomic tonus differently in hypertensive and normotensive rats.
Arterial pressure (AP), heart rate (HR), cardiac sympathetic tonus (ST), and parasympathetic tonus (PT) were determined in spontaneously hypertensive rats (SHR, 8 male and 8 female) and Wistar-Kyoto normotensive rats (WKY, 8 male and 12 female) before and after acute exercise. Before exercise, hypertensive rats (regardless of gender) had an increased ST (+15 beats/min), increased resting HR (+12 beats/min), and decreased PT (-11 beats/min). Similarly, female rats (regardless of strain) also had an increased ST (+15 beats/min), increased resting HR (+39 beats/min), and decreased PT (-14 beats/min). Hypertensive rats had a significant reduction in AP (-17 +/- 3 mmHg), ST (-26 beats/min), PT (-7 beats/min), and HR (-14 beats/min) after exercise. In contrast, AP was not reduced in normotensive rats and ST (+18 beats/min) and HR (+42 beats/min) were increased in female normotensive rats after exercise. However, male normotensive rats had a postexercise reduction in ST (-14 beats/min) and HR (-19 beats/min). In summary, AP, ST, and resting HR were higher whereas PT was lower in hypertensive vs. normotensive rats. Furthermore, females had a higher resting HR, intrinsic HR, and ST and lower PT than male rats. These data demonstrate that gender and the resting level of AP influence cardiac autonomic regulation.


Cluster-enhanced sparse approximation of overlapping ultrasonic echoes.
Ultrasonic pulse-echo methods have been used extensively in non-destructive testing of layered structures. In acoustic measurements on thin layers, the resulting echoes from two successive interfaces overlap in time, making it difficult to assess the individual echo parameters. Over the last decade sparse approximation methods have been extensively used to address this issue. These methods employ a large dictionary of elementary functions (atoms) and attempt to select the smallest subset of atoms (sparsest approximation) that represent the ultrasonic signal accurately. In this paper we propose the cluster-enhanced sparse approximation (CESA) method for estimating overlapping ultrasonic echoes. CESA is specifically adapted to deal with a large number of signals acquired during an ultrasonic scan. It incorporates two principal algorithms. The first is a clustering algorithm, which divides a set of signals comprising an ultrasonic scan into groups of signals that can be approximated by the same set of atoms. The second is a two-stage iterative algorithm, which alternates between update of the atoms associated with each cluster, and re-clustering of the signals according to the updated atoms. Because CESA operates on clusters of signals, it achieves improved results in terms of approximation error and computation time compared with conventional sparse methods, which operate on each signal separately. The superior ability of CESA to approximate highly overlapping ultrasonic echoes is demonstrated through simulation and experiments on adhesively bonded structures.


FTY720 analogues as sphingosine kinase 1 inhibitors: enzyme inhibition kinetics, allosterism, proteasomal degradation, and actin rearrangement in MCF-7 breast cancer cells.
Sphingosine kinase 1 (SK1) catalyzes the conversion of sphingosine to the bioactive lipid sphingosine 1-phosphate. We have previously demonstrated that FTY720 and (S)-FTY720 vinylphosphonate are novel inhibitors of SK1 activity. Here, we show that (S)-FTY720 vinylphosphonate binds to a putative allosteric site in SK1 contingent on formation of the enzyme-sphingosine complex. We report that SK1 is an oligomeric protein (minimally a dimer) containing noncooperative catalytic sites and that the allosteric site exerts an autoinhibition of the catalytic site. A model is proposed in which (S)-FTY720 vinylphosphonate binding to and stabilization of the allosteric site might enhance the autoinhibitory effect on SK1 activity. Further evidence for the existence of allosteric site(s) in SK1 was demonstrated by data showing that two new FTY720 analogues (a conjugate of sphingosine with a fluorophore and (S)-FTY720 regioisomer) increased SK1 activity, suggesting relief of autoinhibition of SK1 activity. Comparisons with the SK1 inhibitor, SKi or siRNA knockdown of SK1 indicated that (S)-FTY720 vinylphosphonate and FTY720 behave as typical SK1 inhibitors in preventing sphingosine 1-phosphate-stimulated rearrangement of actin in MCF-7 cells. These findings are discussed in relation to the anticancer properties of SK1 inhibitors.


The value of N-terminal fragment of brain natriuretic peptide and tissue inhibitor of metalloproteinase-1 levels as predictors of cardiovascular outcome in the LIPID study.
We sought to determine the association between two major biomarkers, the inactive N-terminal fragment of brain natriuretic peptide (NT-proBNP) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and long-term cardiovascular outcomes in a cohort of subjects who had a myocardial infarction or unstable angina 3-36 months previously. Plasma NT-proBNP and TIMP-1 were measured in a nested case control study of 250 randomly matched subject pairs enrolled in the long-term intervention with pravastatin in ischaemic disease (LIPID) and LIPID extended follow-up studies. Cases (n = 250) were defined as those who had a cardiovascular death, non-fatal myocardial infarction or stroke during the studies. Controls (n = 250) remained event-free for the same follow-up duration (average 2.5 years) as the matched cases. The relationships between cases and plasma NT-proBNP and TIMP-1 were adjusted for the LIPID risk score, treatment allocation and other biomarkers (CRP, IL-6 and white cell count), and examined using a multivariable conditional logistic regression model. NT-proBNP levels were significantly higher in the cases than in the controls [389 (152-864) vs. 198 (93-416) pg/mL, median (25%-75% percentiles), P < 0.001]. The odds ratio (OR) of recurrent cardiovascular events in individuals in the highest quartile was three times higher than those in the lowest quartile (95% confidence interval (CI) 1.8-5.1; P < 0.001). Similarly, TIMP-1 levels were significantly higher among cases compared with controls (806 vs. 736 pg/mL, median: highest vs. lowest quartile: OR 2.8, 95% CI 1.6-4.7; P < 0.001). After adjustment for the LIPID risk score, treatment with pravastatin and other biomarkers, both NT-proBNP and TIMP-1 predicted cardiovascular events significantly and independently of each other. The study suggests that in subjects with stable ischaemic disease, NT-proBNP and TIMP-1 are independent predictive markers of coronary heart disease outcome.


An economic framework to prioritize confirmatory tests after a high-throughput screen.
How many hits from a high-throughput screen should be sent for confirmatory experiments? Analytical answers to this question are derived from statistics alone and aim to fix, for example, the false discovery rate at a predetermined tolerance. These methods, however, neglect local economic context and consequently lead to irrational experimental strategies. In contrast, the authors argue that this question is essentially economic, not statistical, and is amenable to an economic analysis that admits an optimal solution. This solution, in turn, suggests a novel tool for deciding the number of hits to confirm and the marginal cost of discovery, which meaningfully quantifies the local economic trade-off between true and false positives, yielding an economically optimal experimental strategy. Validated with retrospective simulations and prospective experiments, this strategy identified 157 additional actives that had been erroneously labeled inactive in at least one real-world screening experiment.


Human-specific features and developmental dynamics of the brain N-glycome.
Comparative "omics" studies have revealed unique aspects of human neurobiology, yet an evolutionary perspective of the brain N-glycome is lacking. We performed multiregional characterization of rat, macaque, chimpanzee, and human brain N-glycomes using chromatography and mass spectrometry and then integrated these data with complementary glycotranscriptomic data. We found that, in primates, the brain N-glycome has diverged more rapidly than the underlying transcriptomic framework, providing a means for rapidly generating additional interspecies diversity. Our data suggest that brain N-glycome evolution in hominids has been characterized by an overall increase in complexity coupled with a shift toward increased usage of α(2-6)-linked N-acetylneuraminic acid. Moreover, interspecies differences in the cell type expression pattern of key glycogenes were identified, including some human-specific differences, which may underpin this evolutionary divergence. Last, by comparing the prenatal and adult human brain N-glycomes, we uncovered region-specific neurodevelopmental pathways that lead to distinct spatial N-glycosylation profiles in the mature brain.


Vital signs: carbapenem-resistant Enterobacteriaceae.
Enterobacteriaceae are a family of bacteria that commonly cause infections in health-care settings as well as in the community. Among Enterobacteriaceae, resistance to broad-spectrum carbapenem antimicrobials has been uncommon. Over the past decade, however, carbapenem-resistant Enterobacteriaceae (CRE) have been recognized in health-care settings as a cause of difficult-to-treat infections associated with high mortality. The percentage of acute-care hospitals reporting at least one CRE from health-care-associated infections (HAIs) in 2012 was estimated using data submitted to the National Healthcare Safety Network (NHSN) in 2012. The proportion of Enterobacteriaceae infections that were CRE was calculated using two surveillance systems: 1) the National Nosocomial Infection Surveillance system (NNIS) and NHSN (for 2001 and 2011, respectively) and 2) the Surveillance Network-USA (TSN) (for 2001 and 2010). Characteristics of CRE culture-positive episodes were determined using data collected as part of a population-based CRE surveillance project conducted by the Emerging Infections Program (EIP) in three states. In 2012, 4.6% of acute-care hospitals reported at least one CRE HAI (short-stay hospitals, 3.9%; long-term acute-care hospitals, 17.8%). The proportion of Enterobacteriaceae that were CRE increased from 1.2% in 2001 to 4.2% in 2011 in NNIS/NHSN and from 0% in 2001 to 1.4% in 2010 in TSN; most of the increase was observed in Klebsiella species (from 1.6% to 10.4% in NNIS/NHSN). In the EIP surveillance, 92% of CRE episodes occurred in patients with substantial health-care exposures. Carbapenem resistance among common Enterobacteriaceae has increased over the past decade; most CRE are associated with health-care exposures. Interventions exist that could slow the dissemination of CRE. Health departments are well positioned to play a leading role in prevention efforts by assisting with surveillance, situational awareness, and coordinating prevention efforts.


The Ronnie Gardiner Rhythm and Music Method - a feasibility study in Parkinson's disease.
To assess the feasibility of the novel intervention, Ronnie Gardiner Rhythm and Music (RGRM™) Method compared to a control group for patients with Parkinson's disease (PD). Eighteen patients, mean age 68, participating in a disability study within a neurological rehabilitation centre, were randomly allocated to intervention group (n = 12) or control group (n = 6). Feasibility was assessed by comparing effects of the intervention on clinical outcome measures (primary outcome: mobility as assessed by two-dimensional motion analysis, secondary outcomes: mobility, cognition, quality of life, adherence, adverse events and eligibility). Univariable analyses showed no significant differences between groups following intervention. However, analyses suggested that patients in the intervention group improved more on mobility (p = 0.006), cognition and quality of life than patients in the control group. There were no adverse events and a high level of adherence to therapy was observed. In this disability study, the use of the RGRM™ Method showed promising results in the intervention group and the adherence level was high. Our results suggest that most assessments chosen are eligible to use in a larger randomized controlled study for patients with PD. The RGRM™ Method appeared to be a useful and safe method that showed promising results in both motor and cognitive functions as well as quality of life in patients with moderate PD. The RGRM™ Method can be used by physiotherapists, occupational, speech and music therapists in neurological rehabilitation. Most measurements were feasible except for Timed-Up-and-Go.


The in silico identification of novel broad-spectrum antidotes for poisoning by organophosphate anticholinesterases.
Because of their potential to cause serious adverse health effects, significant efforts have been made to develop antidotes for organophosphate (OP) anticholinesterases, such as nerve agents. To be optimally effective, antidotes must not only reactivate inhibited target enzymes, but also have the ability to cross the blood brain barrier (BBB). Progress has been made toward brain-penetrating acetylcholinesterase reactivators through the development of a new group of substituted phenoxyalkyl pyridinium oximes. To help in the selection and prioritization of compounds for future synthesis and testing within this class of chemicals, and to identify candidate broad-spectrum molecules, an in silico framework was developed to systematically generate structures and screen them for reactivation efficacy and BBB penetration potential.


Evidence for (Mac1p)2.DNA ternary complex formation in Mac1p-dependent transactivation at the CTR1 promoter.
The Mac1 protein in Saccharomyces cerevisiae is required for the expression CTR1 and FRE1, which, respectively, encode the copper permease and metal reductase that participate in copper uptake. Mac1p binds to a core GCTC sequence present as a repeated unit in the promoters of both genes. We show here that Mac1p DNA binding required an intact N-terminal protein domain that includes a likely zinc finger motif. This binding was enhanced by the presence of a TATTT sequence immediately 5' to the core GCTC, in contrast to a TTTTT one. This increased binding was demonstrated clearly in vitro in electrophoretic mobility shift assays that showed Mac1p.DNA complex formation to a single TATTTGCTC element but not to a TTTTTGCTC one. Furthermore, the fraction of Mac1p in a ternary (Mac1p)2.DNA complex in comparison to a binary Mac1p.DNA complex increased when the DNA included two TATTTGCTC elements. A similar increase in ternary complex formation was demonstrated upon homologous mutation of the FRE1 Mac1p-dependent promoter element. The in vivo importance of this ternary complex formation at the CTR1 promoter was indicated by the stronger trans-activity of this promoter mutated to contain two TATTT elements and the attenuated activity of a mutant promoter containing two TTTTT elements that in vitro supported only a weak ternary complex signal in the shift assay. The stronger binding to TATTT appeared due to a more favorable protein contact with adenine in comparison to thymine at this position. An in vivo two-hybrid analysis demonstrated a Mac1p-Mac1p protein-protein interaction. This Mac1p-Mac1p interaction may promote (Mac1p)2.DNA ternary complex formation at Mac1p-responsive upstream activating sequences.


Intraoperative bleeding in patients with osteogenesis imperfecta type III treated by Fassier-Duval femoral rodding: analysis of risk factors.
The surgical treatment of osteogenesis imperfecta (OI) is negatively influenced by clinical features such as osteoporosis, limb deformities and bone changes caused by bisphosphonate therapy. Blood loss during femoral nailing surgeries in patients with OI is a serious problem. Platelet anomalies have been associated with an elevation of the serum pyrophosphate originating from the platelets during clotting, even if the causality with the platelet dysfunction has not yet been established. To identify predictive risk factors regarding intraoperative bleeding, a retrospective analysis was conducted on 23 patients aged between 6 and 13 years, affected by OI type III, who were treated to correct femoral deformities or to perform an osteosynthesis for femoral shaft fractures, using the Fassier-Duval telescopic nail. Osteotomies were performed in 14 cases of deformities and in two out of seven cases of fractures. A survey about the bleeding had been obtained by calculating the sum of the blood aspirated and that lost with the gauzes or present on the surgical drapes. To obtain an estimate of the intraoperative blood losses, one must resort to a calculation based on an algorithm that evaluates the ratio between the effective blood loss divided by the total blood volume expected as per age and weight (γ distribution). The average blood loss was 237.4 ml (0.12 γ). In seven cases, it was necessary to perform postoperative transfusions, owing to an average blood loss of 502.8 ml (0.27 γ). Patients aged less than 10 years had a minor blood loss. A greater number of osteotomies was associated with a significant increase of average bleeding (P=0.046). Patients who were never treated with bisphosphonates showed a significantly greater bleeding rate (P=0.048). Patients affected by OI type III have a high risk of severe blood loss during surgery, even caused by the platelet disfunction, which characterizes this OI type. In addition to this predisposing factor, there are other risk factors to consider in preoperative surgical planning. In patients who were never treated with bisphosphonates, the bleeding was higher than in the ones treated with bisphosphonates since at least 1 year. The effects of bisphosphonates on bone tissue (such as the medullar canal narrowing and the bone cortex thickening) could reduce the spongious bone amount and the bleeding. Inhibiting the farnesyl pyrophosphate synthase enzyme and reducing the prenylation of many plasma proteins, including the methylene tetrahydrofolate reductase, the bisphosphonates could lead to an alteration of the coagulation cascade. The correlation found with the intake of bisphosphonates, capable of inhibiting the action of the farnesyl pyrophosphate synthase enzyme, thus influencing coagulation, requires further prospective studies with research of the methylene tetrahydrofolate reductase mutation in patients with OI type III undergoing surgical procedures. The number of osteotomies, the patient's age and the intake of bisphosphonates for at least 1 year seem to be the best predictive factors for blood loss.


Adipokines and C-reactive protein as indicators of MetS presence in obese Greek children: The Healthy Growth Study.
Metabolic syndrome (MetS) occurs in a proportion of overweight and obese children and increases their future risk of serious health complications, even in adolescence and young adulthood. We aimed to explore the role of certain adipokines and inflammatory markers in identifying children with MetS. This study is a secondary analysis of data coming from the Healthy Growth Study, a cross-sectional study conducted with schoolchildren in Greece. The present study included data from a representative sample of 1376 schoolchildren (mean age: 11.19 ± 0.66 years), recruited from 77 primary schools in four large regions in Greece. Anthropometric, clinical and biochemical data were recorded. Children's body weight status and the presence of MetS were determined and their correlation with the serum levels of leptin, adiponectin and C-reactive protein (CRP) was explored. The prevalence of the MetS was 21.7 % and 3.7 % in obese and overweight children, respectively. The balance of adipokines was disturbed in obesity, as the serum level of adiponectin decreased as body weight increased, while the serum level of leptin increased. The serum level of the inflammatory marker CRP increased significantly as body weight increased. Discriminant analysis showed that these factors could distinguish the children with MetS as compared to children with no MetS. In the under study Mediterranean childhood population, monitoring of the levels of adipokines and CRP could identify the overweight and obese children with MetS. Appropriate individualized dietary and lifestyle interventions can be applied in these children to prevent health complications associated with MetS.


Post thyroidectomy gossypiboma.
Gossypiboma is an unfrequent surgical complication wich consists in the presence of a mass of textile origin surrounded by a foreign body reaction. The authors present a clinical case of a left paratracheal gossypiboma, diagnosed during the follow-up of a patient submitted to a total thyroidectomy two years before for a papilary carcinoma.


Morphological and physiological responses of beech (Fagus sylvatica) seedlings to grass-induced below ground competition.
We examined morphological and physiological responses of beech (Fagus sylvatica L.) seedlings to grass-induced below ground competition in full-light conditions. Two-year-old beech seedlings were grown during two growing seasons in 160-l containers in bare soil or with a mixture of five grass species widely represented in semi-natural meadows of central France. At the end of the second growing season, beech seedlings in the presence of grass showed significant reductions in diameter and height growth, annual shoot elongation, and stem, root and leaf biomass, but an increase in root to shoot biomass ratio. Grasses greatly reduced soil water availability, which was positively correlated with daily seedling diameter increment. Beech seedlings seemed to respond to water deficit by anticipating stomatal closure. There was evidence of competition for nitrogen (N) by grasses, but its effect on seedling development could not be separated from that of competition for water. By labeling the plants with 15N, we showed that beech seedlings absorbed little N when grasses were present, whereas grasses took up more than 97% of the total N absorbed in the container. We conclude that, even if beech seedlings display morphological and physiological adaptation to below ground competition, their development in full-light conditions may be strongly restricted by competition from grass species.


A new method for clustered survival data: Estimation of treatment effect heterogeneity and variable selection.
We recently developed a new method random-intercept accelerated failure time model with Bayesian additive regression trees (riAFT-BART) to draw causal inferences about population treatment effect on patient survival from clustered and censored survival data while accounting for the multilevel data structure. The practical utility of this method goes beyond the estimation of population average treatment effect. In this work, we exposit how riAFT-BART can be used to solve two important statistical questions with clustered survival data: estimating the treatment effect heterogeneity and variable selection. Leveraging the likelihood-based machine learning, we describe a way in which we can draw posterior samples of the individual survival treatment effect from riAFT-BART model runs, and use the drawn posterior samples to perform an exploratory treatment effect heterogeneity analysis to identify subpopulations who may experience differential treatment effects than population average effects. There is sparse literature on methods for variable selection among clustered and censored survival data, particularly ones using flexible modeling techniques. We propose a permutation-based approach using the predictor's variable inclusion proportion supplied by the riAFT-BART model for variable selection. To address the missing data issue frequently encountered in health databases, we propose a strategy to combine bootstrap imputation and riAFT-BART for variable selection among incomplete clustered survival data. We conduct an expansive simulation study to examine the practical operating characteristics of our proposed methods, and provide empirical evidence that our proposed methods perform better than several existing methods across a wide range of data scenarios. Finally, we demonstrate the methods via a case study of predictors for in-hospital mortality among severe COVID-19 patients and estimating the heterogeneous treatment effects of three COVID-specific medications. The methods developed in this work are readily available in the R ${\textsf {R}}$ package riAFTBART $\textsf {riAFTBART}$ .


High-Resolution Analysis of Growth and Transpiration of Quinoa Under Saline Conditions.
The Plantarray 3.0 phenotyping platform® was used to monitor the growth and water use of the quinoa varieties Pasto and selRiobamba under salinity (0-300 mM NaCl). Salinity reduced the cumulative transpiration of both varieties by 60% at 200 mM NaCl and by 75 and 82% at 300 mM NaCl for selRiobamba and Pasto, respectively. Stomatal conductance was reduced by salinity, but at 200 mM NaCl Pasto showed a lower reduction (15%) than selRiobamba (35%), along with decreased specific leaf area. Diurnal changes in water use parameters indicate that under salt stress, daily transpiration in quinoa is less responsive to changes in light irradiance, and stomatal conductance is modulated to maximize CO2 uptake and minimize water loss following the changes in VPD (vapor pressure deficit). These changes might contribute to the enhanced water use efficiency of both varieties under salt stress. The mechanistic crop model LINTUL was used to integrate physiological responses into the radiation use efficiency of the plants (RUE), which was more reduced in Pasto than selRiobamba under salinity. By the end of the experiment (eleven weeks after sowing, six weeks after stress), the growth of Pasto was significantly lower than selRiobamba, fresh biomass was 50 and 35% reduced at 200 mM and 70 and 50% reduced at 300 mM NaCl for Pasto and selRiobamba, respectively. We argue that contrasting water management strategies can at least partly explain the differences in salt tolerance between Pasto and selRiobamba. Pasto adopted a "conservative-growth" strategy, saving water at the expense of growth, while selRiobamba used an "acquisitive-growth" strategy, maximizing growth in spite of the stress. The implementation of high-resolution phenotyping could help to dissect these complex growth traits that might be novel breeding targets for abiotic stress tolerance.


Experimental evidence for high-temperature organic fractional superconduction in cholates.
Experimental data are presented indicating that six organic compounds (homologous cholates) possess properties associated with high-temperature superconductivity. From magnetic and electrical measurements it is deduced that behavior resembling superconductivity occurs below characteristic transition temperatures in small domains included in the insulating bulk of the sample material, which is therefore designated a fractional o Type III superconductor. The six cholates exhibit this superconductivity below transition temperatures ranging from approximately 7.5 degrees K for sodium dioxycholate to 277 degrees K for sodium cholanate. It has been further established that the diamagnetic shifts with temperature cannot be attributed to ferrielectric, ferroelectric, or capacitive effects. Below the transition temperatures the cholates behave like perfect diamagnets, susceptible to forceful repulsion by a moderate magnetic field. Observed in a sensitive susceptometer, magnetic flux trapped in the material gave rise to a 3% remnant magnetic moment. Studied in particular detail were sodium cholate, sodium deoxycholate, and lithocholic acid, which showed transition temperatures of 30 degrees K, 60 degrees K, and 130 degrees K respectively. The hydrophobic property of the closed four-ring structure (R-group) common to the cholates, along with the hydrophilic property of the carboxylate group (S-group), are responsible for domain formation. Because of those properties, clustering of the S-groups occurs when traces of water are introduced into the material. When followed by slow desiccation, the clusters form the micelles constituting the superconducting domains.


Development and content validity of a hemodialysis symptom patient-reported outcome measure.
To describe the process and preliminary qualitative development of a new symptom-based patient-reported outcome measure (PROM) intended to assess hemodialysis treatment-related physical symptoms. Experienced interviewers conducted concept elicitation and cognitive debriefing interviews with individuals receiving in-center hemodialysis in the United States. Concept elicitation interviews involved eliciting spontaneous reports of symptom experiences and probing to further explore and confirm concepts. We used patient-reported concepts to generate a preliminary symptom PROM. We conducted 3 rounds of cognitive debriefing interviews to evaluate symptom relevance, item interpretability, and draft item structure. We iteratively refined the measure based on cognitive interview findings. Forty-two adults receiving in-center hemodialysis participated in the concept elicitation interviews. A total of 12 symptoms were reported by > 10% of interviewees. We developed a 13-item initial draft instrument for testing in 3 rounds of cognitive interviews with an additional 52 hemodialysis patients. Participant responses and feedback during cognitive interviews led to changes in symptom descriptions, division of the single item "nausea/vomiting" into 2 distinct items, removal of daily activity interference items, addition of instructions, and clarification about the recall period, among other changes. Symptom Monitoring on Renal Replacement Therapy-Hemodialysis (SMaRRT-HD™) is a 14-item PROM intended for use in hemodialysis patents. SMaRRT-HD™ uses a single treatment recall period and a 5-point Likert scale to assess symptom severity. Qualitative interview data provide evidence of its content validity. SMaRRT-HD™ is undergoing additional testing to assess measurement properties and inform measure scoring.


Comparison of gene order of GIGANTEA loci in yellow-poplar, monocots, and eudicots.
GIGANTEA plays an important role in the control of circadian rhythms and photoperiodic flowering. The GIGANTEA gene has been studied in various species, but not in basal angiosperms. Moreover, to the best of our knowledge, no study of the genome organization of a basal angiosperm has yet been published. In this study, we sequenced a bacterial artificial chromosome (BAC) harboring GIGANTEA from yellow-poplar (Liriodendron tulipifera L.) and compared the genomic organization of this gene in yellow-poplar with that in other species from various angiosperm clades. This is the first report on the gene structure and organization of a large contig in any basal angiosperm species. The BAC clone, covering a region of approximately 122 kb from the yellow-poplar genome, was sequenced and assembled by coupling the 454 pyrosequencing technology with ABI capillary sequencing. In addition to GIGANTEA, the gene RPS18.A (encoding ribosomal protein S18.A) was found in this segment of the genome. We found that gene content and order in this region of the yellow-poplar genome were similar to those in the corresponding region in eudicots but not in Oryza sativa and Sorghum bicolor, implying that clustering of the GIGANTEA and RPS18.A genes is ancestral and separation of the genes occurred after the phylogenetic split of monocots from dicots. Phylogenetic analysis of GIGANTEA amino acid sequences placed yellow-poplar closer to eudicots than to monocots. In addition, evidence for transposition and large insertions and duplications was found, suggesting multiple and complex mechanisms of basal angiosperm genome evolution.


Effect of Remediation Parameters on in-Air Ambient Dose Equivalent Rates When Remediating Open Sites with Radiocesium-contaminated Soil.
Calculations are reported for ambient dose equivalent rates [H˙*(10)] at 1 m height above the ground surface before and after remediating radiocesium-contaminated soil at wide and open sites. The results establish how the change in H˙*(10) upon remediation depends on the initial depth distribution of radiocesium within the ground, on the size of the remediated area, and on the mass per unit area of remediated soil. The remediation strategies considered were topsoil removal (with and without recovering with a clean soil layer), interchanging a topsoil layer with a subsoil layer, and in situ mixing of the topsoil. The results show the ratio of the radiocesium components of H˙*(10) post-remediation relative to their initial values (residual dose factors). It is possible to use the residual dose factors to gauge absolute changes in H˙*(10) upon remediation. The dependency of the residual dose factors on the number of years elapsed after fallout deposition is analyzed when remediation parameters remain fixed and radiocesium undergoes typical downward migration within the soil column.


The influence of operator changes on orthodontic treatment times and results in a postgraduate teaching environment.
There is some concern that patients treated by postgraduate students during their specialty training may be disadvantaged in the quality of treatment result and subject to longer treatment times if they are treated by more than one operator. This study analysed the pre- and post-treatment study models of orthodontic patients from a district general hospital department, debonded by one junior member of junior staff in the calendar years 1991 and 1992. All patients were treated using the same pre-adjusted edgewise appliance in both arches. Two groups of patients were identified: patients whose treatment was started and finished by the same operator (registrar A), and those whose treatment was begun by another operator (registrar B), but finished by registrar A. A random sample of 30 patients from each group was selected and the study models at the start and end of treatment were scored using the PAR (Peer Assessment Rating) Index. No significant differences were found between the average PAR scores for each group at the beginning of treatment, or between groups A and B at the end of treatment; the average treatment time for the patients treated by one operator was 17.67 months (SD 4.15 months), while the average treatment time for the patients treated by more than one operator was 26.1 months (SD 6.78 months). Statistically, this difference was highly significant (P < 0.001). A highly linear relationship (R2 = 0.92) was found between the percentage PAR score reduction and the initial PAR score. The findings and their implications are discussed.