Spontaneous cleavage of proteins at serine and threonine is facilitated by zinc.
Old proteins are widely distributed in the body. Over time, they deteriorate and many spontaneous reactions, for example isomerisation of Asp and Asn, can be replicated by incubation of peptides under physiological conditions. One of the signatures of long-lived proteins that has proven to be difficult to replicate in vitro is cleavage on the N-terminal side of Ser residues, and this is important since cleavage at Ser, and also Thr, has been observed in a number of human proteins. In this study, the autolysis of Ser- and Thr-containing peptides was investigated with particular reference to discovering factors that promote cleavage adjacent to Ser/Thr at neutral pH. It was found that zinc catalyses cleavage of the peptide bond on the N-terminal side of Ser residues and further that this process is markedly accelerated if a His residue is adjacent to the Ser. NMR analysis indicated that the imidazole group co-ordinates zinc and that once zinc is co-ordinated, it can polarize the carbonyl group of the peptide bond in a manner analogous to that observed in the active site of the metalloexopeptidase, carboxypeptidase A. The hydroxyl side chain of Ser/Thr is then able to cleave the adjacent peptide bond. These observations enable an understanding of the origin of common truncations observed in long-lived proteins, for example truncation on the N-terminal side of Ser 8 in Abeta, Ser 19 in alpha B crystallin and Ser 66 in alpha A crystallin. The presence of zinc may therefore significantly affect the long-term stability of cellular proteins.


Working memory capacity and its relation to stroop interference and facilitation effects in individuals with mild cognitive impairment.
The purposes of the study were to investigate (a) the task-specific differences in short-term memory (STM) and working memory capacity (WMC) in individuals with mild cognitive impairment (MCI) and normal elderly adults (NEAs), (b) the Stroop interference and facilitation effects, and (c) the relationship of STM and WMC to the Stroop effects. Thirty-two individuals participated in the study (n = 16 for each group). WMC demands were increased using a computerized Stroop-like token task to add more linguistic units. Six STM and WMC measures were administered overall. Digit-related tasks and an alphabet span task sensitively differentiated individuals with MCI from the NEA group. The group with MCI exhibited greater Stroop interference effects than the NEA group, but the 2 groups did not exhibit different Stroop facilitation effects. WMC significantly predicted performance on the response time analyses but not on the error rate analyses. Task-specific differences emerged in the group with MCI, and a reduced WMC accounts for the impaired inhibitory and goal maintenance processes. It is critical that WMC demands be systematically manipulated to tax individuals' WMC in a way that can clearly demonstrate their deficits, especially in individuals who are at risk for clinically demented states.


Bee Venom Acupuncture Alleviates Experimental Autoimmune Encephalomyelitis by Upregulating Regulatory T Cells and Suppressing Th1 and Th17 Responses.
The protective and therapeutic mechanism of bee venom acupuncture (BVA) in neurodegenerative disorders is not clear. We investigated whether treatment with BVA (0.25 and 0.8 mg/kg) at the Zusanli (ST36) acupoints, located lateral from the anterior border of the tibia, has a beneficial effect in a myelin basic protein (MBP)(68-82)-induced acute experimental autoimmune encephalomyelitis (EAE) rat model. Pretreatment (every 3 days from 1 h before immunization) with BVA was more effective than posttreatment (daily after immunization) with BVA with respect to clinical signs (neurological impairment and loss of body weight) of acute EAE rats. Treatment with BVA at the ST36 acupoint in normal rats did not induce the clinical signs. Pretreatment with BVA suppressed demyelination, glial activation, expression of cytokines [interferon (IFN)-γ, IL-17, IL-17A, tumor necrosis factor-alpha (TNF-α), and IL-1β], chemokines [RANTES, monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein (MIP)-1α], and inducible nitric oxide synthase (iNOS), and activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)-κB (p65 and phospho-IκBα) signaling pathways in the spinal cord of acute EAE rats. Pretreatment with BVA decreased the number of CD4(+), CD4(+)/IFN-γ(+), and CD4(+)/IL-17(+) T cells, but increased the number of CD4(+)/Foxp3(+) T cells in the spinal cord and lymph nodes of acute EAE rats. Treatment with BVA at six placebo acupoints (SP9, GB39, and four non-acupoints) did not have a positive effect in acute EAE rats. Interestingly, onset and posttreatment with BVA at the ST36 acupoint markedly attenuated neurological impairment in myelin oligodendrocyte glycoprotein (MOG)(35-55)-induced chronic EAE mice compared to treatment with BVA at six placebo acupoints. Our findings strongly suggest that treatment with BVA with ST36 acupoint could delay or attenuate the development and progression of EAE by upregulating regulatory T cells and suppressing T-helper (Th) 17 and Th1 responses. These results warrant further investigation of BVA as a treatment for autoimmune disorders of the central nervous system.


Protist metabarcoding and environmental biomonitoring: Time for change.
High-throughput amplicon sequencing of environmental DNA and/or RNA proved to be a powerful tool to describe protist diversity. This new approach called also the metabarcoding has totally transformed our view of protist diversity, revealing a large number of novel lineages and expanding the range of protist phylogenetic diversity at almost every taxonomic level. However, until now the objectives of the vast majority of metabarcoding studies were purely academic. Practical applications of protist metabarcoding are surprisingly scarce, despite the fact that several groups of protists are commonly used as bioindicators of environmental impacts in freshwater or marine ecosystems. Here, we are reviewing studies that examine the ecological applications of metabarcoding for two groups of well-known protist bioindicators: diatoms and foraminifera. The results of these studies show that despite some biological and technical biases, molecular data quite faithfully reflect the morphology-based biotic indices and provide a similar assessment of ecosystem status. In view of these results, protist metabarcoding appears as a rapid and accurate tool for the evaluation of the quality of aquatic ecosystems. Hence, we plead for integration of protist metabarcoding in future biomonitoring projects as a complement of traditional methods and a source of new biosensors for environmental impact assessment.


Social working memory: Memory for another rat's spatial choices can increase or decrease choice tendencies.
In two experiments using a radial-arm maze, pairs of rats made choices among eight maze locations, each containing a large quantity of one of two food types. The choices made by 1 rat affected the choices made by the other rat. Under most conditions, visits by 1 rat increased the tendency of the other rat to subsequently choose that maze location. However, the effect depended on the quality of the food available in a particular location. When it was possible for the rats to observe each other on the maze arms and a rat had experienced that a location contained the less preferred food type, a previous visit to that location by the foraging partner decreased the tendency to visit that location. These effects are attributed to working memory for the spatial choices of another rat, and they indicate that memory produced by a rat's own visit to a maze location is integrated with memory for the behavior of another rat to determine spatial choice.


Ozone therapy: A clinical review.
Ozone (O(3)) gas discovered in the mid-nineteenth century is a molecule consisting of three atoms of oxygen in a dynamically unstable structure due to the presence of mesomeric states. Although O(3) has dangerous effects, yet researchers believe it has many therapeutic effects. Ozone therapy has been utilized and heavily studied for more than a century. Its effects are proven, consistent, safe and with minimal and preventable side effects. Medical O(3) is used to disinfect and treat disease. Mechanism of actions is by inactivation of bacteria, viruses, fungi, yeast and protozoa, stimulation of oxygen metabolism, activation of the immune system. Medication forms in a gaseous state are somewhat unusual, and it is for this reason that special application techniques have had to be developed for the safe use of O(3). In local applications as in the treatment of external wounds, its application in the form of a transcutaneous O(3) gas bath has established itself as being the most practical and useful method, for example at low (sub-atmospheric) pressure in a closed system guaranteeing no escape of O(3) into the surrounding air. Ozonized water, whose use is particularly known in dental medicine, is optimally applied as a spray or compress. Diseases treated are infected wounds, circulatory disorders, geriatric conditions, macular degeneration, viral diseases, rheumatism/arthritis, cancer, SARS and AIDS.


Carbon dioxide spectral line frequencies for the 4.3-microm region.
The frequencies of CO(2) lines in the 3.77-4.26-microm region, which were obtained experimentally, have been compared with those listed on two tapes of the AFCRL Atmospheric Absorption Line Parameters Compilation. The experimental line frequencies were obtained in absorption using a high-resolution Michelson interferometer. Discrepancies between the present experimental values and the frequencies listed on the AFCRL tapes are tabulated. Consistency checks were also made by comparing calculated line frequencies with those on the tapes, and these findings are also reported.


Old and homeless: a review and survey of older adults who use shelters in an urban setting.
Research on the mental health and service needs of homeless seniors has been scant. This paper reviews the available literature and presents findings of a Toronto survey in an effort to describe the demographics of homeless seniors, their level of impairment, and their mental and physical health needs. We searched the Medline, AgeLine, and PsycINFO databases, using the following key words: elderly homeless, elderly hostel users, and urban geriatrics. To better describe the service needs of the elderly homeless, we obtained demographic data from the Community and Neighbourhood Services Department and distributed a survey questionnaire to 11 Toronto hostel directors. The questionnaire elicited data relating to reasons for shelter use, problem behaviours, and mental health needs of those over age 65 years. Although seniors represent a small percentage of the homeless population, their numbers are growing. The available literature suggests a high prevalence of psychiatric disorders and cognitive impairment in this population, with a greater proportion of older women than men having severe mental illness. Further, our survey suggests that the service needs of elderly hostel users in Toronto differ from those of their younger counterparts. The homeless elderly are the most vulnerable of this impoverished population. Although more research is needed to define their mental and physical health needs and ways of meeting them, their characteristics appear to be unique. Geriatric psychiatrists could play a significant role in evaluating and treating this population more comprehensively.


The influence of Chinese culture on family caregivers of stroke survivors: A qualitative study.
To explore and describe the caregiving experiences of Chinese stroke caregivers. Previous research has indicated that culture can have a significant impact on the stroke caregiving experience. Moreover, scant research exists on stroke caregivers' experience within the Chinese culture. A qualitative descriptive design was used. In-depth, semistructured interviews were conducted with 25 family caregivers of stroke survivors. The interviews were audiotaped, transcribed and analysed. Content analysis was also performed. Twenty-five family caregivers of stroke survivors were recruited for the study. On average, respondents were 66 years old (range 45-82 years). Of 25 interviewees, 76% were female, 64% were spouse-caregivers and 36% were children-caregivers. Three themes reflecting the influence of Chinese culture on stroke caregiving emerged from the interviews. (i) Caregiving role perception. Informants accepted caregiving for the sick family member as an expected part of life, a culturally prescribed obligation and an expression of reciprocal love. (ii) Coping strategies. Connecting with family resources and connecting with inner strength were frequently reported coping strategies. (iii) Self-sacrifice. Informants identified self-reliance and feeling of restraint in their utilisation or access of formal caregiving service. Chinese caregivers sacrifice themselves for the care recipients regardless of the hardships and the neglect of their own health. Our findings provide a comprehensive and culturally sensitive perspective in understanding the experience of stroke caregivers in Chinese communities. Cultural and religious backgrounds were found to influence Chinese stroke caregivers' experience, coping strategies and self-sacrifice behaviour in idiosyncratic ways. Research on the practice of culture can serve as a basis for the formulation of specific policies and effective interventions for supporting stroke caregivers of different cultural backgrounds.


Hepatocellular damage following therapeutic intravenous iron sucrose infusion in a child.
The maximum tolerated single dose of intravenous iron infusion and iron pharmacokinetics are not known in children and not clear in adults. The case reported here is of a child given a large dose of intravenous iron sucrose (16 mg/kg) over 3 hours, who subsequently developed features of systemic iron toxicity. A TDM consultant discusses the case in the context of toxicokinetic analysis. Because the maximum tolerated dose and pharmacokinetics of intravenous iron preparations are not known, their use in both adults and children should still be undertaken with caution.


Efficacy of Gastric Electrical Stimulation for Gastroparesis: US/European Comparison.
Gastric electrical stimulation (GES) is used in both the US and Europe, but little research has investigated the demographics of gastroparesis patients receiving GES by geographic location. We compared data from 380 patients, 296 female and 84 males, mean age 42 years, 246 idiopathic (ID), 107 diabetic (DM), and 27 post-surgical (PS). The statistical significance was calculated by Chi-square test and a P-value obtained for ID, DM, and PS. The statistical significance was calculated by Fischer exact test and a P-value obtained comparing male vs. female. European centers had 61 GES patients compared to 319 from the US. In Europe, 100% of patients had gastric emptying test (GET) values available; in the US, it was 75% of patients. European centers had more DM patients (59%) than the US (22%), and a smaller proportion of ID patients (25%) than the US (72%). There was a statistical difference between the causes of gastroparesis in the patients receiving GES (P-value < 0.00001). There was also significant difference in the gender of the patients receiving GES, with a greater proportion of women in the US (P value = 0.0023). Comparing GES in US vs. Europe demonstrated significant differences in gastroparesis demographics and percentage of patients with GET data. After analyzing the previously discussed results and reviewing recent updates in evidence-based medicine guidelines, the discrepancy and variance in patient populations in the US and Europe emphasizes the need for a database that allows better analysis and treatment of gastroparesis patients worldwide including stimulation therapies.


Limiting the development of anti-cancer drug resistance in a spatial model of micrometastases.
While chemoresistance in primary tumors is well-studied, much less is known about the influence of systemic chemotherapy on the development of drug resistance at metastatic sites. In this work, we use a hybrid spatial model of tumor response to a DNA damaging drug to study how the development of chemoresistance in micrometastases depends on the drug dosing schedule. We separately consider cell populations that harbor pre-existing resistance to the drug, and those that acquire resistance during the course of treatment. For each of these independent scenarios, we consider one hypothetical cell line that is responsive to metronomic chemotherapy, and another that with high probability cannot be eradicated by a metronomic protocol. Motivated by experimental work on ovarian cancer xenografts, we consider all possible combinations of a one week treatment protocol, repeated for three weeks, and constrained by the total weekly drug dose. Simulations reveal a small number of fractionated-dose protocols that are at least as effective as metronomic therapy in eradicating micrometastases with acquired resistance (weak or strong), while also being at least as effective on those that harbor weakly pre-existing resistant cells. Given the responsiveness of very different theoretical cell lines to these few fractionated-dose protocols, these may represent more effective ways to schedule chemotherapy with the goal of limiting metastatic tumor progression.


Laparoscopic assisted live donor nephrectomy--a comparison with the open approach.
Live donor renal transplantation provides significant advantages when compared with cadaveric donor renal transplantation in terms of improved patient and graft survival, a lower incidence of delayed function, and a shorter waiting time. Yet despite these advantages, live donors continue to be an under utilized source of kidneys for transplantation. Disincentives to live donation include the length of hospitalization, postoperative pain, cosmetic concerns, and the prolonged convalescence associated with the donor operation. In many instances minimally invasive video-assisted techniques have proven more efficacious than standard open procedures in terms of patient discomfort, length of hospital stay, cost, and length of time until the patient can return to full activity. Laparoscopic live donor nephrectomies are being performed at our institution in an attempt to make live donation more attractive to the potential donor. The purpose of this study was to retrospectively review the results of laparoscopic live donor nephrectomy (LapNx) and to compare them with those obtained using the standard open approach (OpenNx). Ten consecutive LapNx were performed from February 1995 through April 1996. The control group consisted of the 20 consecutive OpenNx performed at the same institution from January 1991 through January 1995 immediately before the initiation of the LapNx program. Live donors were considered candidates for LapNx if they possessed at least one kidney with normal renal anatomy with single renal vessels and a single ureter. LapNx was safely performed in all cases. No patients required open conversion or blood transfusions. The allograft warm ischemic time for the laparoscopic cases was 4.2+/-1.3 min. All kidneys harvested laparoscopically produced urine on the table immediately upon revascularization. Presently nine of the ten recipients have functioning allografts. At three months posttransplant the calculated recipient creatinine clearances were 67.0+/-11.5 ml/min and 64.8+/-21.4 ml/min for the LapNx and OpenNx groups, respectively (P=NS). The LapNx donors had a significantly decreased estimated blood loss, shorter time until resumption of oral intake, decreased postoperative pain (in terms of decreased analgesic requirements), shorter hospitalization, and a shorter interval until the resumption of full activities (P<0.05 for all). In addition, the LapNx group donors returned to work sooner than the OpenNx group (3.9+/-1.6 wk vs. 6.4+/-3.1 wk, respectively) (P=0.024). Four individuals agreed to donate a kidney only after learning of the availability of the laparoscopic approach. We conclude that laparoscopic live donor nephrectomy is technically feasible. In addition, it may offer significant advantages over the standard open approach in terms of patient comfort and convenience. These advantages may make live donor renal transplantation more attractive to prospective donors. The potential decrease in hospitalization and convalescence may also prove to be financially advantageous. We believe that further careful study of this procedure is warranted.


Redundant and pathogenic roles for IL-22 in mycobacterial, protozoan, and helminth infections.
IL-22 is a member of the IL-10 cytokine family and signals through a heterodimeric receptor composed of the common IL-10R2 subunit and the IL-22R subunit. IL-10 and IL-22 both activate the STAT3 signaling pathway; however, in contrast to IL-10, relatively little is known about IL-22 in the host response to infection. In this study, using IL-22(-/-) mice, neutralizing Abs to IL-22, or both, we show that IL-22 is dispensable for the development of immunity to the opportunistic pathogens Toxoplasma gondii and Mycobacterium avium when administered via the i.p. or i.v. route, respectively. IL-22 also played little to no role in aerosol infections with Mycobacterium tuberculosis and in granuloma formation and hepatic fibrosis following chronic percutaneous infections with the helminth parasite Schistosoma mansoni. A marked pathogenic role for IL-22 was, however, identified in toxoplasmosis when infections were established by the natural oral route. Anti-IL-22 Ab-treated mice developed significantly less intestinal pathology than control Ab-treated mice even though both groups displayed similar parasite burdens. The decreased gut pathology was associated with reduced IL-17A, IL-17F, TNF-alpha, and IFN-gamma expression. In contrast to the prior observations of IL-22 protective effects in the gut, these distinct findings with oral T. gondii infection demonstrate that IL-22 also has the potential to contribute to pathogenic inflammation in the intestine. The IL-22 pathway has emerged as a possible target for control of inflammation in certain autoimmune diseases. Our findings suggest that few if any infectious complications would be expected with the suppression of IL-22 signaling.


How to Cost the Implementation of Major System Change for Economic Evaluations: Case Study Using Reconfigurations of Specialist Cancer Surgery in Part of London, England.
Studies have been published regarding the impact of major system change (MSC) on care quality and outcomes, but few evaluate implementation costs or include them in cost-effectiveness analysis (CEA). This is despite large potential costs of MSC: change planning, purchasing or repurposing assets, and staff time. Implementation costs can influence implementation decisions. We describe our framework and principles for costing MSC implementation and illustrate them using a case study. We outlined MSC implementation stages and identified components, using a framework conceived during our work on MSC in stroke services. We present a case study of MSC of specialist surgery services for prostate, bladder, renal and oesophagogastric cancers, focusing on North Central and North East London and West Essex. Health economists collaborated with qualitative researchers, clinicians and managers, identifying key reconfiguration stages and expenditures. Data sources (n = approximately 100) included meeting minutes, interviews, and business cases. National Health Service (NHS) finance and service managers and clinicians were consulted. Using bottom-up costing, items were identified, and unit costs based on salaries, asset costs and consultancy fees assigned. Itemised costs were adjusted and summed. Cost components included options appraisal, bidding process, external review; stakeholder engagement events; planning/monitoring boards/meetings; and making the change: new assets, facilities, posts. Other considerations included hospital tariff changes; costs to patients; patient population; and lifetime of changes. Using the framework facilitated data identification and collection. The total adjusted implementation cost was estimated at £7.2 million, broken down as replacing robots (£4.0 million), consultancy fees (£1.9 million), staff time costs (£1.1 million) and other costs (£0.2 million). These principles can be used by funders, service providers and commissioners planning MSC and researchers evaluating MSC. Health economists should be involved early, alongside qualitative and health-service colleagues, as retrospective capture risks information loss. These analyses are challenging; many cost factors are difficult to identify, access and measure, and assumptions regarding lifetime of the changes are important. Including implementation costs in CEA might make MSC appear less cost effective, influencing future decisions. Future work will incorporate this implementation cost into the full CEAs of the London Cancer MSC. Not applicable.


Single-Cell Analysis of the Liver Epithelium Reveals Dynamic Heterogeneity and an Essential Role for YAP in Homeostasis and Regeneration.
The liver can substantially regenerate after injury, with both main epithelial cell types, hepatocytes and biliary epithelial cells (BECs), playing important roles in parenchymal regeneration. Beyond metabolic functions, BECs exhibit substantial plasticity and in some contexts can drive hepatic repopulation. Here, we performed single-cell RNA sequencing to examine BEC and hepatocyte heterogeneity during homeostasis and after injury. Instead of evidence for a transcriptionally defined progenitor-like BEC cell, we found significant homeostatic BEC heterogeneity that reflects fluctuating activation of a YAP-dependent program. This transcriptional signature defines a dynamic cellular state during homeostasis and is highly responsive to injury. YAP signaling is induced by physiological bile acids (BAs), required for BEC survival in response to BA exposure, and is necessary for hepatocyte reprogramming into biliary progenitors upon injury. Together, these findings uncover molecular heterogeneity within the ductal epithelium and reveal YAP as a protective rheostat and regenerative regulator in the mammalian liver.


Insecticide-treated net coverage in Africa: mapping progress in 2000-07.
Insecticide-treated bednets (ITNs) provide a means to improve child survival across Africa. Sales figures of these nets and survey coverage data presented nationally mask inequities in populations at biological and economic risk, and do not allow for precision in the estimation of unmet commodity needs. We gathered subnational ITN coverage sample survey data from 40 malaria-endemic countries in Africa between 2000 and 2007. We computed the projected ITN coverage among children aged less than 5 years for age-adjusted population data that were stratified according to malaria transmission risks, proximate determinants of poverty, and methods of ITN delivery. In 2000, only 1.7 million (1.8%) African children living in stable malaria-endemic conditions were protected by an ITN and the number increased to 20.3 million (18.5%) by 2007 leaving 89.6 million children unprotected. Of these, 30 million were living in some of the poorest areas of Africa: 54% were living in only seven countries and 25% in Nigeria alone. Overall, 33 (83%) countries were estimated to have ITN coverage of less than 40% in 2007. On average, we noted a greater increase in ITN coverage in areas where free distribution had operated between survey periods. By mapping the distribution of populations in relation to malaria risk and intervention coverage, we provide a means to track the future requirements for scaling up essential disease-prevention strategies. The present coverage of ITN in Africa remains inadequate and a focused effort to improve distribution in selected areas would have a substantial effect on the continent's malaria burden.


Efficient generation of connectivity in neuronal networks from simulator-independent descriptions.
Simulator-independent descriptions of connectivity in neuronal networks promise greater ease of model sharing, improved reproducibility of simulation results, and reduced programming effort for computational neuroscientists. However, until now, enabling the use of such descriptions in a given simulator in a computationally efficient way has entailed considerable work for simulator developers, which must be repeated for each new connectivity-generating library that is developed. We have developed a generic connection generator interface that provides a standard way to connect a connectivity-generating library to a simulator, such that one library can easily be replaced by another, according to the modeler's needs. We have used the connection generator interface to connect C++ and Python implementations of the previously described connection-set algebra to the NEST simulator. We also demonstrate how the simulator-independent modeling framework PyNN can transparently take advantage of this, passing a connection description through to the simulator layer for rapid processing in C++ where a simulator supports the connection generator interface and falling-back to slower iteration in Python otherwise. A set of benchmarks demonstrates the good performance of the interface.


[Child psychiatry: limited research, evidence for cost-effectiveness of treatment].
Research into cost-effectiveness of treatment of child psychiatric disorders is extremely limited. There are two main reasons for this: it's a new field and the type of research required is intrinsically complicated.
 AIM: To review selected articles that reveal the prevalence of child psychiatric disorders, demonstrate the complexity of cost-efficiency research in child psychiatry and point to the possible benefits of appropriate treatment.
 METHOD: We provide an overview of a selected number of articles dealing with the prevalence of child psychiatric disorders and the costs involved, we stress the diffulty of assessing whether current treatment is cost-effective and we describe the possible benefits of treatment.
 RESULTS: However, the limited number of articles that we located do indicate that the treatment of children with psychiatric disorders is cost-effective. Not only does it benefit the child, it also eases the burden on the parents and on society as a whole. Findings need to be interpreted in the light of the limited scope and shortcomings of the research done so far.
 CONCLUSION: Although current research seems to be cost-effective, we stress the need for further investigations, particularly in the form of longer-term studies.


CRIMALDDI: a prioritized research agenda to expedite the discovery of new anti-malarial drugs.
The CRIMALDDI Consortium has been a three-year project funded by the EU Framework Seven Programme. It aimed to develop a prioritized set of recommendations to speed up anti-malarial drug discovery research and contribute to the setting of the global research agenda. It has attempted to align thinking on the high priority issues and then to develop action plans and strategies to address these issues. Through a series of facilitated and interactive workshops, it has concluded that these priorities can be grouped under five key themes: attacking artemisinin resistance; creating and sharing community resources; delivering enabling technologies; exploiting high throughput screening hits quickly; and, identifying novel targets. Recommendations have been prioritized into one of four levels: quick wins; removing key roadblocks to future progress; speeding-up drug discovery; and, nice to have (but not essential). Use of this prioritization allows efforts and resources to be focused on the lines of work that will contribute most to expediting anti-malarial drug discovery. Estimates of the time and finances required to implement the recommendations have also been made, along with indications of when recommendations within each theme will make an impact. All of this has been collected into an indicative roadmap that, it is hoped, will guide decisions about the direction and focus of European anti-malarial drug discovery research and contribute to the setting of the global research agenda.


Competence in the context of adversity: pathways to resilience and maladaptation from childhood to late adolescence.
Competent outcomes in late adolescence were examined in relation to adversity over time, antecedent competence and psychosocial resources, in order to investigate the phenomenon of resilience. An urban community sample of 205 (114 females, 90 males; 27% minority) children were recruited in elementary school and followed over 10 years. Multiple methods and informants were utilized to assess three major domains of competence from childhood through adolescence (academic achievement, conduct, and peer social competence), multiple aspects of adversity, and major psychosocial resources. Both variable-centered and person-centered analyses were conducted to test the hypothesized significance of resources for resilience. Better intellectual functioning and parenting resources were associated with good outcomes across competence domains, even in the context of severe, chronic adversity. IQ and parenting appeared to have a specific protective role with respect to antisocial behavior. Resilient adolescents (high adversity, adequate competence across three domains) had much in common with their low-adversity competent peers, including average or better IQ, parenting, and psychological well-being. Resilient individuals differed markedly from their high adversity, maladaptive peers who had few resources and high negative emotionality. Results suggest that IQ and parenting scores are markers of fundamental adaptational systems that protect child development in the context of severe adversity.


Differential effects of single and double parental death on child emotional functioning and daily life in South Africa.
There is a high level of orphaning in Africa due to war, violence, and more recently HIV and AIDS. This study examines parental death in South African children and examines the differential impact on child functioning of double, single and non-orphanhoods. Bereavement, depression, behavior problems, and violence were examined in a consecutive sample of 381 children/adolescents (51.2% girls) between 8 and 19 years of age (M = 12.8). Parental death experience was high; 70 (17.5%) reported the death of one parent, and a further 24 (6%) reported the death of both. Group comparisons showed double orphans had elevated depression, worse psychosocial functioning, were more likely to be kept home from school for household chores, and were more likely to be slapped. Single orphans were more similar to the non-orphans than the double orphans on most scores. Our study reveals that parental loss should be studied with more fine-grained definitions and that emotional sequelae should be addressed.


Association Between Birth Defects and Cancer Risk Among Children and Adolescents in a Population-Based Assessment of 10 Million Live Births.
Birth defects affect approximately 1 in 33 children. Some birth defects are known to be strongly associated with childhood cancer (eg, trisomy 21 and acute leukemia). However, comprehensive evaluations of childhood cancer risk in those with birth defects have been limited in previous studies by insufficient sample sizes. To identify specific birth defect-childhood cancer (BD-CC) associations and characterize cancer risk in children by increasing number of nonchromosomal birth defects. This multistate, population-based registry linkage study pooled statewide data on births, birth defects, and cancer from Texas, Arkansas, Michigan, and North Carolina on 10 181 074 children born from January 1, 1992, to December 31, 2013. Children were followed up to 18 years of age for a diagnosis of cancer. Data were retrieved between September 26, 2016, and September 21, 2017, and data analysis was performed from September 2, 2017, to March 21, 2019. Birth defects diagnoses (chromosomal anomalies and nonchromosomal birth defects) recorded by statewide, population-based birth defects registries. Cancer diagnosis before age 18 years, as recorded in state cancer registries. Cox regression models were used to generate hazard ratios (HRs) and 95% CIs to evaluate BD-CC associations and the association between number of nonchromosomal defects and cancer risk. Compared with children without any birth defects, children with chromosomal anomalies were 11.6 (95% CI, 10.4-12.9) times more likely to be diagnosed with cancer, whereas children with nonchromosomal birth defects were 2.5 (95% CI, 2.4-2.6) times more likely to be diagnosed with cancer before 18 years of age. An increasing number of nonchromosomal birth defects was associated with a corresponding increase in the risk of cancer. Children with 4 or more major birth defects were 5.9 (95% CI, 5.3-6.4) times more likely to be diagnosed with cancer compared with those without a birth defect. In the analysis of 72 specific BD-CC patterns, 40 HRs were statistically significant (adjusted P < .05) after accounting for multiple comparisons. Cancers most frequently associated with nonchromosomal defects were hepatoblastoma and neuroblastoma. Several significant and novel associations were observed between specific birth defects and cancers. Among children with nonchromosomal birth defects, the number of major birth defects diagnosed was significantly and directly associated with cancer risk. These findings could inform clinical treatment for children with birth defects and may elucidate mechanisms that lead to these complex outcomes.


Cyclic stretching stimulates synthesis of matrix components by arterial smooth muscle cells in vitro.
Rabbit aortic medial cells were grown on purified elastin membranes, which were then subjected to repeated elongation and relaxation or to agitation without stretching. Cells remained attached to the membranes, and cyclic stretching resulted in a two- to fourfold increase in rates of collagen, hyaluronate, and chondroitin 6-sulfate synthesis over those in agitated or stationary preparations. Synthesis of types I and III collagen was increased to the same degree. Stretching did not increase rates of chondroitin 4-sulfate or dermatan sulfate synthesis. Differences were not attributable to differences in cell number, for DNA synthetic rates were not increased by stretching. The model system devised to demonstrate these effects provides a means for relating various modes of mechanical stimulation to cell metabolism.


Evaluation of habitat protection under the European Natura 2000 conservation network - The example for Germany.
The world´s largest network of protected areas-Natura 2000 (N2000)-has been implemented to protect Europe´s biodiversity. N2000 is built upon two cornerstones, the Birds Directive, which lists 691 bird species (plus one additional bird genus with no further classification) and the Habitats Directive, which lists next to a variety of species, 233 habitat types to be protected. There is evidence of the positive impact of the Directives on the EU´s biodiversity, although the overall improvement reported for species in favourable condition in the last assessment was low. However, most of the assessments are species focused, while habitats have received very little attention. Here we developed a generic workflow, which we exemplified for Germany, to assess the status of habitat coverage within the N2000 network combining information from publicly available data sources. Applying the workflow allows identification of gaps in habitat protection, followed by the prioritization of potential areas of high protection value using the conservation planning software Marxan. We found that, in Germany, N2000 covers all target habitats. However, common habitats were proportionally underrepresented relative to rare ones, which contrasts with studies focussing on the representation of species. Moreover, the German case study suggests that especially highly protected areas (i.e. covered by more than 90% with N2000 sites) build an excellent basis towards a cost-effective and efficient conservation network. Our workflow provides a generic approach to deal with the common problem of missing habitat distribution data outside of N2000 sites, information which is however crucial for managers to plan conservation actions appropriately across Europe. To avoid a biased representation of habitat types within N2000, our results underpin the importance of defining qualitative and quantitative conservation targets which will allow assesment of the trajectory of habitat protection in Europe as well as adjustment of the network accordingly-a future necessity in the light of climate change.


Spatial pattern analysis of hop powdery mildew in the pacific northwest: implications for sampling.
ABSTRACT The spatial pattern of hop powdery mildew was characterized using 3 years of disease incidence data collected in commercial hop yards in the Pacific Northwest. Yards were selected randomly from yards with a history of powdery mildew, and two to five rows were selected for sampling within each yard. The proportion of symptomatic leaves out of 10 was determined from each of N sampling units in a row. The binomial and the beta-binomial frequency distributions were fit to the N sampling units observed in each row and to SigmaN sampling units observed in each yard. Distributional analyses indicated that disease incidence was better characterized by the beta-binomial than the binomial distribution in 25 and 47% of the data sets at the row and yard scales, respectively, according to a log-likelihood ratio test. Median values of the beta-binomial parameter theta, a measure of small-scale aggregation, were near 0 at both sampling scales, indicating that disease incidence was close to being randomly distributed. The variability in disease incidence among rows sampled in the same yard generally increased with mean incidence at the yard scale. Spatial autocorrelation analysis, used to measure large-scale patterns of aggregation, indicated that disease incidence was not correlated between sampling units over several lag distances. Results of a covariance analysis showed that heterogeneity of disease incidence was not dependent upon cultivar, region, or time of year when sampling was conducted. A hierarchical analysis showed that disease incidence at the sampling unit scale (proportion of sampling units with one or more diseased leaves) increased as a saturation-type curve with respect to incidence at the leaf level and could be described by a binomial function modified to account for the effects of heterogeneity through an effective sample size. Use of these models permits sampling at the sampling unit scale while allowing inferences to be made at the leaf scale. Taken together, hop powdery mildew was nearly randomly distributed with no discernable foci, suggesting epidemics are initiated from a well-distributed or readily dispersible overwintering population. Implications for sampling are discussed.


Assessment of interferon-γ levels and leishmanin skin test results in persons recovered for leishmaniasis.
Patients who recover from leishmaniasis usually show development of strong immunity and induction of interferon-γ (IFN-γ) and delayed type hypersensitivity. In a randomized trial, we analyzed the IFN-γ response by using a Quantiferon-Leishmania assay against three Leishmania peptide antigens and compared it with results of the leishmanin skin test (LST) in persons residing in areas in Iran to which zoonotic cutaneous leishmaniasis (ZCL, 181 persons), anthroponotic cutaneous leishmaniasis (ACL, 104 persons), and zoonotic visceral leishmaniasis (ZVL, 67 persons) are endemic. The percentage of persons with an IFN-γ-positive response (> 0.2 IU/mL) to three antigens and the mean concentration of IFN-γ induced by the antigens were higher for persons from areas endemic for ZVL than for persons from areas endemic for ZCL and ACL. The percentage of persons with LST-positive results (≥ 5 mm indurations) was 99%, 94%, and 70% for areas with ZCL, ACL, and ZVL, respectively. Our data indicate that the LST is significantly more sensitive than IFN-γ levels in persons who have been cured of cutaneous leishmaniasis than in persons who have been cured of ZVL.


Readiness Assessment for Extubation Planning in the Intensive Care Unit: A Quality Improvement Initiative.
Extubation failure is the reintubation of patients meeting criteria for weaning from mechanical ventilation. Extubation failure is correlated with mortality, prolonged mechanical ventilation, and longer hospital stays. Noninvasive ventilation or high-flow nasal cannula oxygen therapy after extubation is recommended to prevent extubation failure in high-risk patients. The extubation failure rate is unknown. Prophylactic measures (noninvasive ventilation or high-flow nasal cannula) after extubation are not commonly used and vary among clinicians. The objective was to assess extubation planning readiness by determining extubation failure rate, identifying high-risk patients, and determining prophylactic measure compliance. A quality improvement initiative included an evidence-based extubation failure risk assessment that identified high-risk patients and determined prophylactic measure compliance. A 2-year retrospective medical record review was used to determine baseline patient characteristics and extubation failure rate. Results Extubation failure rate within the retrospective cohort was 13 of 146 patients (8.9%). Extubation failure did not correlate with previously identified risk factors; however, 150 identified patients were excluded from analysis. During risk assessment integration, the extubation failure rate was 3 of 37 patients (8.1%) despite identifying 24 high-risk patients (65%). Few high-risk patients received prophylactic measures (noninvasive ventilation, 17%; high-flow nasal cannula, 12%). Extubation failure should be routinely measured because of its effects on patient outcomes. This project reveals the multifactorial nature of extubation failure. Further research is needed to assess patients' risk and account for acute conditions. This project used best practice guidelines for routine patient care and added transparency to a previously unmeasured event.


Endomyocardial proteomic signature corresponding to the response of patients with dilated cardiomyopathy to immunoadsorption therapy.
Dilated cardiomyopathy (DCM) is a disease of the myocardium with reduced left ventricular ejection fraction (LVEF). Cardiac autoantibodies (AAbs) play a causal role in the development and progression of DCM. Removal of AAbs using immunoadsorption (IA/IgG) has been shown as a therapeutic option to improve cardiac function. However, the response to therapy differs significantly among patients. The reasons for this variability are not completely understood. Hitherto, no potential biomarker is available to predict improvement of cardiac function after therapy accurately. This shotgun proteome study aims to disclose the differences in the endomyocardial proteome between patients with improved LVEF after IA/IgG (responders) and those without improvement (non-responders) before therapy start. Comparative analysis revealed 54 differentially abundant proteins that were mostly confined to carbohydrate and lipid metabolism, energy and immune regulation, and cardioprotection. Selected proteins representing various functional categories were further confirmed by multiple reaction monitoring (MRM). Among those, protein S100-A8, perilipin-4, and kininogen-1 were found the most robust candidates differentiating responders and non-responders. Receiver operating characteristic curve (ROC) analysis of these proteins revealed highest potential for protein S100-A8 (AUC 0.92) with high sensitivity and specificity to be developed as a classifier for the prediction of cardiac improvement after IA/IgG therapy. We evaluated the differences in the myocardial proteome of responder and non-responder DCM patients before immunoadsorption therapy and identified a number of differentially abundant proteins involved in energy and lipid metabolism, immune system, and cardioprotection. MRM was used for verification of results. Proteins S100-A8, perilipin-4, and kininogen-1 were found to display the largest differences. The results provide a lead for further studies to screen for protein biomarker candidates in plasma that might be helpful to stratify patients for immunoadsorption therapy treatment.


Human binucleate hepatocytes: are they a defence during chronic liver diseases?
Binucleate cells are commonly found in various human organs including liver, salivary glands and endometrium, but their functional advantage remains unknown. The increased occurrence of binucleate hepatocytes during the necro-inflammation stage of progressive chronic hepatitis and its end-stage of cirrhosis, but their absence in hepatocellular carcinoma (HCC), has led us to hypothesise that they may be an index of the severity of hepatic illness rather than the result of errors occurring during the course of the cell cycle. This hypothesis is supported by the immunohistochemical analysis of retinol-binding protein expression, and the different life cycles of hepatitis B virus in mononucleate and binucleate hepatocytes. If founded, this hypothesis would add to our understanding of the relationship between binucleate hepatocytes and the evolution of chronic liver disease, and promises the ideation of new criteria for identifying potential HCC patients.


The use of computerized tomography for diagnosis and treatment planning in implant dentistry.
Preoperative radiographic imaging of recipient sites for implant placement is imperative to obtain a functional and aesthetic implant-supported prosthesis. Although conventional radiographic techniques have inherent problems that restrict accurate imaging, the main drawback of panoramic and periapical radiography is the two-dimensional image. Computerized tomography provides cross-sectional radiographic images that facilitate proper assessment of potential recipient sites for implant placement. This paper reviews the role of computerized tomography in implant dentistry.


Altered primary chromatin structures and their implications in cancer development.
Cancer development is a complex process involving both genetic and epigenetic changes. Genetic changes in oncogenes and tumor-suppressor genes are generally considered as primary causes, since these genes may directly regulate cellular growth. In addition, it has been found that changes in epigenetic factors, through mutation or altered gene expression, may contribute to cancer development. In the nucleus of eukaryotic cells DNA and histone proteins form a structure called chromatin which consists of nucleosomes that, like beads on a string, are aligned along the DNA strand. Modifications in chromatin structure are essential for cell type-specific activation or repression of gene transcription, as well as other processes such as DNA repair, DNA replication and chromosome segregation. Alterations in epigenetic factors involved in chromatin dynamics may accelerate cell cycle progression and, ultimately, result in malignant transformation. Abnormal expression of remodeler and modifier enzymes, as well as histone variants, may confer to cancer cells the ability to reprogram their genomes and to yield, maintain or exacerbate malignant hallmarks. At the end, genetic and epigenetic alterations that are encountered in cancer cells may culminate in chromatin changes that may, by altering the quantity and quality of gene expression, promote cancer development. During the last decade a vast number of studies has uncovered epigenetic abnormalities that are associated with the (anomalous) packaging and remodeling of chromatin in cancer genomes. In this review I will focus on recently published work dealing with alterations in the primary structure of chromatin resulting from imprecise arrangements of nucleosomes along DNA, and its functional implications for cancer development. The primary chromatin structure is regulated by a variety of epigenetic mechanisms that may be deregulated through gene mutations and/or gene expression alterations. In recent years, it has become evident that changes in chromatin structure may coincide with the occurrence of cancer hallmarks. The functional interrelationships between such epigenetic alterations and cancer development are just becoming manifest and, therefore, the oncology community should continue to explore the molecular mechanisms governing the primary chromatin structure, both in normal and in cancer cells, in order to improve future approaches for cancer detection, prevention and therapy, as also for circumventing drug resistance.


Effect of yoga-nidra on blood glucose level in diabetic patients.
Diabetes is a metabolic disorder, which has become a major health challenge worldwide. South East Asian countries have a highest burden of diabetes. In India the prevalence of diabetes is rising rapidly especially in the urban population because of increasing obesity and reduced physical activity. An objective of this study is to evaluate the effect of Yoga-Nidra on blood glucose level in diabetic patients. This study was conducted on 41, middle aged, type-2 diabetic patients, who were on oral hypoglycaemic. These patients were divided in to two groups: (a) 20 patients on oral hypoglycaemic with yoga-nidra, and (b) 21 were on oral hypoglycaemic alone. Yoga-nidra practiced for 30 minutes daily up to 90 days, parameters were recorded every. 30th day. Results of this study showed that most of the symptoms were subsided (P < 0.004, significant), and fall of mean blood glucose level was significant after 3-month of Yoga-nidra. This fall was 21.3 mg/dl, P < 0.0007, (from 159 +/- 12.27 to 137.7 +/- 23.15,) in fasting and 17.95 mg/dl, P = 0.02, (from 255.45 +/- 16.85 to 237.5 +/- 30.54) in post prandial glucose level. Results of this study suggest that subjects on Yoga-nidra with drug regimen had better control in their fluctuating blood glucose and symptoms associated with diabetes, compared to those were on oral hypoglycaemics alone.


The impact of home-delivered meal services on the nutritional intake of community living older adults: a systematic literature review.
There is a global increase in populations aged over 65 years. Physiological changes that occur during ageing may increase the nutritional risk for older adults. To avoid malnutrition and address some of the barriers to obtain an adequate food supply, home-delivered meals services provide meals in the home or in congregate settings for older adults who require nutritional support. This systematic literature review explored whether nutritional intake is improved in community-living older adults when receiving meal services compared to when meal services are not received. Four electronic databases were searched up to 31 January 2019. In total, 13 original studies were included in this analysis with the components: intervention of home-delivered meal or congregate meal services to older adults; comparison with groups not receiving meal services or days not receiving the meal service; and nutritional intake as an outcome measured by food history, dietary recall and/or food frequency questionnaire. The results supported a beneficial effect of home-delivered meals on dietary intake of energy, protein and/or certain micronutrients in older adults. The increased total energy intake is a positive influence on malnutrition risk in frail older adults and the increased protein intake supports good health, promotes recovery from illness and assists in maintaining functionality in older adults. Additionally, there was a particular increase in calcium intake, which is relevant in ageing, especially for bone health.


Long-term Consequences of Finasteride vs Placebo in the Prostate Cancer Prevention Trial.
Finasteride has been found to reduce the risk of low-grade prostate cancer but to have no impact on overall survival. The long-term adverse and beneficial consequences of finasteride have not been examined. We used a linkage between data from the Prostate Cancer Prevention Trial (PCPT) and Medicare claims. Patients were examined by randomized study arm (finasteride vs placebo for 7 years) for long-term consequences of the intervention, including cardiac, endocrine, and sexual dysfunction, depression, diabetes, and benign prostatic hyperplasia (BPH)-related events. To examine time to events, we used cumulative incidence and Cox regression, adjusting for covariates. All statistical tests were two-sided. A total of 13 935 of 18 880 participants (73.8%) in the PCPT were linked to Medicare claims, with median Medicare follow-up assessment time of 16 years from trial registration. There were no differences between finasteride and placebo participants with respect to important baseline factors or amount of Medicare follow-up assessment time. Finasteride patients had a 10% higher risk of new claims for depression (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.01 to 1.19, P = .04) and a 6% lower risk of procedures for BPH-related events (primarily lower urinary tract symptoms; HR = 0.94, 95% CI = 0.89 to 1.00, P = .03). No other differences were found in rates of long-term consequences of intervention in the two study arms. Finasteride use is associated with reduced need for procedures for relief of BPH-related events and a modest increase in depression. Overall, there is little need to worry about long-term noncancer consequences of finasteride use in those who use it for treatment of symptomatic BPH, hair growth, or prevention of cancer.


Determinants of global perceived health in community-dwelling elderly screened for heart failure and sleep-disordered breathing.
The relationships between heart failure (HF), sleep-disordered breathing (SDB), insomnia, depressive symptoms, and excessive daytime sleepiness (EDS), as well as their relationship to Global Perceived Health (GPH) in an elderly community-dwelling population, have not been explored. Data from 331 community-dwelling elderly (71-87 years old) were collected by echocardiography, polygraphy, and specific questionnaires. Factor analyses and structural equation modeling were used to explore the relationships between HF, SDB, sleep, psychosocial factors, and GPH. Exploratory and confirmatory factor analyses derived a 5-factor model representing SDB, insomnia, systolic function, breathlessness/physical function, and psychosocial function. Structural equation modeling analyses were used to explore the relationships between the 5 factors and to GPH. Sleep-disordered breathing had a weak effect on systolic function, but no effects on any of the other factors or GPH were found. Psychosocial function and breathlessness/physical function directly affected GPH. Indirect effects on GPH, mediated by psychosocial function, were found for breathlessness/physical function and insomnia. Systolic function also had an indirect effect on GPH. The fact that SDB in the elderly has no obvious negative associations to sleep complaints or GPH does not exclude them from being adequately treated for SDB. However, the present study has shown that SDB, by means of self-rated sleep complaints and health-related quality of life, can be problematic to detect. Psychosocial function was the most important factor for perceived GPH as it had a direct effect, as well as mediated the factors breathlessness/physical function and insomnia effects, on GPH. This study indicates that interventions in clinical practice targeting psychosocial dysfunction, such as depressive symptoms, could help to improve GPH in the elderly with or without HF.


Smoking, alcohol, and analgesics in dyspepsia and among dyspepsia subgroups: lack of an association in a community.
Dyspepsia is common in the general population, and despite a paucity of data, smoking, alcohol, and analgesics are believed to be important risk factors. The role of these environmental factors in subjects with uninvestigated dyspepsia was evaluated in a representative population sample. An age and gender stratified random sample of residents of Olmsted County, Minnesota, aged 20 to 64 years was mailed a valid self report questionnaire; 77% responded (n = 1644). Age and gender adjusted (1990 US white population) prevalence rates for dyspepsia (defined as frequent pain located in the upper abdomen, or nausea in the absence of a history of peptic ulcer disease) were calculated. Logistic regression analysis was used to estimate the association between dyspepsia and potential risk factors. The age and gender adjusted prevalence (per 100) of dyspepsia in the community was 21.8 (95% confidence interval 19.6, 23.9). Dyspepsia was significantly more common in younger subjects and females. Adjusting for age and gender, paracetamol (odds ratio (OR) = 2.2), aspirin (OR = 1.8), and smoking (OR = 1.5), but not alcohol (OR = 0.9), were associated with dyspepsia (all p < 0.05). When non-gastrointestinal somatic complaints were included in the logistic models, however, these environmental factors were no longer significant (OR = 1.3, 1.1, 1.2 and 0.9, respectively). Similar results were obtained when ulcer-like, dysmotility-like, and reflux-like dyspepsia were considered separately. The results were not significantly changed when subjects with a history of ulcer disease were included in the analyses. Smoking, alcohol, and analgesics may not therefore be important risk factors for dyspepsia in the community.


A randomised controlled clinical trial on the additional effect of hypnosis in a comprehensive treatment programme for in-patients with conversion disorder of the motor type.
The primary aim of this study was threefold: (1) to examine the additional effects of hypnosis aimed at symptom reduction, using symptom-oriented and expression- and insight-oriented techniques in a comprehensive clinical treatment programme for in-patients with a persistent conversion disorder of the motor type; (2) to assess whether the level of hypnotisability was predictive of treatment outcome, and (3) to explore the efficacy of the total clinical treatment programme. The study population consisted of 45 in-patients between 18 and 65 years of age meeting the DSM-III-R criteria for conversion disorder of the motor type or somatisation disorder with motor conversion symptoms. A randomised controlled clinical trial was undertaken. The primary outcome measures were the Video Rating Scale for Motor Conversion Symptoms, the D(isabilities) code items from the International Classification of Impairments, Disabilities and Handicaps and the Symptom Checklist-90. Measures of the credibility of treatment and patient expectations of treatment outcome were used as manipulation checks. Hypnotisability was measured using the Stanford Hypnotic Clinical Scale. Significant treatment results for all outcome measures were found for the total sample. These effects proved to be clinically significant. The use of hypnosis had no additional effect on treatment outcome. Hypnotisability was not predictive of treatment outcome. A comprehensive treatment programme, either with or without hypnosis, can be worthwhile for patients with long-standing conversion symptoms.


Sulfidogenic fluidized-bed treatment of metal-containing wastewater at low and high temperatures.
The applicability of a fluidized-bed reactor (FBR)-based sulfate reducing bioprocess was investigated for the treatment of iron-containing (40-90 mg/L) acidic wastewater at low (8 degrees C) and high (65 degrees C) temperatures. The FBRs operated at low and high temperatures were inoculated with cultures of sulfate-reducing bacteria (SRB) originally enriched from arctic and hot mining environments, respectively. Ethanol was supplemented as carbon and electron source for SRB. At 8 degrees C, ethanol oxidation and sulfate reduction rates increased steadily and reached 320 and 265 mg/L.day, respectively, after 1 month of operation. After this point, the rates did not change significantly during 130 days of operation. Despite the complete ethanol oxidation and iron precipitation, the average sulfate reduction efficiency was 35 +/- 4% between days 30 and 130 due to the accumulation of acetate. At 65 degrees C, a rapid startup was observed as 99.9, 46, and 29% ethanol, sulfate, acetate removals, in respective order, were observed after 6 days. The feed pH was decreased gradually from its initial value of 6 to around 3.7 during 100 days of operation. The wastewater pH of 4.3-4.4 was neutralized by the alkalinity produced in acetate oxidation and the average effluent pH was 7.8 +/- 0.8. As in the low temperature FBR, acetate accumulated. Hence, the oxidation of acetate is the rate-limiting step in the sulfidogenic ethanol oxidation by thermophilic and psychrotrophic SRB. The sulfate reduction rate is three times and acetate oxidation rate is four times higher at 65 degrees C than at 8 degrees C.


Hypoxia and the regulation of gene expression.
The optimal delivery of oxygen to tissues is essential both to ensure adequate energy provision and to avoid the toxic effects of higher oxygen concentrations. For this to occur, organisms must be able to sense oxygen and respond to changes in oxygen tension by altering gene expression. The analysis of the regulation of erythropoiesis has provided important insights into the mechanisms of oxygen-regulated gene expression. These mechanisms have a role in the regulation of many genes, in many cell types and appear to be of relevance to many common pathologies in which disturbances of oxygen supply are central.


Engineering more stable proteins.
Protein function requires the folded protein form, but this form is unstable mainly because it readily unfolds into a flexible, unstructured form. Protein folding is favored by burying of hydrophobic side chains and hydrogen bonding between the amino acids. Protein unfolding is favored by the increase in conformational freedom of the main chain of amino acids upon unfolding. Protein stability is usually measured by the reversible unfolding of the protein with either heat or chemical additives like urea. Engineering mores stable proteins involves making substitutions that shift the folding-unfolding balance toward the folded form. Stabilizing substitutions can either stabilize the folded conformation or destabilize the unfolded ensemble. This tutorial emphasizes web-based tools to identify substitutions that stabilize proteins. Besides unfolding, other sources of protein instability are chemical modifications like oxidations or cleavage by proteases and aggregation of partly unfolded proteins into insoluble particles.


The initial break-up of Pangæa elicited by Late Palæozoic deglaciation.
The break-up of Pangæa was principally facilitated by tensional plate stress acting on pre-existing suture zones. The rifting of Pangæa began during the Early Permian along the southern Tethys margin and produced the lenticular-shaped continent known as Cimmeria. A mantle-plume model is ascribed to explain the rift-related volcanism but the NW-SE oriented Cimmerian rifts do not correlate well with pre-existing suture zones or 'structural heterogeneities' but appear to have a pertinent spatial and temporal association with Late Palæozoic glacial-interglacial cycles. Mantle potential temperature estimates of Cimmerian rift-related basalts (1410 °C ± 50 °C) are similar to ambient mantle conditions rather than an active mantle-plume rift as previously suggested. Moreover, we find that the distribution of glacial deposits shows significant temporal and spatial concurrence between the glacial retreat margins and rifting sites. We conclude that the location and timing of Cimmerian rifting resulted from the exploitation of structural heterogeneities within the crust that formed due to repeated glacial-interglacial cycles during the Late Palæozoic. Such effects of continental deglaciation helped to create the lenticular shape of Cimmeria and Neotethys Ocean suggesting that, in some instances, climate change may directly influence the location of rifting.


Current concepts and management approaches in nonalcoholic fatty liver disease.
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver dysfunction worldwide. NAFLD may progress to nonalcoholic steatohepatitis (NASH) and in turn cirrhosis. Importantly, hepatic cancer can occur in NASH in the absence of cirrhosis. The cardinal histologic feature of NAFLD is the presence of an excessive accumulation of triacylglycerols and diacylglycerols in hepatocytes. The presence of obesity and insulin resistance lead to an increased hepatic-free fatty acid (FFA) flux creating an environment appropriate for the development of NAFLD. The generation of toxic reactive oxygen species with the production of hepatic injury and inflammation as a consequence of FFA oxidation will ultimately lead to the initiation and progression of fibrosis. Lifestyle modifications specifically weight loss, physical exercise, and cognitive behavior therapy have been recommended as treatments for NASH. Dietary fructose is an independent risk factor for the development of NAFLD. Pioglitazone can be used to treat biopsy-proven NASH; however, its safety risks should be considered carefully. Greater consumption for coffee, independent of its caffeine component, has been associated with a significant reduced risk of advanced fibrosis in NASH. Additional data are needed before recommending bariatric surgery as an established option for the specific treatment of NASH.


In-lake processes offset increased terrestrial inputs of dissolved organic carbon and color to lakes.
Increased color in surface waters, or browning, can alter lake ecological function, lake thermal stratification and pose difficulties for drinking water treatment. Mechanisms suggested to cause browning include increased dissolved organic carbon (DOC) and iron concentrations, as well as a shift to more colored DOC. While browning of surface waters is widespread and well documented, little is known about why some lakes resist it. Here, we present a comprehensive study of Mälaren, the third largest lake in Sweden. In Mälaren, the vast majority of water and DOC enters a western lake basin, and after approximately 2.8 years, drains from an eastern basin. Despite 40 years of increased terrestrial inputs of colored substances to western lake basins, the eastern basin has resisted browning over this time period. Here we find the half-life of iron was far shorter (0.6 years) than colored organic matter (A₄₂₀; 1.7 years) and DOC as a whole (6.1 years). We found changes in filtered iron concentrations relate strongly to the observed loss of color in the western basins. In addition, we observed a substantial shift from colored DOC of terrestrial origin, to less colored autochthonous sources, with a substantial decrease in aromaticity (-17%) across the lake. We suggest that rapid losses of iron and colored DOC caused the limited browning observed in eastern lake basins. Across a wider dataset of 69 Swedish lakes, we observed greatest browning in acidic lakes with shorter retention times (< 1.5 years). These findings suggest that water residence time, along with iron, pH and colored DOC may be of central importance when modeling and projecting changes in brownification on broader spatial scales.


Refined X-ray structure of Dictyostelium discoideum nucleoside diphosphate kinase at 1.8 A resolution.
The X-ray structure of the nucleoside diphosphate kinase (NDP kinase) from Dictyostelium discoideum has been refined at 1.8 A resolution from a hexagonal crystal form with a 17 kDa monomer in its asymmetric unit. The atomic model was derived from the previously determined structure of a point mutant of the protein. It contains 150 amino acid residues out of 155, and 95 solvent molecules. The R-factor is 0.196 and the estimated accuracy of the average atomic position, 0.25 A. The Dictyostelium structure is described in detail and compared to those of Drosophila and Myxococcus xanthus NDP kinases. The protein is a hexamer with D3 symmetry. Residues 8 to 138 of each subunit form a globular alpha/beta domain. The four-stranded beta-sheet is antiparallel; its topology is different from other phosphate transfer enzymes, and also from the HPr protein which, like NDP kinase, carries a phosphorylated histidine. The same topology is nevertheless found in several other proteins that bind mononucleotides, RNA or DNA. Strand connections in NDP kinase involve alpha-helices and a 20-residue segment called the Kpn loop. The beta-sheet is regular except for a beta-bulge in edge strand beta 2 and a gamma-turn at residue Ile120 just preceding strand beta 4. The latter may induce strain in the main chain near the active site His122. The alpha 1 beta 2 motif participates in forming dimers within the hexamer, helices alpha 1 and alpha 3, the Kpn loop and C terminus, in forming trimers. The subunit fold and dimer interactions found in Dictyostelium are conserved in other NDP kinases. Trimer interactions probably occur in all eukaryotic enzymes. They are absent in the bacterial Myxococcus xanthus enzyme which is a tetramer, even though the subunit structure is very similar. In Dictyostelium, contacts between Kpn loops near the 3-fold axis block access to a central cavity lined with polar residues and filled with well-defined solvent molecules. Biochemical data on point mutants highlight the contribution of the Kpn loop to protein stability. In Myxococcus, the Kpn loops are on the tetramer surface and their sequence is poorly conserved. Yet, their conformation is maintained and they make a similar contribution to the substrate binding site.


Validation of PRISM (Pictorial Representation of Illness and Self Measure) as a novel visual assessment tool for the burden of suffering in tinnitus patients.
Chronic subjective tinnitus is a frequent condition that affects the subject's quality of life. The lack of objective measures of tinnitus necessitates the use of self-reporting and often time-consuming questionnaires for evaluating tinnitus severity. The Pictorial Representation of Illness and Self Measure (PRISM) is a two dimensional pictorial method to assess the burden of suffering. Patients illustrate their burden of suffering by the distance from a "self" to an illness circle, whereby a shorter distance indicates a higher burden of suffering. The aim of this prospective observational study was to validate the burden of suffering measured with PRISM in tinnitus patients by comparing it with different standardized questionnaires currently used in tinnitus evaluation. A total of 188 patients filled out an online-based survey including sociodemographic variables and the following questionnaires: Tinnitus Handicap Inventory (THI), Tinnitus Questionnaire (TQ), WHO Quality of Life-Questionnaire (WHOQOL-BREF), and the Beck Depression Inventory (BDI). The subtle differences in the burden of suffering were accessed by using PRISM as an iPad version. Based on PRISM performance patients could easily be assigned in three groups, these being mildly, moderately, or severely affected akin to the standard questionnaires. The burden of suffering measured with PRISM correlated with the tinnitus severity (THI and TQ), depressive symptoms (BDI), and health related quality of life (WHOQOL-BREF) (all p ≤ 0.001). In the three PRISM groups tinnitus severity (THI and TQ), and depressive symptoms (BDI) differed significantly (all p ≤ 0.01). PRISM is an easily understood and time saving method for the assessment of burden of suffering in tinnitus patients. In daily clinical practice PRISM can help to identify patients with decompensated tinnitus that require more intensive treatment.


The Cutaneous Physiological Redox: Essential to Maintain but Difficult to Define.
Skin is a unique tissue, possessing extremely efficient protective and regulative mechanisms, similar only to the gut and lungs. These tissues serve as an interface with the environment and are exposed to stressors from both endogenous and exogenous sources. Interestingly, all these stressors lead downstream to a cellular production of reactive oxygen species (ROS) and other electrophiles, which, in turn could have deleterious outcomes for the living organism. Hence, such tissues should always maintain a "high-alert" condition in order to cope with these various insults. Nevertheless, a moderate production of ROS induced by stressors could actually be beneficial, although it is impossible to predict if and which exposure would lead to which outcome. Consequently, a parameter which would indicate the skin's readiness to cope with continuously fluctuating conditions is required. It has been proposed that the redox status may serve as a suitable indicator. In this opinion manuscript, we argue that the redox status is a vague parameter that is difficult to characterized and quantify due to its extremely dynamic nature. The common convention that the redox status is composed solely of the balance between oxidants and reductants (ROS and antioxidants) is also thought-provoking. Since this parameter in vivo behaves in a dynamic and complex manner, it better fits the description of a process, rather than an individual parameter. We suggest that the homeostatic modulation of the physiological redox (PR) should be in focus, rather than the redox status parameter itself. It is further suggested that low molecular weight antioxidants (LMWA) are, in fact, rather insignificant concerning the PR maintenance, and that the major contributors to this delicate modulation are regulative, protein-based systems such as the protective phase II antioxidant enzymes. Moreover, we show that skin microbiome and cutaneous advanced lipid peroxidation end-products (ALEs) take part in sustaining the cutaneous PR homoeostasis via activation of the Nrf2-Keap1 protective pathway.


The molecular basis of genetic dominance.
Studies of mutagenesis in many organisms indicate that the majority (over 90%) of mutations are recessive to wild type. If recessiveness represents the 'default' state, what are the distinguishing features that make a minority of mutations give rise to dominant or semidominant characters? This review draws on the rapid expansion in knowledge of molecular and cellular biology to classify the molecular mechanisms of dominant mutation. The categories discussed include (1) reduced gene dosage, expression, or protein activity (haploinsufficiency); (2) increased gene dosage; (3) ectopic or temporally altered mRNA expression; (4) increased or constitutive protein activity; (5) dominant negative effects; (6) altered structural proteins; (7) toxic protein alterations; and (8) new protein functions. This provides a framework for understanding the basis of dominant genetic phenomena in humans and other organisms.


Natural history of the neck remnant of a cerebral aneurysm treated with the Guglielmi detachable coil system.
The long-term durability of Guglielmi detachable coil (GDC) embolization of cerebral aneurysms is still unknown. The purpose of this study was to evaluate the anatomical evolution of neck remnants in aneurysms treated with GDCs. Of 455 aneurysms treated with GDCs from 1990 to 1998 at the University of California at Los Angeles Medical Center, 178 aneurysms (39%) had residual necks postembolization. Long-term follow-up angiograms were obtained in 73 of these aneurysms in 71 patients. The mean duration of angiographic follow up was 17.3 months. Twenty-four of the aneurysms were small with small necks, 24 were small with wide necks, 15 were large, and 10 were giant aneurysms. In small aneurysms with small necks, postembolization angiography revealed 12 aneurysms (50%) with progressive thrombosis, eight (33%) unchanged, and four (17%) with recanalization. In small aneurysms with wide necks, six (25%) had progressive thrombosis, eight (33%) remained unchanged, and 10 (42%) had recanalization. In large aneurysms, two (13%) were unchanged and 13 (87%) had recanalization. Of the giant aneurysms only one (10%) remained unchanged and nine (90%) had recanalization. Overall, 18 aneurysms (25%) exhibited progressive thrombosis, 19 (26%) remained unchanged, and 36 (49%) displayed recanalization on follow-up angiography. During the last 2 years of the study, the recanalization rate decreased and a higher rate of progressive thrombosis was noted in aneurysms with small necks. These positive changes are related to important new technical developments. Treatment with GDCs appears to be effective and the results permanent in most small aneurysms with small necks. However, there are important technical limitations in the current GDC technology that prevent recanalization in wide-necked or large or giant aneurysms.


Validation of activity questionnaires in patients with cystic fibrosis by accelerometry and cycle ergometry.
The objective of this study was to validate physical activity questionnaires for cystic fibrosis (CF) against accelerometry and cycle ergometry. 41 patients with CF (12-42 years) completed the Habitual Activity Estimation Scale (HAES), the 7-Day Physical Activity Recall questionnaire (7D-PAR) and the Lipid Research Clinics questionnaire (LRC) and performed an incremental exercise test according to the Godfrey protocol up to volitional fatigue. Time spent in moderate and vigorous physical activity (MVPA) assessed objectively by accelerometry was related to the time spent in the respective activity categories by correlation analyses and calculating intraclass correlation coefficients (ICC). Furthermore, the results of the exercise test were correlated with the results of the questionnaires. Time spent in the categories 'hard','very hard' and 'hard & very hard' of the 7D-PAR (0.41 < r < 0.56) and 'active' (r = 0.33) of the HAES correlated significantly with MVPA. The activity levels of the LRC were not related to objectively determined physical activity. Significant ICCs were only observed between the 7D-PAR activitiy categories and MVPA (ICC = 0.40-0.44). Only the LRC showed moderate correlations with the exercise test (Wmax: r = 0.46, p = 0.002; VO2peak: r = 0.32, p = 0.041). In conclusion, the activity categories 'hard' and 'very hard' of the 7D-PAR best reflected objectively measured MVPA. Since the association was at most moderate, the 7D-PAR may be selected to describe physical activity within a population. None of the evaluated questionnaires was able to generate valid physical activity data exercise performance data at the individual level. Neither did any of the questionnaires provide a valid assessment of aerobic fitness on an invidual level.


The impact of contact lens wear and visual display terminal work on ocular surface and tear functions in office workers.
To evaluate the effect of contact lens (CL) wear and visual display terminal (VDT) work on the ocular surface and tear functions. Prospective case-control study. Sixty-nine CL wearers (45 women and 24 men; mean age, 35.2 ± 7.3 years), and 102 age- and sex-matched non-CL wearers were enrolled in the study (66 women and 36 men; mean age, 36.7 ± 7.3 years). Ocular surface and tear function tests, including vital stainings (fluorescein and rose bengal), Schirmer test, tear meniscus height measurement, and tear film break-up time were performed. The subjective symptoms of dry eyes were evaluated using a dry eye symptom questionnaire. The participants were divided into 4 subgroups according to the total time of VDT work in 1 day (VDT work time in 1 day ≥ 4 hours or < 4 hours) and presence of CL wear. Main outcome measures included ocular surface vital staining scores, Schirmer test results, tear film break-up time, tear meniscus height measurement, and symptom questionnaire score. CL users and long-term VDT workers showed significantly worse tear meniscus height values than non-CL users and short-term VDT workers (P < .001). The mean visual symptom scores in CL wearers and long-term VDT workers were significantly higher than the other groups (P < .001). Office workers who wore CLs and spent more than 4 hours engaged in VDT work had a lower tear meniscus volume with significant dry eye and visual symptoms triggered by environmental factors.


Geographic mapping of meniscus and cartilage lesions associated with anterior cruciate ligament injuries.
Detailed descriptions of meniscus and articular cartilage lesions associated with anterior cruciate ligament injury have not been presented in the literature. Our goal was to determine the associations between patient sex, age, and surgical delay and the frequency and location of meniscus and articular cartilage lesions seen at the time of the anterior cruciate ligament reconstruction. Data were obtained retrospectively from a database of 1209 consecutive patients undergoing anterior cruciate ligament reconstruction between 1988 and 2002. All knee cartilage, meniscus, and ligament injuries were documented on anatomic maps at the time of surgery, and the data were analyzed. Meniscus injuries were identified in 722 (65%) of the 1104 patients who met the criteria for inclusion in the study. Female patients were less likely to have a meniscus injury than male patients were (56% compared with 71%), and male patients were more likely to have combined medial and lateral meniscus injuries than female patients were (20% compared with 11%). Patients with a surgical delay of less than three months were less likely to have a medial meniscus injury (8% compared with 19%). Femoral articular cartilage injuries were identified in 472 patients (43%). Patients who were twenty-five years of age or older were more likely to have multiple cartilage lesions throughout the knee (7.7% compared with 1.3%) and to have more isolated medial femoral condyle lesions (24.2% compared with 13.3%). Patients with a surgical delay of more than one year were more likely to have a lesion (60% compared with 47% for all others), and a surgical delay of more than one year resulted in a greater proportion of large and grade-3 lesions of the lateral femoral condyle. Female patients had a greater proportion of grade-1 lesions of the medial femoral condyle (29% compared with 16%), whereas male patients had a greater proportion of grade-3 and 4 lesions of the medial femoral condyle (49% compared with 35%). In patients who were thirty-five years of age or older, meniscus injuries were more frequent and were located more frequently on the medial side; femoral articular cartilage lesions were also located more frequently on the medial side. Increased age, male sex, and increased surgical delay all increase the frequency and severity of injuries of the meniscus and/or articular cartilage after an anterior cruciate ligament tear.


Observations on Neotricula aperta (Gastropoda: Pomatiopsidae) population densities in Thailand and central Laos: implications for the spread of Mekong schistosomiasis.
The snail Neotricula aperta transmits Mekong schistosomiasis in southern Laos and Cambodia, with about 1.5 million people at risk of infection. Plans are under consideration for at least 12 hydroelectric power dams on the lower Mekong river and much controversy surrounds predictions of their environmental impacts. Unfortunately, there are almost no ecological data (such as long-term population trend studies) available for N. aperta which could be used in impact assessment. Predictions currently assume that the impacts will be the same as those observed in Africa (i.e., a worsening of the schistosomiasis problem); however, marked ecological differences between the snails involved suggest that region specific models are required. The present study was performed as an initial step in providing data, which could be useful in the planning of water resource development in the Mekong. Snail population density records were analyzed for populations close to, and far downstream of, the Nam Theun 2 (NT2) project in Laos in order to detect any changes that might be attributable to impoundment. The population immediately downstream of NT2 and that sampled 400 km downstream in Thailand both showed a long-term trend of slow growth from 1992 to 2005; however, both populations showed a marked decline in density between 2005 and 2011. The decline in Thailand was to a value significantly lower than that predicted by a linear mixed model for the data, whilst the population density close to NT2 fell to undetectable levels in 2011 from densities of over 5000 m(-2) in 2005. The NT2 dam began operation in 2010. The impact of the NT2 dam on N. aperta population density could be more complex than first thought and may reflect the strict ecological requirements of this snail. There was no indication that responses of N. aperta populations to dam construction are similar to those observed with Bulinus and Schistosoma haematobium in Africa, for example. In view of the present findings, more ecological data (in particular population density monitoring and surveillance for new habitats) are urgently required in order to understand properly the likely impacts of water resource development on Mekong schistosomiasis.


Amphotericin B liposomes with prolonged circulation in blood: in vitro antifungal activity, toxicity, and efficacy in systemic candidiasis in leukopenic mice.
Pegylated amphotericin B (AmB) liposomes (PEG-AmB-LIP) were compared with laboratory-prepared nonpegylated AmB liposomes (AmB-LIP), a formulation with a lipid composition the same as that in AmBisome, as well as with industrially prepared AmBisome regarding their in vitro antifungal activities, toxicities, blood residence times, and therapeutic efficacies. Killing of Candida albicans (> 99.9%) during short-term (6-h) incubation was observed at 0.2 mg of AmB per liter for AmB desoxycholate, 0.4 mg of AmB per liter for PEG-AmB-LIP, 0.8 mg of AmB per liter for AmB-LIP, and 12.8 mg of AmB per liter for AmBisome. The maximum tolerated doses of PEG-AmB-LIP, AmB-LIP, and AmBisome were 15, 19, and > 31 mg of AmB per kg of body weight, respectively. In contrast to AmB-LIP, the blood residence time of PEG-AmB-LIP was prolonged and dose independent. In a model of systemic candidiasis in leukopenic mice at a dose of 5 mg of AmB per kg, PEG-AmB-LIP was completely effective and AmB-LIP was partially effective, whereas AmBisome was not effective. AmB-LIP at 11 mg of AmB per kg was partially effective. AmBisome at 29 mg of AmB per kg was completely effective. In conclusion, the therapeutic efficacies of AmB liposomes can be improved by preparing AmB liposomes in which a substantial reduction in toxicity is achieved while antifungal activity is retained. In addition, therapeutic efficacy is favored by a prolonged residence time of AmB liposomes in blood.


Patient global assessment in psoriatic arthritis: a multicenter GRAPPA and OMERACT study.
During OMERACT 8, delegates selected patient global assessment (PGA) of disease as a domain to be evaluated in randomized controlled trials in psoriatic arthritis (PsA). This study assessed the reliability of the PGA, measured by means of 0-100 mm visual analog scale (VAS), and the additional utility of separate VAS scales for joints (PJA) and skin (PSA). In total, 319 consecutive patients with PsA (186 men, 133 women, mean age 51 ± 13 yrs) were enrolled. PGA, PJA, and PSA were administered at enrolment (W0) and after 1 week (W1). Detailed clinical data, including ACR joint count, Psoriasis Area and Severity Index (PASI), and Hospital Anxiety and Depression Scale, were recorded. Comparison of W0 and W1 scores showed no significant variations (intraclass correlation coefficients for PGA 0.87, PJA 0.86, PSA 0.78), demonstrating the reliability of the instrument. PGA scores were not influenced by patient anxiety or depression, but were dependent on PJA and PSA (p = 0.00001). PJA was dependent on the number of swollen and tender joints (p < 0.00001). PSA scores were influenced by the extent of skin psoriasis and by hand skin involvement (p = 0.00001). Joint and skin disease were found not to correlate in terms of disease activity as evidenced by the swollen joint count compared to PASI (r = 0.11) and by the PJA compared to PSA (r = 0.38). PGA assessed by means of VAS is a reliable tool related to joint and skin disease activity. Because joint and skin disease often diverge it is suggested that in some circumstances both PJA and PSA are also assessed.


Bulk tank milk urea nitrogen: seasonal patterns and relationship to individual cow milk urea nitrogen values.
The objectives of this study were: 1) to determine if bulk tank milk urea nitrogen (BTMUN) and whole herd weighted average of the individual cow MUN levels (WHMUN) were equivalent measurements of herd MUN status; and 2) to determine the seasonal variation in BTMUN concentrations in Prince Edward Island (PEI) dairy herds. For BTMUN-WHMUN correlation testing, bulk tank milk samples from 176 herds were tested for MUN once every 1 to 2 wk between September 1999 and August 2002, as part of routine BTM testing for milk components. During this 3-year period, all herds had all milking cows tested for MUN once a month at the same lab. The WHMUN levels (weighted for milk production) were calculated for each month, and were compared to BTMUN levels using a concordance correlation coefficient (CCC) and a graphic procedure. Tests were only compared if they occurred on the same date, producing a final dataset of 669 comparisons. The BTMUN had good (but not perfect) correlation with WHMUN (CCC = 0.91). This high reliability extended to both the pasture and non-pasture seasons, various milk sampling protocols, and all herd sizes seen in PEI. For evaluating the seasonal variation of BTMUN, the 3 y worth of data (24 803 observations) were divided into 15 seasonal categories, 5 seasons per year (early, mid, and late pasture, and early and late stable). Using linear mixed modelling, significantly (P < 0.05) higher BTMUN values were found during the mid and late pasture seasons of 2000, likely because the precipitation was unusually high during this period, enhancing pasture growth.


A large deletion within the T-cell receptor beta-chain gene complex in New Zealand white mice.
The T-cell receptor beta-chain gene complex contains a duplication of D beta, J beta, and C beta gene segments in mice and man. When DNA from many inbred strains of mice was screened an unusual allele of the beta locus was identified in New Zealand White (NZW) mice. This allele is distinguished by the deletion of an 8.8-kilobase segment of DNA containing C beta 1, D beta 2 and the J beta 2 cluster. Despite the fact that all NZW T-cell receptors must be derived from a single set of beta-chain gene segments, this strain has functional T cells and is phenotypically normal. This deletion of T-cell receptor beta-chain segments occurs in a strain known to contribute to lupus-like autoimmune disease.


Indications for lower urinary tract reconstruction in women after cystectomy for bladder cancer: a pathological review of female cystectomy specimens.
In an attempt to identify women who may be appropriate candidates for orthotopic lower urinary tract reconstruction, archival cystectomy specimens from female patients undergoing cystectomy for primary bladder cancer were reviewed. These pathological findings should provide a better understanding of tumor involvement at the bladder neck (vesicourethral junction) and urethra in women with transitional cell carcinoma of the bladder. Cystectomy specimens of 67 consecutive women undergoing surgery for biopsy proved transitional cell carcinoma of the bladder between July 1982 and July 1990 were pathologically reviewed. Histological evidence of tumor (carcinoma in situ or gross carcinoma) involving the urethra was present in 9 patients (13%). Tumor was confined to the proximal and mid urethra, and the distal urethra was not involved. All patients with carcinoma involving the urethra had concomitant evidence of carcinoma involving the bladder neck. A total of 17 patients (25%) had tumor involvement of the bladder neck and those with an uninvolved bladder neck also had an uninvolved urethra. The association between the presence of tumor in the bladder neck and urethra was highly significant (p < or = 0.00012). Tumor involving the bladder neck and urethra tended to be more commonly associated with high grade and stage tumors, and node-positive disease. Although the fate of the retained urethra following cystectomy for bladder cancer in women is unknown, these results show that women with transitional cell carcinoma of the bladder without evidence of tumor involving the bladder neck are at low risk for urethral malignancy. These patients may be offered lower urinary tract reconstruction that includes preservation of and diversion through the urethra (orthotopic diversion). Urethral surveillance will be necessary, as it is in men after orthotopic urinary diversion.


Long-term visual outcomes of laser anterior ciliary excision.
To determine the long-term visual outcomes of six eyes of 3 patients up to 13 years following the Laser Anterior Ciliary Excision (LaserACE) procedure. Three male patients of ages 59, 59, and 60 presented for evaluation at Storm Eye Institute, Medical University of South Carolina at 8, 10, and 13 years after the LaserACE procedure for presbyopia, respectively. All 3 patients had a history of laser vision correction (LVC) prior to LaserACE treatment. Visual performance was evaluated using ray-tracing aberrometry, specifically higher-order aberrations, visual Strehl of the optical transfer function (VSOTF), depth of focus (DoF), and effective range of focus (EROF). VSOTF was computed as a function of defocus using a through-focus curve. Subjective DoF was overlaid on the VSOTF through-focus curve to establish the best image quality metric threshold value for correlation between subjective and objective DoF. EROF was determined by measuring the difference in diopters between the near and distance DoF curves, at 50% of VSOTF. Distance-corrected visual acuity, distance-corrected intermediate visual acuity, and distance-corrected near visual acuity for all patients remained at 20/20 or better up to 13 years postoperatively. EROF averaged 1.56 ± 0.36 (D) for all eyes. LaserACE provided improvement in near vision functionality in these LVC patients with long-term stability. The LaserACE procedure is not on the visual axis, therefore these patients could still receive correction to their hyperopic regression.