Nonproportional changes in plasma renin concentration, renal renin content, and rat renin messenger RNA.
The expression of the renin gene in rat kidneys was studied using mouse submaxillary gland renin complementary DNA. The length of rat renin messenger RNA (mRNA) was approximately 1600 nucleotides, similar to that of mouse submaxillary gland and kidney renin mRNA. Rat renin mRNA was quantified by a radiodensitometric complementary DNA hybridization assay. The effects of intense long-term stimulation and short-term inhibition of renin secretion on plasma renin concentration, renal renin concentration, and renin mRNA content were compared with those of controls. After 15 days of sodium depletion and captopril treatment, plasma renin concentration increased 46-fold, renal renin concentration only 1.5-fold, and renin mRNA content increased about threefold. Following a 1-hour infusion of angiotensin II in sodium-depleted and captopril-treated rats, plasma renin concentration decreased by 84% whereas no significant changes in either renal renin concentration or renin mRNA content were observed. These results show that sodium depletion and captopril treatment increase the level of renin gene transcription and renin biosynthesis. However, there are nonproportional changes in plasma renin levels, renal renin content, and its mRNA. These results suggest that newly synthesized renin is not stored in the kidney but is rapidly secreted into the blood. Short-term inhibition of plasma renin concentration by angiotensin II is most likely mediated by posttranslational mechanisms.


A case of autoimmune polyendocrine syndrome type I with strong positive GAD antibody titer, followed up with glucose tolerance measured by oral glucose tolerance test.
A 26-year-old Japanese woman presented with adrenal insufficiency, and treatment was started with cortisone and fludrocortisone in 1975. A few years later, she presented with hypoparathyroidism and was diagnosed with autoimmune polyendocrine syndrome type I (APS I), and treatment with calcium and alfacalcidol was started. She was found to have subacute thyroiditis and relative adrenal failure in 2006. Her condition remained stable under treatment with cortisone, fludrocortisone, levothyroxine, calcium lactate, precipitated calcium carbonate and alfacalcidol. While antibodies against pancreatic glutamic acid decarboxylase (GAD) were strongly positive (7,690 U/ml), fasting glucose level was 4.9 mmol/L and HbA1c was 6.3% on admission. As GAD antibody showed a high-titer of >10,000 U/ml and fasting plasma glucose level showed a rising trend, we performed 75-g oral glucose tolerance test (OGTT) 6 years after discharge. Whereas OGTT in 2012 showed impaired glucose tolerance, glucose tolerance had reverted to normal in 2014. A patient with a high-titer GAD antibody does not always have progressive glucose intolerance. GAD antibody positivity is common in not only type 1 diabetes, but also APS I and stiff-person syndrome (SPS). There are differences in recognized epitopes among the three disorders. Epitopes for GAD65 antibody associated with type 1 diabetes are located in the middle region and the COOH-terminal of the GAD65 protein, whereas epitopes associated with SPS reside in the NH2-terminal in addition to the middle region and COOH-terminal. The present case suggests that these differences in epitopes may be related to various pathogenic mechanisms including glucose intolerance.


Cancer quasispecies and stem-like adaptive aneuploidy.
In this paper we develop a theoretical frame to understand self-regulation of aneuploidy rate in cancer and stem cells. This is accomplished building upon quasispecies theory, by leaving its formal mathematical structure intact, but by drastically changing the meaning of its objects. In particular, we propose a novel definition of chromosomal master sequence, as a sequence of physically distinct whole or fragmented chromosomes, whose length is taken to be the sum of the copy numbers of each whole or fragmented chromosome. This fundamental change in the functional objects of quasispecies theory allows us to show that previously measured aneuploidy rates in cancer populations are already close to a formally derived aneuploid error threshold, and that any value of aneuploidy rate larger than the aneuploid error threshold would lead to a loss of fitness of a tumor population. Finally, we make a phenomenological analysis of existing experimental evidence to argue that single clone cancer cells, derived from an aneuploid cancer subpopulation, are capable of self-regulating their aneuploidy rate and of adapting it to distinct environments, namely primary and metastatic microenvironments. We also discuss the potential origin of this self-regulatory ability in the wider context of developmental and comparative biology and we hypothesize the existence of a diversification factor, i.e. a cellular mechanism that regulates adaptation of aneuploidy rates, active in all embryo, adult and cancer stem cells.


Gene3D: comprehensive structural and functional annotation of genomes.
Gene3D provides comprehensive structural and functional annotation of most available protein sequences, including the UniProt, RefSeq and Integr8 resources. The main structural annotation is generated through scanning these sequences against the CATH structural domain database profile-HMM library. CATH is a database of manually derived PDB-based structural domains, placed within a hierarchy reflecting topology, homology and conservation and is able to infer more ancient and divergent homology relationships than sequence-based approaches. This data is supplemented with Pfam-A, other non-domain structural predictions (i.e. coiled coils) and experimental data from UniProt. In order to enhance the investigations possible with this data, we have also incorporated a variety of protein annotation resources, including protein-protein interaction data, GO functional assignments, KEGG pathways, FUNCAT functional descriptions and links to microarray expression data. All of this data can be accessed through a newly re-designed website that has a focus on flexibility and clarity, with searches that can be restricted to a single genome or across the entire sequence database. Currently Gene3D contains over 3.5 million domain assignments for nearly 5 million proteins including 527 completed genomes. This is available at: http://gene3d.biochem.ucl.ac.uk/


[Analysis of diet composition and overlap in four species of the genus Diplectrum (Perciformes: Serranidae) in the Mexican Central Pacific].
Analysis of diet composition and overlap in four species of the genus Diplectrum (Perciformes: Serranidae) in the Mexican Central Pacific. The information of trophic interactions among species is essential to understand ecosystem function. To assess this in four Diplectrum species, we analyzed the stomach contents of 397 individuals caught using shrimp trawling nets off the coasts of Jalisco and Colima, Mexico. Main food component of D. eumelum were fish of the Order Pleuronectiformes, followed by shrimps (Metapenaeopsis spp). D. euryplectrum feeds mainly on crustaceans, with stomatopods (Squilla mantoidea) as main food items followed by shrimps and brachyurans. Fish and polychaetes had a low representation in the diet of this species. D. labarum feeds mainly on crustaceans, mollusks and fish. The stomatopod Eurysquilla veleronis contributed to with a high diet percentage by weight, followed by shrimps (mostly Solenoceraflorae) and brachyurans, as well as the squid Lolliguncula diomedae. Fishes (Ophidion spp.) were also an important component of the diet of this species. The most common preys of D. rostrum were crustaceans, mollusks, polychaetes and fish. The squid Lolliguncula diomedae and fishes of genus Ophidion were also well represented in the diet. Diet breadth index yielded significant differences between species. The number of diet items varied from 16 in D. euryplectrum to 6 in D. eumelum. The average value of overlap (0.247) was not significantly different (p = 0.118) from the expected one for a null model (0.174). The observed variance of the overlap index (0.071) was significantly higher (V = 0.025, p = 0.0004) than the value expected for a null model.


A longitudinal analysis of diet quality scores and the risk of incident depression in the SUN Project.
Some studies have pointed out that several dietary patterns could be associated with a reduced risk of depression among adults. This association seems to be consistent across countries, cultures and populations. The objective of the study was to compare and to establish the type of relationship between three diet quality scores and depression in the SUN (Seguimiento Universidad de Navarra) Cohort study. We performed a dynamic cohort study based on Spanish university graduates free of depression at baseline. Dietary intake was repeatedly assessed at baseline and after 10 years of follow-up with a validated semi-quantitative food-frequency questionnaire. Three previously described diet quality scores: Mediterranean Diet Score (MDS), Pro-vegetarian Dietary Pattern (PDP) and Alternative Healthy Eating Index-2010 (AHEI-2010) were built. Participants were classified as having depression if they reported a new clinical diagnosis of depression by a physician or initiated the use of an antidepressant drug during follow-up. Time-dependent Cox regression models with cumulative averages of diet and restricted cubic splines were used to estimate hazard ratios of depression according to quintiles of adherence to the MDS, PDP and AHEI-2010. One thousand and fifty one incident cases of depression were observed among 15,093 participants from the SUN Cohort after a median follow-up of 8.5 years. Inverse and significant associations were observed between the three diet quality scores and depression risk. The hazard ratios and 95 % confidence intervals for extreme quintiles (fifth versus first) of updated adherence to MDS, PDP and AHEI-2010 were 0.84 (0.69-1.02), 0.74 (0.61-0.89) and 0.60 (0.49-0.72), respectively. The dose-response analyses showed non-linear associations, suggesting that suboptimal adherence to these dietary patterns may partially be responsible for increased depression risk. Better adherence to the MDS, PDP and AHEI-2010 was associated with a reduced risk of depression among Spanish adults. However, our data suggested a threshold effect so that although the risk of depression was reduced when comparing moderate versus lower adherence, there was not much extra benefit for the comparison between moderate and high or very high adherence.


New developments in genetics-knowledge, attitudes and information needs of practice nurses.
In response to increased referrals to geneticists and the predicted patient demand for genetic counselling, it has been proposed that some genetics services should be provided in primary care. Practice nurses are ideally placed to collect family history information and advise patients accordingly in new patient, family planning, well women/men and chronic disease clinics, but little is known about their knowledge, skills and attitudes towards providing genetic advice. The survey aimed to measure the current situation with regard to: the prevalence of family history recording by practice nurses; confidence in collecting and acting upon family history; and practice nurses' knowledge about familial disorders and genetics. It also investigated what practice nurses think their role should be in relation to the delivery of genetic services; their educational needs; and the most appropriate ways of delivering training/support. A postal questionnaire survey was carried out of all practices nurses (n = 909) in four Health Authorities in England (Oxfordshire, Northamptonshire, Nottingham and North Nottinghamshire) and one Health Board in Scotland (Lothian). Analyses were primarily descriptive. A total of 600 nurses (response rate = 66.0%) returned a completed questionnaire. Ninety-six per cent of practice nurses reported that they routinely collect family history information. Over half of the respondents had been consulted in the previous 3 months by patients with a worry about family history of cancer. Approximately 60% of nurses felt confident about collecting the relevant details regarding a family history of breast cancer but felt less confident in collecting the information regarding familial colorectal cancer. Nurses were also unsure how to proceed, with over a third of nurses referring patients to the GP even if they thought the patient was at population risk or, conversely, not referring those that they thought were at considerably higher risk to the GP. There was a reported need for education about familial disease in general and overall agreement that nurses could play a role in genetics in primary care. This study provides evidence of considerable activity from practice nurses regarding routine collection of family history. There is a need for further education for practice nurses regarding family history information and the new genetics so that this information is managed appropriately.


Patient outcomes in Lubumbashi, Democratic Republic of Congo after a disruption in HIV care due to decreased global fund appropriations.
This study examines care seeking behaviors, clinical outcomes, and satisfaction with care of HIV-positive adults in Lubumbashi, DRC, one year after a disruption in care due to decreased global fund appropriations. We describe outcomes before and after the disruption. We compared characteristics of those who completed the survey and those who did not using the Wald F test. Most patients sought care after the disruption and continued antiretroviral therapy (ART), though use of cotrimoxizole prophylaxis declined. Though there was little change in WHO clinical stage at the new site of care, the majority of participants lost weight, adherence decreased, support group participation dropped, and satisfaction with care worsened. Patients were more likely to participate in the study if they were taking ART. This study highlights the importance of provider-patient communication during a transfer and the vulnerability of pre-ART patients to becoming lost to follow-up.


A crucial role for Olig2 in white matter astrocyte development.
The mechanisms underlying astrocyte heterogeneity in the developing mouse brain are poorly understood. The bHLH transcription factor Olig2 is essential for motoneuron and oligodendrocyte formation; however, its role in astrocyte development remains obscure. During cortical development, Olig2 is transiently expressed in immature developing astrocytes at neonatal stages and is progressively downregulated in astrocytes at late postnatal stages. To assess the function of Olig2 in astrocyte formation, we conditionally ablated Olig2 in a spatiotemporally controlled manner. In the Olig2-ablated cortex and spinal cord, the formation of astrocytes in the white matter is severely compromised. Temporally controlled mutagenesis revealed that postnatal Olig2 function is required for astrocyte differentiation in the cerebral white matter. By contrast, astrocytes in the cortical gray matter are formed, but with sustained GFAP upregulation in the superficial layers. Cell type-specific mutagenesis and fate-mapping analyses indicate that abnormal astrocyte formation is at least in part attributable to the loss of Olig2 in developing astrocytes and their precursors. Thus, our studies uncover a crucial role for Olig2 in white matter astrocyte development and reveal divergent transcriptional requirements for, and developmental sources of, morphologically and spatially distinct astrocyte subpopulations.


A new functional classification of tumor-suppressing genes and its therapeutic implications.
Cell fusion studies have demonstrated that malignancy can be suppressed by a single dose of malignancy suppressor genes (MSGs), indicating that malignancy is a recessive phenotype. Correspondingly, it is widely believed that mutational inactivation of both alleles of tumor suppressor genes (TSGs), in familial and sporadic tumors, is the formal proof of the recessive nature of malignancy. Evidence presented here, however, shows that unlike MSGs, identified solely through cell fusion studies with no gene of this class yet cloned, many well-known TSGs have gene dosage effects and inhibit cellular growth in vitro. Moreover, homozygous inactivation of a growth-inhibitory TSG (GITSG) is not directly correlated with malignancy. An alternative interpretation is provided for the loss of wild-type alleles of these genes in the tumors. It is concluded that the MSGs and the GITSGs do not belong to the same class of genes. The functional classification of tumor-suppressing genes has important implications for developing effective cancer therapies.


Control of basal ganglia output by direct and indirect pathway projection neurons.
The direct and indirect efferent pathways from striatum ultimately reconverge to influence basal ganglia output nuclei, which in turn regulate behavior via thalamocortical and brainstem motor circuits. However, the distinct contributions of these two efferent pathways in shaping basal ganglia output are not well understood. We investigated these processes using selective optogenetic control of the direct and indirect pathways, in combination with single-unit recording in the basal ganglia output nucleus substantia nigra pars reticulata (SNr) in mice. Optogenetic activation of striatal direct and indirect pathway projection neurons produced diverse cellular responses in SNr neurons, with stimulation of each pathway eliciting both excitations and inhibitions. Despite this response heterogeneity, the effectiveness of direct pathway stimulation in producing movement initiation correlated selectively with the subpopulation of inhibited SNr neurons. In contrast, effective indirect pathway-mediated motor suppression was most strongly influenced by excited SNr neurons. Our results support the theory that key basal ganglia output neurons serve as an inhibitory gate over motor output that can be opened or closed by striatal direct and indirect pathways, respectively.


Randomized controlled trial on drowning prevention for parents with children aged below five years in Bangladesh: a study protocol.
Drowning is the third leading cause of death for children aged 0-4 years in many Asian countries, and is a serious but neglected health problem in low and middle-income countries like Bangladesh. The aim of the study is to outline the study protocol of a trial to test the efficacy of a mobile coach based intervention for the prevention of childhood drowning. A two-arm cluster randomized community trial will be conducted to test the efficacy of the mobile coach intervention for childhood drowning on parents with children below five years of age and compared to an assessment only control group. A total of 1680 parents in the villages with children aged below five years of age will participate. The village will be used as a randomized unit, randomly assigned to an intervention group (N = 840) receiving the mobile coach based intervention or an assessment only control group (N = 840). An individualized mobile coach intervention based on the demographic data and the individual will be developed, and SMSs, audio messages, videos and images about childhood drowning will be sent to the participants of the intervention group over a period of six months. The participants will receive per week one text message (SMS) and image and one video and audio text per month. The primary outcome measure will be increased knowledge and safety awareness, and behaviour practice about childhood drowning assessed at the six-month follow-up, and the secondary outcome measure will be the reduced incidence of childhood drowning in Bangladesh. The study assistants conducting the baseline and the follow-up assessments will be blinded regarding the group assignment. This is the first study testing a fully mobile coach intervention for childhood drowning prevention in Bangladesh. It is hoped that the programme will offer an effective and inexpensive way to prevent childhood drowning among children aged below five years and also increase the awareness of parents concerning the risks to their children from drowning. ISRCTN13774693, 08/03/2015.


Muscle activation strategies at the knee during running and cutting maneuvers.
The purpose of this article was to investigate the activation patterns of muscles surrounding the knee during preplanned (PP) and unanticipated (UN) running and cutting tasks, with respect to the external moments applied to the joint. It was hypothesized that activation strategies during PP tasks would correspond to the magnitude and direction of the external loads applied to the knee joint, and the muscle activation patterns would differ between PP and UN tasks. Eleven healthy male subjects performed a series of running and cutting tasks under PP and UN conditions. Activation from 10 knee muscles were determined using full-wave rectified, filtered, and normalized EMG calculated during a precontact phase and two epochs across the stance phase. Knee joint flexor and extensor muscle group ratios indicated the level of co-contraction. Individual muscles were also grouped into medial/lateral and internal/external rotation muscle groups, based upon their ability to counter externally applied varus/valgus and internal/external rotation joint loads, respectively. Selective activation of medial/lateral and internal/external rotation muscles and co-contraction of flexors and extensors were used to stabilize the joint under PP conditions, whereas generalized co-contraction strategies were employed during the UN condition. Net muscle activation during the UN sidestepping tasks increased by 10-20%, compared with an approximately 100% increase in applied varus/valgus and internal/external rotation joint moments. In PP conditions, activation patterns appear to be selected to support the external loads experienced at the knee, e.g., medial muscles activated to resist applied valgus moments. Under UN conditions, there was no selective activation of muscles to counter the external knee load, with generalized co-contraction being the activation pattern adopted. These findings have implications for the etiology of noncontact knee ligament injuries.


Abnormal visual pathways in normally pigmented cats that are heterozygous for albinism.
The various forms of albinism affect about one in 10,000 births in the United States. An additional 1 to 2 percent of the population has normal pigmentation but is heterozygous and carries a recessive allele for albinism. The retinogeniculocortical pathways were studied in normally pigmented cats that carry a recessive allele for albinism. The cats exhibited abnormalities in their visual pathways similar to those present in homozygous albinos. These results imply that visual anomalies like those found in albinos may be present in 1 to 2 percent of the human population.


Thought insertion, cognitivism, and inner space.
Whatever its underlying causes, even the description of the phenomenon of thought insertion, of the content of the delusion, presents difficulty. It may seem that the best hope of a description comes from a broadly cognitivist approach to the mind which construes content-laden mental states as internal mental representations within what is literally an inner space: the space of the brain or nervous system. Such an approach objectifies thoughts in a way which might seem to hold out the prospect of describing the ''alienated'' relation to one's own thoughts that seems to be present in thought insertion.1 Firstly, I examine the general structure of cognitivist accounts of intentional or content-laden mental states. I raise the general difficulty of explaining how free-standing, and thus world-independent, inner states can still have bearing on the outer world. Secondly, I briefly examine Frith's model for explaining thought insertion and other passivity phenomena by postulating a failure of an internal monitoring mechanism of inner states. I question what account can be given of non-pathological cases and raise two specific objects. Cognitivist accounts of the mind face a general, and possibly insuperable, challenge: explaining the intentionality of mental states in non-intentional, nonquestion-begging terms. There have so far been no satisfactory solutions. Cognitivist accounts of passivity phenomena in terms of a failure of internal monitoring face two objections. Firstly, accounting for non-pathological cases generates an infinite regress. Secondly, no account can be given of the paradoxical nature of utterances of the form of Moore's paradox: ''it is raining but I do not believe it''. A cognitivist approach presents an alienated account of thought in normal, non-pathological cases and is no help in accounting for thought insertion.


Mutations in codons 12 and 13 of K-ras exon 2 in colorectal tumors of Saudi Arabian patients: frequency, clincopathological associations, and clinical outcomes.
Mutations in codons 12/13 of K-ras exon 2 are associated with reduced benefit from anti-epidermal growth factor receptor antibody treatment for metastatic colorectal cancer (CRC). Here, we evaluated the frequency of K-ras mutations and their relationship with clinicopathological features and treatment outcomes in Saudi Arabian patients with CRC. The genetic status of K-ras was determined in 300 patients diagnosed with CRC. Clinical information was collected retrospectively. K-ras was wild-type in 58% and mutated in 42% of the tumors. Most mutations were at codon 12 (89%) and were associated with metastasis [odds ratio (OR) = 1.38 (95%CI = 1.14-1.67] and occurrence of >40 µg/L carcinoembryonic antigen (CEA) [OR = 1.33 (1.1-1.74)] during diagnosis. Patients in stages I-III of the disease with wild-type K-ras tumors had a median relapse free survival (RFS) of 29 months in contrast to 22 months for those with the mutated K-ras tumor (P = 0.0357). In multivariate analysis, only the stage of the disease significantly predicted RFS (P = 0.001). Patients in stage IV of CRC with the wild-type K-ras tumor did not reach the median overall survival (OS), whereas patients with the mutated K-ras tumor survived for 23.5 months (P = 0.044). CEA level >40 µg/L (P = 0.004) and status of K-ras (P = 0.044) were independent predictors of OS. This is the largest study investigating K-ras mutations in patients with CRC in the Middle East. Mutations were associated with advanced stage of CRC, higher serum CEA, shorter RFS and OS.


On the Front Lines of the COVID-19 Pandemic: Occupational Experiences of the Intimate Partner Violence and Sexual Assault Workforce.
In the face of increasing risk for intimate partner violence (IPV) and sexual assault during the COVID-19 pandemic, there is an urgent need to understand the experiences of the workforce providing support to survivors, as well as the evolving service delivery methods, shifting safety planning approaches, and occupational stress of frontline workers. We addressed this gap by conducting an online survey of members of IPV and sexual assault workforce using a broad, web-based recruitment strategy. In total, 352 staff from 24 states participated. We collaborated with practitioner networks and anti-violence coalitions to develop the brief survey, which included questions about work and health, safety planning, and stress. We used chi-square, t-test, and ANOVA analysis techniques to analyze differences within position and demographic variables. For qualitative data, we used thematic analysis to analyze responses from four open-ended questions. The sample was majority female-identified (93.7%) and essential workers in dual IPV and sexual assault programs (80.7%). Findings demonstrated that since the pandemic began, IPV and sexual assault staff are experiencing more personal and professional stressors, perceive a decrease in client safety, and lack resources needed to help survivors and themselves. Common problems included a lack of food or supplies at home and work and housing and financial support for survivors. There was a 51% increase in the use of video conference for work, which contributed to workforce strain. Reductions in overall service capacity and a shift to remote service provision have implications for both survivors and staff. These findings suggest a critical need for additional training, infrastructure, and support for the IPV and sexual assault workforce. There is an urgent need to classify IPV and sexual assault staff as first responders and address the occupational stress associated with the COVID-19 pandemic.


SNP Discovery through Next-Generation Sequencing and Its Applications.
The decreasing cost along with rapid progress in next-generation sequencing and related bioinformatics computing resources has facilitated large-scale discovery of SNPs in various model and nonmodel plant species. Large numbers and genome-wide availability of SNPs make them the marker of choice in partially or completely sequenced genomes. Although excellent reviews have been published on next-generation sequencing, its associated bioinformatics challenges, and the applications of SNPs in genetic studies, a comprehensive review connecting these three intertwined research areas is needed. This paper touches upon various aspects of SNP discovery, highlighting key points in availability and selection of appropriate sequencing platforms, bioinformatics pipelines, SNP filtering criteria, and applications of SNPs in genetic analyses. The use of next-generation sequencing methodologies in many non-model crops leading to discovery and implementation of SNPs in various genetic studies is discussed. Development and improvement of bioinformatics software that are open source and freely available have accelerated the SNP discovery while reducing the associated cost. Key considerations for SNP filtering and associated pipelines are discussed in specific topics. A list of commonly used software and their sources is compiled for easy access and reference.


Livin promotes Smac/DIABLO degradation by ubiquitin-proteasome pathway.
Livin, a member of the inhibitor of apoptosis protein (IAP) family, encodes a protein containing a single baculoviral IAP repeat (BIR) domain and a COOH-terminal RING finger domain. It has been reported that Livin directly interacts with caspase-3 and -7 in vitro and caspase-9 in vivo via its BIR domain and is negatively regulated by Smac/DIABLO. Nonetheless, the detailed mechanism underlying its antiapoptotic function has not yet been fully characterized. In this report, we provide, for the first time, the evidence that Livin can act as an E3 ubiquitin ligase for targeting the degradation of Smac/DIABLO. Both BIR domain and RING finger domain of Livin are required for this degradation in vitro and in vivo. We also demonstrate that Livin is an unstable protein with a half-life of less than 4 h in living cells. The RING domain of Livin promotes its auto-ubiquitination, whereas the BIR domain is likely to display degradation-inhibitory activity. Mutation in the Livin BIR domain greatly enhances its instability and nullifies its binding to Smac/DIABLO, resulting in a reduced antiapoptosis inhibition. Our findings provide a novel function of Livin: it exhibits E3 ubiquitin ligase activity to degrade the pivotal apoptotic regulator Smac/DIABLO through the ubiquitin-proteasome pathway.


Implementation of associative memory using grating structures.
An associative-memory model and its optical implementation with grating structures are presented. The transmission function of each pixel of the content-addressable memory is calculated by use of scalar diffraction theory. The filter of the calculated transmission function can be fabricated with computer-generated holography and a multiexposure holographic technique. The proposed approach is found useful in terms of storage and the simple thresholding at the number of on-state pixels in the input.


Maternal infection and cerebral palsy in infants of normal birth weight.
Exposure to maternal or placental infection is related to risk of preterm birth and, in premature infants, of brain lesions predictive of cerebral palsy (CP). Few studies have investigated whether maternal infection is associated with risk of CP in children of normal birth weight. To investigate maternal infection during the admission for delivery as a possible risk factor for CP in infants born weighing 2500 g or more. Population-based case-control study. All hospitals in 4 northern California counties, 1983 through 1985. A total of 46 children with disabling spastic CP who had no recognized prenatal brain lesions and 378 randomly selected control children weighing 2500 g or more at birth and surviving to age 3 years. Disabling spastic CP and signs of neonatal morbidity. Maternal fever exceeding 38 degrees C in labor was associated with increased risk of unexplained CP (odds ratio [OR], 9.3; 95% confidence interval [CI], 2.7-31.0), as was a clinical diagnosis of chorioamnionitis. One or more indicators of maternal infection were present in 2.9% of control children, 22% of children with CP (OR, 9.3; 95% CI, 3.7-23.0), and 37% of those with the spastic quadriplegic subtype of CP (OR, 19.0; 95% CI, 6.5-56.0). Newborns exposed to maternal infection, both cases and controls, had 5-minute Apgar scores below 6 more often than those unexposed. Among children with CP, those born to infected women were more often hypotensive, needed intubation, had neonatal seizures, and received a clinical diagnosis of hypoxic-ischemic encephalopathy. Intrauterine exposure to maternal infection was associated with a marked increase in risk of CP in infants of normal birth weight. Maternal infection was also linked with low Apgar scores, other evidence of hypotension [corrected] and need for resuscitation, and neonatal seizures-signs commonly attributed to birth asphyxia.


Robotic autopositioning of the operating microscope.
Use of the operating microscope has become pervasive since its introduction to the neurosurgical world. Neuronavigation fused with the operating microscope has allowed accurate correlation of the focal point of the microscope and its location on the downloaded imaging study. However, the robotic ability of the Pentero microscope has not been utilized to orient the angle of the microscope or to change its focal length to hone in on a predefined target. To report a novel technology that allows automatic positioning of the operating microscope onto a set target and utilization of a planned trajectory, either determined with the StealthStation S7 by using preoperative imaging or intraoperatively with the microscope. By utilizing the current motorized capabilities of the Zeiss OPMI Pentero microscope, a robotic autopositioning feature was developed in collaboration with Surgical Technologies, Medtronic, Inc. (StealthStation S7). The system is currently being tested at the Barrow Neurological Institute. Three options were developed for automatically positioning the microscope: AutoLock Current Point, Align Parallel to Plan, and Point to Plan Target. These options allow the microscope to pivot around the lesion, hover in a set plane parallel to the determined trajectory, or rotate and point to a set target point, respectively. Integration of automatic microscope positioning into the operative workflow has potential to increase operative efficacy and safety. This technology is best suited for precise trajectories and entry points into deep-seated lesions.


Sub-kBT micro-electromechanical irreversible logic gate.
In modern computers, computation is performed by assembling together sets of logic gates. Popular gates like AND, OR and XOR, processing two logic inputs and yielding one logic output, are often addressed as irreversible logic gates, where the sole knowledge of the output logic value is not sufficient to infer the logic value of the two inputs. Such gates are usually believed to be bounded to dissipate a finite minimum amount of energy determined by the input-output information difference. Here we show that this is not necessarily the case, by presenting an experiment where a OR logic gate, realized with a micro-electromechanical cantilever, is operated with energy well below the expected limit, provided the operation is slow enough and frictional phenomena are properly addressed.


Demonstrating a driven reset protocol for a superconducting qubit.
Qubit reset is crucial at the start of and during quantum information algorithms. We present the experimental demonstration of a practical method to force qubits into their ground state, based on driving appropriate qubit and cavity transitions. Our protocol, called the double drive reset of population, is tested on a superconducting transmon qubit in a three-dimensional cavity. Using a new method for measuring population, we show that we can prepare the ground state with a fidelity of at least 99.5% in less than 3 μs; faster times and higher fidelity are predicted upon parameter optimization.


PIN-FORMED 1 regulates cell fate at the periphery of the shoot apical meristem.
The process of organ positioning has been addressed, using the pin-formed 1 (pin1) mutant as a tool. PIN1 is a transmembrane protein involved in auxin transport in Arabidopsis. Loss of function severely affects organ initiation, and pin1 mutants are characterised by an inflorescence meristem that does not initiate any flowers, resulting in the formation of a naked inflorescence stem. This phenotype, combined with the proposed role of PIN1 in hormone transport, makes the mutant an ideal tool to study organ formation and phyllotaxis, and here we present a detailed analysis of the molecular modifications at the shoot apex caused by the mutation. We show that meristem structure and function are not severely affected in the mutant. Major alterations, however, are observed at the periphery of the pin1 meristem, where organ initiation should occur. Although two very early markers of organ initiation, LEAFY and AINTEGUMENTA, are expressed at the periphery of the mutant meristem, the cells are not recruited into distinct primordia. Instead a ring-like domain expressing those primordium specific genes is observed around the meristem. This ring-like domain also expresses a boundary marker, CUP-SHAPED COTYLEDON 2, involved in organ separation, showing that the zone at the meristem periphery has a hybrid identity. This implies that PIN1 is not only involved in organ outgrowth, but that it is also necessary for organ separation and positioning. A model is presented in which PIN1 and the local distribution of auxin control phyllotaxis.


Defining parametric dependencies for the correct interpretation of speckle dynamics in photon Doppler velocimetry.
Laser speckle dynamics manifest themselves in photon Doppler velocimetry (PDV) data as low-frequency amplitude fluctuations, and analysis of these fluctuations provides insight into the transverse speed of the surface under observation. We previously demonstrated that a single measurement probe is capable of simultaneously measuring (1) axial motion, through frequency analysis of Doppler shifts, and (2) transverse speed, through analysis of the speckle's coherence time. However, the performance of this technique hinges on a correct understanding of the speckle pattern's response to surface motion. In this paper, we model the origination of the speckle pattern, and we describe a methodology for calculating the speckle's coherence time from the autocorrelation of a noisy signal. We then test a suite of optical probes over a range of standoff distances, demonstrating a significant reduction in the speckle's coherence time, which correlates to the increase in speckle boiling when the target surface is located near a probe's focal length. We show that spatial regions of decreased coherence time may be predicted a priori by a probe's parameters, since they stem from boiling dominance. We analyze this result as a function of probe parameters for a surface-scattering target and a volume-scattering target. Although the coherence time's behavior in the focal plane makes velocity extraction difficult, far from the probe's focal lengths, we are able to measure rigid body transverse speeds exceeding 20 m/s with an absolute accuracy of ±15% using the speckle dynamics measured by a PDV setup.


Pregnancy modifies the large conductance Ca2+-activated K+ channel and cGMP-dependent signaling pathway in uterine vascular smooth muscle.
Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, Ca(2+)-activated K(+) channels (BK(Ca)), consisting of alpha- and regulatory beta-subunits, are expressed in uterine vascular smooth muscle (UVSM) and contribute to the maintenance of UPBF in the last third of ovine pregnancy, but their expression pattern and activation pathways are unclear. We examined BK(Ca) subunit expression, the cGMP-dependent signaling pathway, and the functional role of BK(Ca) in uterine arteries (UA) from nonpregnant (n = 7), pregnant (n = 38; 56-145 days gestation; term, approximately 150 days), and postpartum (n = 15; 2-56 days) sheep. The alpha-subunit protein switched from 83-87 and 105 kDa forms in nonpregnant UVSM to 100 kDa throughout pregnancy, reversal occurring >30 days postpartum. The 39-kDa beta(1)-subunit was the primary regulatory subunit. Levels of 100-kDa alpha-subunit rose approximately 70% during placentation (P < 0.05) and were unchanged in the last two-thirds of pregnancy; in contrast, beta(1)-protein rose throughout pregnancy (R(2) = 0.996; P < 0.001; n = 13), increasing 50% during placentation and approximately twofold in the remainder of gestation. Although UVSM soluble guanylyl cyclase was unchanged, cGMP and protein kinase G(1alpha) increased (P < 0.02), paralleling the rise and fall in beta(1)-protein during pregnancy and the puerperium. BK(Ca) inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced alpha-agonist-induced vasoconstriction. UVSM BK(Ca) modify relaxation-contraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in alpha-subunit composition, alpha:beta(1)-subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BK(Ca) activation via NO-cGMP and beta(1) augmentation may contribute to the regulation of UPBF.


Vitamin B12 absorption and metabolism in milk-fed lambs.
To quantify aspects of absorption and retention of vitamin B12 from milk in pre-ruminant lambs, and the possible effect of activation of dependent metabolic pathways (propionate-succinate) on vitamin B12 concentrations in tissues. In Experiment 1, two groups of eight newborn lambs each received either milk substitute alone, or milk substitute with added propionate for 4 weeks. Half of the lambs in each group received vitamin B12 injections twice weekly. Blood and liver samples were taken on Day -1 and at the end of the trial, and blood was also collected twice weekly, for measurement in plasma of vitamin B12, methylmalonic acid (MMA), and blood-binder transcobalamin II/haptocorrin. The lambs were weighed at 0, 2 and 4 weeks. In Experiment 2, 12 milk-fed newborn lambs (n=2 or 3/group) were injected I/M with 0.2, 0.4, 0.8, 1.6 or 3.2 microg vitamin B12 and a further 12 were supplemented orally with 2, 4, 8, 16 or 32 microg vitamin B12, daily for 2 weeks. Three lambs remained as untreated controls. Blood and liver samples were taken at the start and end of the trial, and blood was also collected twice weekly, for measurement of vitamin B12 and MMA concentrations in plasma. The lambs were weighed on Days 0, 7 and 14. In Experiment 3, 14 lambs from Experiment 2 were used to repeat the highest I/M and oral rates of supplementation used in Experiment 2. Blood samples were taken at frequent intervals for 24 hours, and analysed for concentrations of vitamin B12 in plasma. Propionate supplementation was associated with increased concentrations of vitamin B12 in plasma in lambs supplemented with vitamin B12 but not in those not supplemented (p=0.047), but had no detectable effect on concentrations of vitamin B12 in liver (Experiment 1). Lambs with concentrations of vitamin B12 in plasma and liver in the marginal reference range were able to metabolise propionate and maintain normal concentrations of MMA at a rate of intake of propionate close to that which would depress appetite. Close to 100% of the vitamin B12 administered by I/M injection appeared in plasma in the first hour but 85% was removed from the circulation within 16 hours. The maximum liver concentration was achieved at 900 nmol/kg (=1,200 microg) fresh tissue. There were no significant differences in liveweight gain (LWG) regardless of treatment. Lambs with concentrations of vitamin B12 in plasma and liver in the marginal reference range were able to metabolise propionate and maintain normal concentrations of MMA in plasma at a rate of absorption of propionate close to that which would depress appetite. The coefficient of absorption of oral vitamin B12 in milk-fed lambs was low (<10%), and the ability of lambs to retain the vitamin even when tissues had physiologically low concentrations was poor. Pre-ruminant lambs had a low requirement for vitamin B12, and even at low tissue concentrations had poor ability to absorb and retain the vitamin. However, if supplementation is required, a method that provides a modest but continual supply may be most effective in protection against deficiency.


Retinal remodeling triggered by photoreceptor degenerations.
Many photoreceptor degenerations initially affect rods, secondarily leading to cone death. It has long been assumed that the surviving neural retina is largely resistant to this sensory deafferentation. New evidence from fast retinal degenerations reveals that subtle plasticities in neuronal form and connectivity emerge early in disease. By screening mature natural, transgenic, and knockout retinal degeneration models with computational molecular phenotyping, we have found an extended late phase of negative remodeling that radically changes retinal structure. Three major transformations emerge: 1) Müller cell hypertrophy and elaboration of a distal glial seal between retina and the choroid/retinal pigmented epithelium; 2) apparent neuronal migration along glial surfaces to ectopic sites; and 3) rewiring through evolution of complex neurite fascicles, new synaptic foci in the remnant inner nuclear layer, and new connections throughout the retina. Although some neurons die, survivors express molecular signatures characteristic of normal bipolar, amacrine, and ganglion cells. Remodeling in human and rodent retinas is independent of the initial molecular targets of retinal degenerations, including defects in the retinal pigmented epithelium, rhodopsin, or downstream phototransduction elements. Although remodeling may constrain therapeutic intervals for molecular, cellular, or bionic rescue, it suggests that the neural retina may be more plastic than previously believed.


Communal nursing in wild house mice is not a by-product of group living: females choose.
Communal nursing, the provision of milk to non-offspring, has been argued to be a non-adaptive by-product of group living. We used 2 years of field data from a wild house mouse population to investigate this question. Communal nursing never occurred among females that previously lacked overlap in nest box use. Females nursed communally in only 33% of cases in which there was a communal nursing partner available from the same social group. Solitarily nursing females were not socially isolated in their group; nevertheless, high spatial associations prior to reproduction predict which potential female partner was chosen for communal nursing. An increase in partner availability increased the probability of communal nursing, but population density itself had a negative effect, which may reflect increased female reproductive competition during summer. These results argue that females are selective in their choice of nursing partners and provide further support that communal nursing with the right partner is adaptive.


Sibship assignment to the founders of a Bangladeshi Catla catla breeding population.
Catla catla (Hamilton) fertilised spawn was collected from the Halda, Jamuna and Padma rivers in Bangladesh from which approximately 900 individuals were retained as 'candidate founders' of a breeding population. These fish were fin-clipped and genotyped using the DArTseq platform to obtain, 3048 single nucleotide polymorphisms (SNPs) and 4726 silicoDArT markers. Using SNP data, individuals that shared no putative parents were identified using the program COLONY, i.e. 140, 47 and 23 from the Halda, Jamuna and Padma rivers, respectively. Allele frequencies from these individuals were considered as representative of those of the river populations, and genomic relationship matrices were generated. Then, half-sibling and full-sibling relationships between individuals were assigned manually based on the genomic relationship matrices. Many putative half-sibling and full-sibling relationships were found between individuals from the Halda and Jamuna rivers, which suggests that catla sampled from rivers as spawn are not necessarily representative of river populations. This has implications for the interpretation of past population genetics studies, the sampling strategies to be adopted in future studies and the management of broodstock sourced as river spawn in commercial hatcheries. Using data from individuals that shared no putative parents, overall multi-locus pairwise estimates of Wright's fixation index (FST) were low (≤ 0.013) and the optimum number of clusters using unsupervised K-means clustering was equal to 1, which indicates little genetic divergence among the SNPs included in our study within and among river populations.


The repertoire of transfer RNA genes is tuned to codon usage bias in the genomes of Phytophthora sojae and Phytophthora ramorum.
In all, 238 and 155 transfer (t)RNA genes were predicted from the genomes of Phytophthora sojae and P. ramorum, respectively. After omitting pseudogenes and undetermined types of tRNA genes, there remained 208 P. sojae tRNA genes and 140 P. ramorum tRNA genes. There were 45 types of tRNA genes, with distinct anticodons, in each species. Fourteen common anticodon types of tRNAs are missing altogether from the genome in the two species; however, these appear to be compensated by wobbling of other tRNA anticodons in a manner which is tied to the codon bias in Phytophthora genes. The most abundant tRNA class was arginine in both P. sojae and P. ramorum. A codon usage table was generated for these two organisms from a total of 9,803,525 codons in P. sojae and 7,496,598 codons in P. ramorum. The most abundant codon type detected from the codon usage tables was GAG (encoding glutamic acid), whereas the most numerous tRNA gene had a methionine anticodon (CAT). The correlation between the frequencies of tRNA genes and the codon frequencies in protein-coding genes was very low (0.12 in P. sojae and 0.19 in P. ramorum); however, the correlation between amino acid tRNA gene frequency and the corresponding amino acid codon frequency in P. sojae and P. ramorum was substantially higher (0.53 in P. sojae and 0.77 in P. ramorum). The codon usage frequencies of P. sojae and P ramorum were very strongly correlated (0.99), as were tRNA gene frequencies (0.77). Approximately 60% of orthologous tRNA gene pairs in P sojae and P. ramorum are located in regions that have conserved synteny in the two species.


Single source sound production and dynamic beam formation in echolocating harbour porpoises (Phocoena phocoena).
Echolocating toothed whales produce high-powered clicks by pneumatic actuation of phonic lips in their nasal complexes. All non-physeteroid toothed whales have two pairs of phonic lips allowing many of these species to produce both whistles and clicks at the same time. That has led to the hypothesis that toothed whales can increase the power outputs and bandwidths of clicks, and enable fast clicking and beam steering by acutely timed actuation of both phonic lip pairs simultaneously. Here we test that hypothesis by applying suction cup hydrophones on the sound-producing nasal complexes of three echolocating porpoises (Phocoena phocoena) with symmetrical pairs of phonic lips. Using time of arrival differences on three hydrophones, we show that all recorded clicks from these three porpoises are produced by the right pair of phonic lips with no evidence of simultaneous or independent actuation of the left pair. It is demonstrated that porpoises, despite actuation of only one sound source, can change their output and sound beam probably through conformation changes in the sound-producing soft tissues and nasal sacs, and that the coupling of the phonic lips and the melon acts as a waveguide for sound energy between 100 and 160 kHz to generate a forward-directed sound beam for echolocation.


Alcohol consumption, cigarette smoking and the risk of subtypes of head-neck cancer: results from the Netherlands Cohort Study.
Prospective data on alcohol consumption, cigarette smoking and risk of head-neck cancer (HNC) subtypes, i.e. oral cavity cancer (OCC), oro-/hypopharyngeal cancer (OHPC), and laryngeal cancer (LC), are limited. We investigated these associations within the second largest prospective study on this topic so far, the Netherlands Cohort Study. 120,852 participants completed a questionnaire on diet and other cancer risk factors in 1986. After 17.3 years of follow-up, 395 HNC (110 OCC, 83 OHPC, and 199 LC) cases and 4288 subcohort members were available for case-cohort analysis using Cox proportional hazards models. For total HNC, the multivariable adjusted incidence rate ratio (RR) was 2.74 (95% confidence interval (CI) 1.85-4.06) for those drinking ≥30 g ethanol/day compared with abstainers; in subtypes, RRs were 6.39 for OCC, 3.52 for OHPC, and 1.54 for LC. Compared with never cigarette smokers, current cigarette smokers had a RR of 4.49 (95%CI 3.11-6.48) for HNC overall, and 2.11 for OCC, 8.53 for OHPC, and 8.07 for LC. A significant, positive, multiplicative interaction between categories of alcohol consumption and cigarette smoking was found for HNC overall (P interaction 0.03). Alcohol consumption and cigarette smoking were independently associated with risk of HNC overall, with a positive, multiplicative interaction. The strength of these associations differed among HNC-subtypes: OCC was most strongly associated with alcohol consumption but most weakly with cigarette smoking, whereas LC was not statistically significantly associated with alcohol consumption.


Mitochondrial volume density in human skeletal muscle following heavy resistance training.
Needle biopsies were taken from triceps brachii of 6 healthy males before and after a 6 month intensive weight training programme. The tissue was sectioned, photographed under a Philips EM200 and subjected to stereological analysis. Cross sectional fibre areas were also calculated from cryostat sections stained for ATPase activity. Morphometric analysis indicated that training resulted in a significant 26% reduction in mitochondrial volume density and a 25% reduction in the mitochondrial volume to myofibrillar volume ratio. These changes were accompanied by significant increases in fibre area for both FT (33%) and ST (27%) fibres as determined from the light microscope. There was a significant correlation between the reduction in mitochondrial volume density and the increase in FT fibre area following training (r=0.845). It was concluded that heavy resistance training leads to a dilution of the mitochondrial volume density through an increase in myofibrillar size with hypertrophy.


Environmental exposure characterization of fish processing workers.
Aerosolization of seafood and subsequent inhalation, during processing is a potential high-risk activity for allergic respiratory disease. To quantify total thoracic particulate, protein concentration and specific fish (pilchard, anchovy) antigen concentrations in fish processing plants; to determine the correlation between these exposure metrics; and to identify the major determinants of variability and the optimal grouping strategies for establishing dose-response relationships for fish antigen exposures. Exposure assessments were conducted on randomly selected individuals within each of the identified 'exposure groups' (EGs) in two fish processing factories. Personal time-integrated sampling was conducted with a thoracic fraction sampler and analysed for particulate mass, total protein and specific fish antigens. Exposure metrics were developed on the basis of individually measured exposures and average levels of these personal samples within EGs. The main components of the exposure variability were determined using ANOVA techniques. A total of 198 full-shift personal aerosol samples were collected and analysed. Twenty-two percent of the samples were below the limit of detection (LOD) for pilchard and 23% for anchovy assays. Personal sampling revealed wide variations across EGs in arithmetic mean concentrations of thoracic particulate 0.61 mg m(-3) (range: LOD-11.3), total protein 0.89 microg m(-3) (LOD-11.5), pilchard antigen 150 ng m(-3) (LOD-15 973) and anchovy antigen 552 ng m(-3) (LOD-75 748) levels. The fishmeal loading and bagging sections of both plants showed consistently high thoracic particulate mass (0.811-2.714 mg m(-3)), total protein (0.185-1.855 microg m(-3)), pilchard antigen (538-3288 ng m(-3)) and anchovy antigen (1708-15 431 ng m(-3)). The a priori strategy that grouped workers according to EGs produced reasonably satisfactory summary exposure metric statistics. An alternative grouping strategy based on department revealed comparable elasticity (exposure contrast). While the correlation between the log-transformed thoracic particulate mass and fish antigen concentrations were generally modest (Pearson's r = 0.32-0.35, P < 0.001), a high correlation was found between pilchard and anchovy antigen concentrations (Pearson's r = 0.71, P < 0.001). Models using factory and department grouping strategies accounted for a significant portion of the variability (adjusted r(2) = 0.18, P = 0.043) in pilchard antigen levels. Grouping strategies using a combination of factory and department yielded the highest degree of elasticity for thoracic particulate (0.38) and pilchard antigen (0.42) levels. Workers involved in bony fish processing are at risk of inhaling aerosols containing pilchard and anchovy fish antigens. Antigen exposures are highest during fishmeal production and bagging. Grouping strategies based on department and factory may provide a more efficient approach than a priori classification of EGs for evaluating fish antigen exposures.


Insulin action and determinants of glycaemia in a rat model of type 2 (non-insulin-dependent) diabetes mellitus.
We aimed to assess prandial responses, basal glucose turnover and insulin action (euglycaemic clamp) in a very low-dose neonatal streptozotocin model of Type 2 (non-insulin-dependent) diabetes mellitus. Male Wistar rats were injected at 2 days of age with 45 mg/kg streptozotocin or vehicle (control). At 8 weeks, the groups were subdivided and fed either a high-fat or high-starch diet for 3 weeks. Both the fat diet and streptozotocin treatments had independent hyperglycaemic effects (streptozotocin/fat 9.3 +/- 0.3 mmol/l; streptozotocin/starch 7.5 +/- 0.3 mmol/l; control/fat 7.4 +/- 0.1 mmol/l; all p less than 0.01 vs control/starch 6.4 +/- 0.1 mmol/l). The fat diet effect was associated with both a reduction in basal glucose clearance (p less than 0.001) and in basal hepatic glucose output (p less than 0.05). Streptozotocin increased basal hepatic glucose output. Significantly higher prandial glycaemia in the streptozotocin/starch group occurred despite similar insulin levels and appeared to be related to an impaired early insulin response. Whole-body and tissue-specific insulin sensitivity were significantly depressed in fat-fed animals compared to starch-fed animals, however there were no significant effects of streptozotocin treatment. We conclude that fasting hyperglycaemia associated with abnormalities in both glucose production and clearance can exist in the presence of a basal hepatic glucose output which is reduced compared to control animals. Furthermore, dietary-fat-induced insulin resistance is not exacerbated by the relative insulin deficiency and/or mild hyperglycaemia observed when dietary fat and neonatal streptozotocin-treatments are combined.


Dietary niacin and the risk of incident Alzheimer's disease and of cognitive decline.
Dementia can be caused by severe niacin insufficiency, but it is unknown whether variation in intake of niacin in the usual diet is linked to neurodegenerative decline. We examined whether dietary intake of niacin was associated with incident Alzheimer's disease (AD) and cognitive decline in a large, prospective study. This study was conducted in 1993-2002 in a geographically defined Chicago community of 6158 residents aged 65 years and older. Nutrient intake was determined by food frequency questionnaire. Four cognitive tests were administered to all study participants at 3 year intervals in a 6 year follow up. A total of 3718 participants had dietary data and at least two cognitive assessments for analyses of cognitive change over a median 5.5 years. Clinical evaluations were performed on a stratified random sample of 815 participants initially unaffected by AD, and 131 participants were diagnosed with 4 year incident AD by standardised criteria. Energy adjusted niacin intake had a protective effect on development of AD and cognitive decline. In a logistic regression model, relative risks (95% confidence intervals) for incident AD from lowest to highest quintiles of total niacin intake were: 1.0 (referent) 0.3 (0.1 to 0.6), 0.3 (0.1 to 0.7), 0.6 (0.3 to 1.3), and 0.3 (0.1 to 0.7) adjusted for age, sex, race, education, and ApoE e4 status. Niacin intake from foods was also inversely associated with AD (p for linear trend = 0.002 in the adjusted model). In an adjusted random effects model, higher food intake of niacin was associated with a slower annual rate of cognitive decline, by 0.019 standardised units (SU) per natural log increase in intake (mg) (p = 0.05). Stronger associations were observed in analyses that excluded participants with a history of cardiovascular disease (beta = 0.028 SU/year; p = 0.008), those with low baseline cognitive scores (beta = 0.023 SU/year; p = 0.02), or those with fewer than 12 years' education (beta = 0.035 SU/year; p = 0.002) Dietary niacin may protect against AD and age related cognitive decline.


Sex difference in thermal preference of adult mice does not depend on presence of the gonads.
The thermoneutral zone (TNZ) is a species-specific range of ambient temperature (T a), at which mammals can maintain a constant body temperature with the lowest metabolic rate. The TNZ for an adult mouse is between 26 and 34 °C. Interestingly, female mice prefer a higher T a than male mice although the underlying mechanism for this sex difference is unknown. Here, we tested whether gonadal hormones are dominant factors controlling temperature preference in male and female mice. We performed a temperature preference test in which 10-week-old gonadectomized and sham-operated male and female C57BL/6J mice were allowed to choose to reside at the thermoneutral cage of 29 °C or an experimental cage of 26, 29, or 32 °C. All mice preferred a T a higher than 26 °C, especially in the inactive phase. Choosing between 29 and 32 °C, female mice resided more at 32 °C while male mice had no preference between the temperatures. Hence, the preferred T a for female mice was significantly higher (0.9 ± 0.2 °C) than that for male mice. However, gonadectomy did not influence the T a preference. Female mice prefer a warmer environment than male mice, a difference not affected by gonadectomy. This suggests that thermal-sensing mechanisms may be influenced by sex-specific pathways other than gonadal factors or that the thermoregulatory set point has already been determined prior to puberty.


Efficacy of once-daily administration of udenafil for 24 weeks on erectile dysfunction: results from a randomized multicenter placebo-controlled clinical trial.
The method of administration of oral phosphodiesterase-5 inhibitors has been expanded to once-daily repeated administration with lower initial dosage than on-demand administration. The aim of this study was to evaluate the efficacy and safety of once-daily udenafil as a treatment for erectile dysfunction (ED) for intermediate-term period. This multicenter, randomized, double-blind clinical trial included 346 ED patients (placebo, udenafil 50 mg, udenafil 75 mg). Subjects were treated with each medication once daily for 24 weeks. Subjects were asked to complete the International Index of Erectile Function (IIEF)-erectile function (EF) domain at baseline, 12 weeks, and 24 weeks and the development of adverse drug reactions (ADRs) was inspected. Both dosages of udenafil induced a significant increase in IIEF-EF compared with placebo at both 12 and 24 weeks. When patients were divided according to the severity of baseline EF score, significant improvement was observed only with udenafil 75 mg regardless of the degree of ED. At 24 weeks, the proportions of patients who reported a return to normal EF (IIEF-EF over 26) were 39.1% for udenafil 50 mg and 47.0% for udenafil 75 mg. In terms of safety, ADRs were observed in 6.1%, 12.9%, and 17.9% for placebo, udenafil 50 mg, and 75 mg, respectively. Although a statistically higher rate of ADRs was observed in the udenafil 75 mg group (P = 0.024), the majority were mild and recovered without treatment. Once-daily administration of udenafil 50 mg and 75 mg for 24 weeks resulted in improvement of EF. In particular, udenafil 75 mg improves EF regardless of the baseline degree of ED.


On why left events are the right ones: neural mechanisms underlying the left-hemifield advantage in rapid serial visual presentation.
When simultaneous series of stimuli are rapidly presented left and right, containing two target stimuli T1 and T2, T2 is much better identified when presented in the left than in the right hemifield. Here, this effect was replicated, even when shifts of gaze were controlled, and was only partially compensated when T1 side provided the cue where to expect T2. Electrophysiological measurement revealed earlier latencies of T1- and T2-evoked N2(pc) peaks at the right than at the left visual cortex, and larger right-hemisphere T2-evoked N2(pc) amplitudes when T2 closely followed T1. These findings suggest that the right hemisphere was better able to single out the targets in time. Further, sustained contralateral slow shifts remained active after T1 for longer time at the right than at the left visual cortex, and developed more consistently at the right visual cortex when expecting T2 on the contralateral side. These findings might reflect better capacity of right-hemisphere visual working memory. These findings about the neurophysiological underpinnings of the large right-hemisphere advantage in this complex visual task might help elucidating the mechanisms responsible for the severe disturbance of hemineglect following damage to the right hemisphere.


Evolution of specific 3'-5'-linkages in RNA in pre-biotic soup: a new hypothesis.
This article reviews the different possibilities towards progression of the formation of DNA/RNA in the chemical world, before life, in enzyme-free conditions. The advent of deoxyribo- and ribopentose-sugars, nucleosides, nucleotides and oligonucleotides in the prebiotic soup is briefly discussed. Further, the formation of early single stranded oligomers, base-pairing possibilities and information transfer based on the stability parameters of the derived duplexes is reviewed. Each theory has its own merits and demerits which we have elaborated upon. Lastly, using clues from this literature, a possible explanation for the specific 3'-5'-linkages in RNA is proposed.


SpCOUP-TF: a sea urchin member of the steroid/thyroid hormone receptor family.
Embryonic nuclear proteins from the sea urchin Strongylocentrotus purpuratus bind in vitro to a cis-acting element that lies upstream of the actin gene CyIIIb and consists of two direct repeats homologous to steroid hormone response elements. This sea urchin element is specifically recognized by transcription factor COUP-TF from HeLa cell nuclear extracts as well. A sea urchin gene homologous to the human COUP-TF1 gene was detected by blot hybridization to S. purpuratus genomic DNA. Screening of a genomic DNA library with a human COUP-TF1 cDNA probe produced overlapping genomic clones that carry the S. purpuratus gene. Our results indicate that the sea urchin homologue has a structure similar to the human COUP-TF1 gene, i.e., conserved intron positions characteristic of this subgroup of steroid hormone receptors. Sequencing of the exons that encode the DNA- and ligand-binding domains of the sea urchin protein revealed 96% and 92% amino acid identity to the domains of the human protein, respectively. Transcripts derived from the S. purpuratus COUP-TF homologous gene were detected in ovarian and embryonic RNAs from various stages.


Regulatory pathways for vaccines for developing countries.
Vaccines that are designed for use only in developing countries face regulatory hurdles that may restrict their use. There are two primary reasons for this: most regulatory authorities are set up to address regulation of products for use only within their jurisdictions and regulatory authorities in developing countries traditionally have been considered weak. Some options for regulatory pathways for such products have been identified: licensing in the country of manufacture, file review by the European Medicines Evaluation Agency on behalf of WHO, export to a country with a competent national regulatory authority (NRA) that could handle all regulatory functions for the developing country market, shared manufacturing and licensing in a developing country with competent manufacturing and regulatory capacity, and use of a contracted independent entity for global regulatory approval. These options have been evaluated on the basis of five criteria: assurance of all regulatory functions for the life of the product, appropriateness of epidemiological assessment, applicability to products no longer used in the domestic market of the manufacturing country, reduction of regulatory risk for the manufacturer, and existing rules and regulations for implementation. No one option satisfies all criteria. For all options, national infrastructures (including the underlying regulatory legislative framework, particularly to formulate and implement local evidence-based vaccine policy) must be developed. WHO has led work to develop this capacity with some success. The paper outlines additional areas of action required by the international community to assure development and use of vaccines needed for the developing world.


Treatment of severe skin and soft tissue infections: a review.
To review the salient features of the management of severe skin and soft tissue infections (SSTIs), including toxic shock syndrome, myonecrosis/gas gangrene, and necrotizing fasciitis. For severe SSTIs, intensive care, source control, and broad-spectrum antimicrobials are required for the initial phase of illness. There is an increasing focus on the utility of rapid diagnostic tests to help in selection and de-escalation of antimicrobials for SSTIs. In addition, clinical prediction scores have shown promise in helping predict patients who do not require antimicrobials directed against methicillin-resistant Staphylococcus aureus. Immune status has been shown to be important in clinical outcomes of some, but not all types of SSTIs. The debate for benefits of intravenous immunoglobulin continues to be waged in the recent literature. Severe SSTIs are common and their management complex due to regional variation in predominant pathogens and antimicrobial resistance patterns, as well variations in host immune responses. Unique aspects of care for severe SSTIs are discussed including the role of surgical consultation and source control. The unique features of SSTIs in immunocompromised hosts are also described.


Pathological heterogeneity in amyotrophic lateral sclerosis with FUS mutations: two distinct patterns correlating with disease severity and mutation.
Mutations in the gene encoding the fused in sarcoma (FUS) protein are responsible for ~3% of familial amyotrophic lateral sclerosis (ALS) and <1% of sporadic ALS (ALS-FUS). Descriptions of the associated neuropathology are few and largely restricted to individual case reports. To better define the neuropathology associated with FUS mutations, we have undertaken a detailed comparative analysis of six cases of ALS-FUS that include sporadic and familial cases, with both juvenile and adult onset, and with four different FUS mutations. We found significant pathological heterogeneity among our cases, with two distinct patterns that correlated with the disease severity and the specific mutation. Frequent basophilic inclusions and round FUS-immunoreactive (FUS-ir) neuronal cytoplasmic inclusions (NCI) were a consistent feature of our early-onset cases, including two with the p.P525L mutation. In contrast, our late-onset cases that included two with the p.R521C mutation had tangle-like NCI and numerous FUS-ir glial cytoplasmic inclusions. Double-labeling experiments demonstrated that many of the glial inclusions were in oligodendrocytes. Comparison with the neuropathology of cases of frontotemporal lobar degeneration with FUS-ir pathology showed significant differences and suggests that FUS mutations are associated with a distinct pathobiology.


No Permanent Fix: MACRA, MIPS, and the Politics of Physician Payment Reform.
Organized medicine long yearned for the demise of Medicare's Sustainable Growth Rate (SGR) formula for updating physician fees. Congress finally obliged in 2015, repealing the SGR as part of the Medicare Access and CHIP Reauthorization Act (MACRA). MACRA established value-based metrics for physician payment and financial incentives for doctors to join alternative delivery models like patient-centered medical homes. Throughout the law's initial implementation, the politics of accommodation prevailed, with federal officials crafting final rules that made MACRA more favorable for physicians. However, the era of accommodation could be short-lived. The discretion that the Centers for Medicare and Medicaid Services had during the first two years of implementation is ending. Additionally, euphoria over the SGR's repeal has given way to concerns over the new program's value-based purchasing arrangements and uncertainty over their sustainability. MACRA eliminated the SGR, but not the politics of physician payment.


A genetic linkage map of the apicomplexan protozoan parasite Eimeria tenella.
Apicomplexan protozoan parasites have complex life cycles that involve phases of asexual and sexual reproduction. Some genera have intermediate insect hosts, for example, Plasmodium spp. (the cause of malaria), but related genera such as Eimeria spp. (causative agents of coccidiosis in poultry) have a direct life cycle occurring in only a single host. Mechanisms that regulate the life cycles of apicomplexan parasites are unknown, but the intracellular growth of avian Eimeria spp. is easily shortened by serial selection for the first parasites to complete the transition from asexual to sexual reproduction (to yield so-called precocious lines). To investigate the genetic basis of such an abbreviated life cycle, we have used the species E. tenella and analyzed the inheritance of 443 polymorphic DNA markers in 22 recombinant cloned progeny derived from a cross between parents that had selectable phenotypes of precocious development or resistance to an anticoccidial drug. The markers were placed in 16 linkage groups (which defined 12 chromosomes) and a further 57 unlinked groups. Two linkage groups showed an association (P =.0105) with the traits of precocious development or drug-resistance and were mapped to chromosome 2 (ca 1.2 Mbp) and chromosome 1 (ca 1.0 Mbp), respectively. The map provides a framework for further studies on the identification of genetic loci implicated in the regulation of the life cycle of an important protozoan parasite and a representative of a major taxonomic group. [A table with the segregation data is available as an online supplement at http://www.genome.org.]


QuASAR: quantitative allele-specific analysis of reads.
Expression quantitative trait loci (eQTL) studies have discovered thousands of genetic variants that regulate gene expression, enabling a better understanding of the functional role of non-coding sequences. However, eQTL studies are costly, requiring large sample sizes and genome-wide genotyping of each sample. In contrast, analysis of allele-specific expression (ASE) is becoming a popular approach to detect the effect of genetic variation on gene expression, even within a single individual. This is typically achieved by counting the number of RNA-seq reads matching each allele at heterozygous sites and testing the null hypothesis of a 1:1 allelic ratio. In principle, when genotype information is not readily available, it could be inferred from the RNA-seq reads directly. However, there are currently no existing methods that jointly infer genotypes and conduct ASE inference, while considering uncertainty in the genotype calls. We present QuASAR, quantitative allele-specific analysis of reads, a novel statistical learning method for jointly detecting heterozygous genotypes and inferring ASE. The proposed ASE inference step takes into consideration the uncertainty in the genotype calls, while including parameters that model base-call errors in sequencing and allelic over-dispersion. We validated our method with experimental data for which high-quality genotypes are available. Results for an additional dataset with multiple replicates at different sequencing depths demonstrate that QuASAR is a powerful tool for ASE analysis when genotypes are not available. http://github.com/piquelab/QuASAR. firstname.lastname@example.com or email@example.com Supplementary Material is available at Bioinformatics online.


An Objective Computational Method to Quantify Ankle Osteoarthritis From Low-Dose Weightbearing Computed Tomography.
The treatment of ankle osteoarthritis (OA) varies depending on the severity and distribution of the associated joint degeneration. Disease staging is typically based on subjective grading of appearance on conventional plain radiographs, with reported subpar reproducibility and reliability. The purpose of this study was to develop and describe computational methods to objectively quantify radiographic changes associated with ankle OA apparent on low-dose weightbearing CT (WBCT). Two patients with ankle OA and 1 healthy control who had all undergone WBCT of the foot and ankle were analyzed. The severity of OA in the ankle of each patient was scored using the Kellgren-Lawrence (KL) classification using plain radiographs. For each ankle, a volume of interest (VOI) was centered on the tibiotalar joint. Initial computation analysis used WBCT image intensity (Hounsfield units [HU]) profiles along lines perpendicular to the subchondral bone/cartilage interface of the distal tibia extending across the entire VOI. Graphical plots of the HU distributions were generated and recorded for each line. These plots were then used to calculate the joint space width (JSW) and HU contrast. The average JSW was 3.89 mm for the control ankle, 3.06 mm for mild arthritis (KL 2), and 1.57 mm for severe arthritis (KL 4). The average HU contrast was 72.31 for control, 62.69 for mild arthritis, and 33.98 for severe arthritis. The use of 4 projections at different locations throughout the joint allowed us to visualize specifically which quadrants have reduced joint space width and contrast. In this technique report, we describe a novel methodology for objective quantitative assessment of OA using JSW and HU contrast. Objective, software-based measurements are generally more reliable than subjective qualitative evaluations. This method may offer a starting point for the development of a more robust OA classification system or deeper understanding of the pathogenesis and response to ankle OA treatment.


[The role of -omics technology in the pathophysiology, diagnosis, and treatment of cardiovascular diseases].
Although evident improvement has occurred in the diagnosis and treatment of cardiovascular disease (CVD), it is still the most important cause of mortality worldwide. The majority of the CVDs are multifactorial and polygenic. Therefore, it is logical to use genomics, proteomics, lipidomics, and metabolomics together for diagnosis and effective treatment of CVD. "Genome" is the combination of the words "gene" and "chromosome," and includes all protein-coding genes and intergenic spaces (as well as intragenic regions, or introns, within genes) in an organism. Proteins that are synthesized in a cell, tissue, or organism are all called proteomes. Proteomics is the study of proteomes. The analysis of the lipodome, or all lipids synthesized in the organism, as well as lipidderived mediators, and the functions of these mediators in biological systems, is the field of lipidomics. The metabolome is the complete set of low-molecular-weight metabolites and molecules in a human or any living organism. Metabolomic is the systematic analysis of small molecules and metabolites in human or animal biological fluids. The number of biomarkers used for the purpose of evaluating the risk of cardiovascular events is very limited and many of them are old. The drugs that were produced 30 years ago are still used in treatment. Development of -omics science plays an important role in the search for new biological markers that can be used in the diagnosis of CVD and there is a growing need for advancement of these branches of genetics. The recognition and internalization of -omics by clinicians is a time-consuming process, but will be more important in the near future.


Escaping Policy Traps: Strategic Options for Overcoming Entrenchment.
Policy entrenchment per se is a neutral concept; both good and bad policies may become entrenched. A policy trap, however, is entrenchment's pathological form: a self-reinforcing array of policies that simultaneously creates (1) well-established, often widely recognized failures in society, and (2) high barriers to change. A familiar type of policy trap arises when the benefits of a policy are concentrated while the costs, albeit greater, are widely diffused, opaque to many who bear them, or seemingly remote. But policy traps are not necessarily permanent; they may persist only as long as reformers are unable to identify their vulnerabilities and seize moments of political opportunity. Reconstituting a domain of policy ultimately requires formulating an alternative. Without presuming to be exhaustive, this article outlines four general strategies for overcoming policy entrenchment: Schumpeterian innovation, globally oriented innovation, institutional conversion, and social creativity (the nonmarket analog to Schumpeterian change). Focusing on three areas, the article examines how policy traps have arisen and might be overcome in fossil fuels, the internet economy, and the US health care system.


Three-dimensional power Doppler ultrasound improves the diagnostic accuracy for ovarian cancer prediction.
The goal of this study was to determine if three-dimensional power Doppler ultrasound improves the specificity for ovarian cancer detection as compared with two-dimensional ultrasound. Seventy-one women with a known complex pelvic mass were referred for a preoperative ultrasound evaluation with both two-dimensional and three-dimensional gray-scale ultrasonography. The 3D studies were performed with the Kretz Voluson 530D using a mechanized transvaginal probe. Surface rendering and power Doppler imaging were performed by the same gynecologic sonologist, and reassigned to one of four echo patterns: cystic, multicystic, complex, or solid. Sonographic criteria used for diagnosing ovarian cancer were based on a system that included morphological characteristics, histological prediction, and power Doppler imaging. Seventy-one women underwent surgical exploration: 14 (19.7%) had ovarian cancer (2 FIGO stage I, 2 stage II, 7 stage III, and 3 metastatic colon) and 2 had uterine cancer. Two-dimensional gray-scale ultrasound identified 40 masses as suspicious for cancer, including all 14 malignancies, yielding a sensitivity, specificity, and positive predictive value of 100, 54, and 35%, respectively. However, evaluation with 3D power Doppler identified only 28 cases as suspicious (including all 14 cancers), resulting in a sensitivity, specificity, and positive predictive value of 100, 75, and 50%, respectively. Three-dimensional power Doppler imaging better defines the morphological and vascular characteristics of ovarian lesions. All malignancies were correctly identified by both 2D and 3D imaging; however, the specificity significantly improved with the addition of 3D power Doppler. This improved diagnostic accuracy may promote improved patient care by separating complex benign masses from ovarian cancer, therefore facilitating appropriate physician referral.


Characteristics of recurrent utilization in pediatric emergency departments.
Nationally, frequent utilizers of emergency departments (EDs) are targeted for quality improvement initiatives. The objective was to compare the characteristics and ED health services of children by their ED visit frequency. A retrospective study in 1,896,547 children aged 0 to 18 years with 3,263,330 visits to 37 EDs in 2011. The number of ED visits per child within 365 days of their first visit was counted. Patient characteristics (age, chronic condition) and ED care (medications, testing [laboratory and radiographic], and hospital admission) were assessed. We evaluated the relationship between patient characteristics and ED health services received with multivariable regression. Children with ≥4 ED visits (8%) accounted for 24% of all visits and 31% ($1.4 billion) of all costs. As visit frequency increased from 1 to ≥4, the percentage of children aged <1 year increased (12.1% to 33.2%) and the percentage of children without a chronic condition decreased (81.9% to 45.6%) (P < .001 for both). Children with ≥4 ED visits had a higher percentage of visits without medication administration (aside from acetaminophen or ibuprofen), testing, or hospital admission when compared with children with 1 visit (35.4% vs 29.0%; P < .001). Children with ≥4 ED visits who were aged <1 year (odds ratio: 3.8; 95% confidence interval: 3.7-3.9) and who were without a chronic condition (odds ratio: 3.1; 95% confidence interval: 3.0-3.1) had the highest likelihood of experiencing this type of visit. With a disproportionate share of pediatric ED cost and utilization, frequent utilizers, especially infants without a chronic condition, are the least likely to need medications, testing, and hospital admission.


Comparison of peak expiratory flow rates applying European and Iranian equations to Palestinian students.
Measurement of peak expiratory flow rate (PEFR) is required for effective asthma treatment, but ethnic differences affect the application of prediction equations for lung function. PEFR was measured in a representative sample of 1000 students in Nablus, Palestine. Predicted PEFR equations for Europeans and Iranians were applied to both males and females in age groups < 21 and > or = 21 years. There was a statistically significant correlation between the predicted PEFR values in Palestinians and both equations in both males and females regardless of age. Equations developed on Iranians were more useful for Palestinians than the European equations, but there is a need to develop our own nomograms.


Barriers to the implementation of a computer-based rehabilitation programme in two public psychiatric settings.
Working memory (WM) deficits have a negative impact on treatment adherence and quality of life. Efficient and effective interventions are needed in order to improve the cognitive functioning of those affected, especially in low-resource communities. Computer-based rehabilitation programmes (CBRP) are low-cost therapeutic approaches for WM deficits. Perceptions and experiences of target users may influence whether CBRP constitute an effective therapeutic option for adults with cognitive impairment in under-resourced environments. The goal of the study was to explore the experiences of a group of volunteers with WM deficits (associated with diagnoses of HIV and schizophrenia), in terms of the perceived barriers they encountered during their participation in a CBRP. A qualitative, descriptive research design was implemented. Short interviews and field notes were used in order to investigate the experiences of nine participants in relation to the CBRP. The sample included four participants living with HIV and five with schizophrenia, all with WM deficits. Using a thematic analysis, eight barriers were identified: unawareness of the cognitive deficit, anticipation of negative results, stigma, difficulties accessing a computer and/or Internet connection, ill health, negative emotional experiences, daily routine challenges and non-conducive or sabotaging environments. A representational model of these barriers is proposed. The implementation of a cognitive rehabilitation strategy should not only take into consideration issues of access to particular strategies and materials but should also be preceded by an exploration of how individual and contextual barriers are experienced by the potential users, as these contribute to the risk of dropout.


The use of patient-reported outcome measures and patient satisfaction ratings to assess outcome in hemiarthroplasty of the shoulder.
We have compared the outcome of hemiarthroplasty of the shoulder in three distinct diagnostic groups, using survival analysis as used by the United Kingdom national joint registers, patient-reported outcome measures (PROMs) as recommended by Darzi in the 2008 NHS review, and transition and satisfaction questions. A total of 72 hemiarthroplasties, 19 for primary osteoarthritis (OA) with an intact rotator cuff, 22 for OA with a torn rotator cuff, and 31 for rheumatoid arthritis (RA), were followed up for between three and eight years. All the patients survived, with no revisions or dislocations and no significant radiological evidence of loosening. The mean new Oxford shoulder score (minimum/worst 0, maximum/best 48) improved significantly for all groups (p < 0.001), in the OA group with an intact rotator cuff from 21.4 to 38.8 (effect size 2.9), in the OA group with a torn rotator cuff from 13.3 to 27.2 (effect size 2.1) and in the RA group from 13.7 to 28.0 (effect size 3.1). By this assessment, and for the survival analysis, there was no significant difference between the groups. However, when ratings using the patient satisfaction questions were analysed, eight (29.6%) of the RA group were 'disappointed', compared with one (9.1%) of the OA group with cuff intact and one (7.7%) of the OA group with cuff torn. All patients in the OA group with cuff torn indicated that they would undergo the operation again, compared to ten (90.9%) in the OA group with cuff intact and 20 (76.9%) in the RA group. The use of revision rates alone does not fully represent outcome after hemiarthroplasty of the shoulder. Data from PROMs provides more information about change in pain and the ability to undertake activities and perform tasks. The additional use of satisfaction ratings shows that both the rates of revision surgery and PROMs need careful interpretation in the context of patient expectations.


The in vitro hepatic metabolism of ABT-418, a cholinergic channel activator, in rats, dogs, cynomolgus monkeys, and humans.
The metabolism of the cholinergic channel activator [3H]ABT-418 was studied in 9,000g supernatant (S-9) fractions and precision-cut tissue slices prepared from rat, dog, monkey, and human livers. In rat S-9 fractions and tissue slices, the lactam and trans N'-oxide were detected as major metabolites. The lactam was also the major metabolite in monkey and human S-9 fractions and tissue slices, although the rate of formation was greater in monkey (Vmax' of 428 vs. 103 pmol/min/mg S-9 protein). Trans N'-oxide was not detected in either species, but low levels of the cis N'-oxide were detected in tissue slice preparations from two human subjects. In contrast, trans ABT-418 N'-oxide was identified as a major metabolite in dog S-9 fractions (Vmax' of 266 pmol metabolite formed/min/mg S-9 protein) and tissue slices. Although identified as a minor metabolite in dog S-9 fractions, the lactam metabolite was shown to account for a sizeable proportion of the total radioactivity in the corresponding tissue slice preparations (22% of the total radioactivity at 12 hr); the rank order of lactam formation by the precision-cut liver slices was monkey > human > rat > or = dog. Evidence that N'-oxidation and C-oxidation (to lactam) of ABT-418 was mediated by liver microsomal flavin-containing mono-oxygenase (FMO) and cytochromes P-450 (CYPs), respectively, was obtained with the inhibitors thiobenzamide and clotrimazole. The involvement of cytosolic aldehyde oxidase (AO) was suggested by a significant correlation (r2 = 0.998, p < 0.01) between the observed rate of lactam formation and AO (N1-methylnicotinamide oxidase) activity in rat, dog, monkey, and human S-9 fractions; inhibition of lactam formation by the AO substrate N1-methylnicotinamide; and the lack of lactam formation in the absence of cytosol. Data indicate that the species-related differences in the hepatic metabolism of ABT-418 may be dependent on the relative levels and/or activity of FMO, CYP, and AO. In this regard, ABT-418 is very similar to nicotine. However, unlike nicotine, the N-demethylation of parent drug and the further products of lactam metabolism was not detected.


Intertidal pool fish Girella laevifrons (Kyphosidae) shown strong physiological homeostasis but shy personality: The cost of living in hypercapnic habitats.
Tide pools habitats are naturally exposed to a high degree of environmental variability. The consequences of living in these extreme habitats are not well established. In particular, little it is known about of the effects of hypercanic seawater (i.e. high pCO2 levels) on marine vertebrates such as intertidal pool fish. The aim of this study was to evaluate the effects of increased pCO2 on the physiology and behavior in juveniles of the intertidal pool fish Girella laevifrons. Two nominal pCO2 concentrations (400 and 1600μatm) were used. We found that exposure to hypercapnic conditions did not affect oxygen consumption and absorption efficiency. However, the lateralization and boldness behavior was significantly disrupted in high pCO2 conditions. In general, a predator-risk cost of boldness is assumed, thus the increased occurrence of shy personality in juvenile fishes may result in a change in the balance of this biological interaction, with significant ecological consequences.


The occasional venous thromboses seen in patients with severe (homozygous) FXII deficiency are probably due to associated risk factors: a study of prevalence in 21 patients and review of the literature.
According to our personal experience and to the study of the literature, 11 cases of venous thrombosis have been described as sporadic reports in patients with severe (homozygous) factor XII (FXII) deficiencies. In every cases but 4, associated risk factors were found to be present (pregnancy, post-partum period, surgery, trauma, in dwelling catheter, AT deficiency, heterozygous factor V Leiden, Burger's disease). In some instances more then one condition was present. The four patients for whom no information is supplied, were cases gathered from old and logically incomplete files and therefore the existence of associated risk factors cannot be excluded. The papers which investigated the presence of venous thrombosis in cohorts of patients with homoxygous FXII deficiency demonstrated the occurrence of venous thrombosis in 2 additional cases out of a total of 63 patients investigated. In these latter cases thrombosis occurred during pregnancy. This brings the total number of patients with FXII deficiency who showed a venous thrombosis to 13. Only a few of these patients were investigated for the presence of concomitant congenital prothrombotic conditions. The conclusion of the study seem to suggest that the role played by FXII deficiency in the pathogenesis of venous thrombosis is minor, if any.


The cardiotonic steroid hormone marinobufagenin induces renal fibrosis: implication of epithelial-to-mesenchymal transition.
We recently demonstrated that the cardiotonic steroid marinobufagenin (MBG) induced fibrosis in rat hearts through direct stimulation of collagen I secretion by cardiac fibroblasts. This stimulation was also responsible for the cardiac fibrosis seen in experimental renal failure. In this study, the effect of MBG on the development of renal fibrosis in rats was investigated. Four weeks of MBG infusion triggered mild periglomerular and peritubular fibrosis in the cortex and the appearance of fibrotic scars in the corticomedullary junction of the kidney. MBG also significantly increased the protein levels and nuclear localization of the transcription factor Snail in the tubular epithelia. It is known that activation of Snail is associated with epithelial-to-mesenchymal transition (EMT) during renal fibrosis. To examine whether MBG alone can trigger EMT, we used the porcine proximal tubular cell line LLC-PK1. MBG (100 nM) caused LLC-PK1 cells grown to confluence to acquire a fibroblast-like shape and have an invasive motility. The expressions of the mesenchymal proteins collagen I, fibronectin, and vimentin were increased twofold. However, the total level of E-cadherin remained unchanged. These alterations in LLC-PK1 cells in the presence of MBG were accompanied by elevated expression and nuclear translocation of Snail. During the time course of EMT, MBG did not have measurable inhibitory effects on the ion pumping activity of its natural ligand, Na(+)-K(+)-ATPase. Our data suggest that the MBG may be an important factor in inducing EMT and, through this mechanism, elevated levels of MBG in chronic renal failure may play a role in the progressive fibrosis.