Scurvy results in decreased collagen synthesis and bone density in the guinea pig animal model.
The effect of severe ascorbic acid deficiency on bone remodeling and collagen synthesis was evaluated in a 21 day experiment, using the scorbutic guinea pig model. Animals (n = 6-7/group) were assigned to one of three groups: scorbutic, pair-fed ascorbic acid-replete, or ad libitum ascorbic acid-replete groups. After 2 weeks, scorbutic animals started voluntarily decreasing food intake and losing weight. By day 19-21, at which time bone and tissue samples were collected and analyzed, scorbutic animals decreased food intake to 46% of usual and lost 9% body weight. Serum 25OHD3, 1,25(OH)2D3, calcium, and albumin were significantly lower (p < 0.05) in the scorbutic animals than in the other groups. Bone mineral density and bone mineral content of the proximal and central femur were significantly lower in the scorbutic group than in the other groups (p < 0.05). Morphometric analysis of tibia indicated significantly lower bone volume, fewer and thinner trabeculae, and a thinner growth plate in the scorbutic group, compared to the pair-fed and ad libitum groups (p < 0.05). Osteoclast surface was about 60% higher in the scorbutic group than in the pair-fed and ad libitum control groups (0.05 < p < 0.10). Mechanical strength of the femur and lumbar vertebral body tended to be lower when bone mass was altered in the same group. Collagen synthesis of articular cartilage and tendons was lower in the scorbutic group than in the pair-fed or ad libitum groups (p < 0.05). In conclusion, scurvy but not food restriction, per se, results in alterations in bone mass and tissue collagen synthesis.


Auditing local methods for quality assurance in radiotherapy using the same set of predefined treatment plans.
Local implementation of plan-specific quality assurance (QA) methods for intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) treatment plans may vary because of dissimilarities in procedures, equipment and software. The purpose of this work is detecting possible differences between local QA findings and those of an audit, using the same set of treatment plans. A pre-defined set of clinical plans was devised and imported in the participating institute's treatment planning system for dose computation. The dose distribution was measured using an ionisation chamber, radiochromic film and an ionisation chamber array. The centres performed their own QA, which was compared to the audit findings. The agreement/disagreement between the audit and the institute QA results were assessed along with the differences between the dose distributions measured by the audit team and computed by the institute. For the majority of the cases the results of the audit were in agreement with the institute QA findings: ionisation chamber: 92%, array: 88%, film: 76% of the total measurements. In only a few of these cases the evaluated measurements failed for both: ionisation chamber: 2%, array: 4%, film: 0% of the total measurements. Using predefined treatment plans, we found that in approximately 80% of the evaluated measurements the results of local QA of IMRT and VMAT plans were in line with the findings of the audit. However, the percentage of agreement/disagreement depended on the characteristics of the measurement equipment used and on the analysis metric.


Jaguar movement database: a GPS-based movement dataset of an apex predator in the Neotropics.
The field of movement ecology has rapidly grown during the last decade, with important advancements in tracking devices and analytical tools that have provided unprecedented insights into where, when, and why species move across a landscape. Although there has been an increasing emphasis on making animal movement data publicly available, there has also been a conspicuous dearth in the availability of such data on large carnivores. Globally, large predators are of conservation concern. However, due to their secretive behavior and low densities, obtaining movement data on apex predators is expensive and logistically challenging. Consequently, the relatively small sample sizes typical of large carnivore movement studies may limit insights into the ecology and behavior of these elusive predators. The aim of this initiative is to make available to the conservation-scientific community a dataset of 134,690 locations of jaguars (Panthera onca) collected from 117 individuals (54 males and 63 females) tracked by GPS technology. Individual jaguars were monitored in five different range countries representing a large portion of the species' distribution. This dataset may be used to answer a variety of ecological questions including but not limited to: improved models of connectivity from local to continental scales; the use of natural or human-modified landscapes by jaguars; movement behavior of jaguars in regions not represented in this dataset; intraspecific interactions; and predator-prey interactions. In making our dataset publicly available, we hope to motivate other research groups to do the same in the near future. Specifically, we aim to help inform a better understanding of jaguar movement ecology with applications towards effective decision making and maximizing long-term conservation efforts for this ecologically important species. There are no costs, copyright, or proprietary restrictions associated with this data set. When using this data set, please cite this article to recognize the effort involved in gathering and collating the data and the willingness of the authors to make it publicly available.


Socioeconomic Attainment of Extremely Low Birth Weight Survivors: The Role of Early Cognition.
To determine: (1) if childhood cognitive and academic abilities mediate the association between being born at extremely low birth weight (ELBW) and socioeconomic attainment at age 29 to 36 years; (2) which cognitive abilities (IQ, verbal abilities, fluid intelligence, mathematical abilities, or academic achievement) most strongly mediate this association; and (3) if the mediating role of cognition is different in ELBW survivors with significant neurosensory impairment (NSI). A prospective, longitudinal cohort of 100 Canadian ELBW survivors born between 1977 and 1982 and 89 normal birth weight comparison participants were used to examine the mediating role of childhood cognition by using 5 cognitive mediators assessed at age 8 years (overall IQ, verbal IQ, performance IQ, quantitative ability, and academic achievement) on socioeconomic attainment at adulthood. Socioeconomic attainment was defined as personal annual earnings and full-time employment assessed via self-report at age 29 to 36 years. Mediation models revealed that childhood cognition mediated the association between ELBW status and income attainment, with mathematical abilities and overall IQ each accounting for 26% of the direct effect. Mediated effects were not statistically significant in full-time employment models. For both outcomes, the mediating effect of cognition was stronger for ELBW survivors with NSI. Childhood cognitive abilities partially mediate associations between ELBW status and adult income attainment. Early life cognition is a critical predictor of socioeconomic attainment in ELBW survivors, particularly in those born with NSI. Interventions aimed at enhancing early cognition in ELBW survivors may help optimize their later socioeconomic attainment.


gb'clock is expressed in the optic lobe and is required for the circadian clock in the cricket Gryllus bimaculatus.
Reverse genetic studies have revealed that common clock genes, such as period (per), timeless (tim), cycle (cyc), and Clock (Clk), are involved in the circadian clock mechanism among a wide variety of insects. However, to what degree the molecular oscillatory mechanism is conserved is still to be elucidated. In this study, cDNA of the clock gene Clk was cloned in the cricket Gryllus bimaculatus, and its function was analyzed using RNA interference (RNAi). In adult optic lobes, the Clk mRNA level showed no significant rhythmic changes both under light-dark cycle (LD) and constant darkness (DD). A single injection of Clk double-stranded RNA (dsRNA) resulted in a knockdown of the mRNA level to about 25% of the peak level of control animals. The injected crickets lost their locomotor rhythms in DD. The arrhythmicity in locomotor activity persisted for up to 50 days after the Clk dsRNA injection. Control animals injected with DsRed2 dsRNA showed a clear locomotor rhythm like intact animals. Injection of Clk dsRNA not only suppressed the mRNA levels of both per and tim but also abolished their rhythmic expression. per RNAi down-regulates the Clk mRNA levels, suggesting that per is required for sufficient expression of Clk. These results suggest that Clk is an essential component and plays an important role in the cricket's circadian clock machinery like in Drosophila, but regulation of its expression is probably different from regulation in Drosophila.


The patho-anatomy of patellofemoral subluxation.
Patella subluxation assessed on dynamic MRI has previously been shown to be associated with anterior knee pain. In this MRI study of 60 patients we investigated the relationship between subluxation and multiple bony, cartilaginous and soft-tissue factors that might predispose to subluxation using discriminant function analysis. Patella engagement (% of patella cartilage overlapping with trochlea cartilage) had the strongest relationship with subluxation. Patellae with > 30% engagement tended not to sublux; those with < 30% tended to sublux. Other factors that were associated with subluxation included the tibial tubercle-trochlea notch distance, vastus medialis obliquus distance from patella, patella alta, and the bony and cartilaginous sulcus angles in the superior part of the trochlea. No relationship was found between subluxation and sulcus angles for cartilage and bone in the middle and lower part of the trochlea, cartilage thicknesses and Wiberg classification of the patella. This study indicates that patella engagement is a key factor associated with patellar subluxation. This suggests that in patients with anterior knee pain with subluxation, resistant to conservative management, surgery directed towards improving patella engagement should be considered. A clinical trial is necessary to test this hypothesis.


Intermittent preventive treatment with sulfadoxine-pyrimethamine against malaria and anemia in pregnant women.
The effectiveness of intermittent preventive treatment during pregnancy with sulfadoxine-pyrimethamine (IPTp-SP) against malaria and anemia is unclear because of the spread of SP-resistant Plasmodium falciparum. This study evaluates the effectiveness of IPTp-SP among pregnant women attending the antenatal clinic at Korle-Bu Teaching Hospital in Accra, Ghana. A cross-sectional study comparing malaria and anemia prevalence among pregnant women using IPTp-SP with non-IPTp-SP users was conducted during June-August 2009. A total of 363 pregnant women (202 of IPTp users and 161 non-IPTp users) were recruited. A total of 15.3% of IPTp users had malaria compared with 44.7% of non-IPTp users (P < 0.001). A total of 58.4% of non-IPTp users were anemic compared with 22.8% of IPTp users (P < 0.001). When we controlled for other variables, the difference in the prevalence of malaria (odds ratio = 0.18, 95% confidence interval = 0.08-0.37) and anemia (odds ratio = 0.20, 95% confidence interval = 0.12-0.34) remained significant. The recommended IPTp-SP regimen is useful in preventing malaria and anemia among pregnant women in Ghana.


An improved approach for measuring the impact of multiple CO2 conductances on the apparent photorespiratory CO2 compensation point through slope-intercept regression.
Biochemical models of leaf photosynthesis, which are essential for understanding the impact of photosynthesis to changing environments, depend on accurate parameterizations. One such parameter, the photorespiratory CO2 compensation point can be measured from the intersection of several CO2 response curves measured under sub-saturating illumination. However, determining the actual intersection while accounting for experimental noise can be challenging. Additionally, leaf photosynthesis model outcomes are sensitive to the diffusion paths of CO2 released from the mitochondria. This diffusion path of CO2 includes both chloroplastic as well as cell wall resistances to CO2 , which are not readily measurable. Both the difficulties of determining the photorespiratory CO2 compensation point and the impact of multiple intercellular resistances to CO2 can be addressed through application of slope-intercept regression. This technical report summarizes an improved framework for implementing slope-intercept regression to evaluate measurements of the photorespiratory CO2 compensation point. This approach extends past work to include the cases of both Rubisco and Ribulose-1,5-bisphosphate (RuBP)-limited photosynthesis. This report further presents two interactive graphical applications and a spreadsheet-based tool to allow users to apply slope-intercept theory to their data.


Generalization through the recurrent interaction of episodic memories: a model of the hippocampal system.
In this article, we present a perspective on the role of the hippocampal system in generalization, instantiated in a computational model called REMERGE (recurrency and episodic memory results in generalization). We expose a fundamental, but neglected, tension between prevailing computational theories that emphasize the function of the hippocampus in pattern separation (Marr, 1971; McClelland, McNaughton, & O'Reilly, 1995), and empirical support for its role in generalization and flexible relational memory (Cohen & Eichenbaum, 1993; Eichenbaum, 1999). Our account provides a means by which to resolve this conflict, by demonstrating that the basic representational scheme envisioned by complementary learning systems theory (McClelland et al., 1995), which relies upon orthogonalized codes in the hippocampus, is compatible with efficient generalization-as long as there is recurrence rather than unidirectional flow within the hippocampal circuit or, more widely, between the hippocampus and neocortex. We propose that recurrent similarity computation, a process that facilitates the discovery of higher-order relationships between a set of related experiences, expands the scope of classical exemplar-based models of memory (e.g., Nosofsky, 1984) and allows the hippocampus to support generalization through interactions that unfold within a dynamically created memory space.


Glcci1 deficiency leads to proteinuria.
Unbiased transcriptome profiling and functional genomics approaches identified glucocorticoid-induced transcript 1 (GLCCI1) as being a transcript highly specific for the glomerulus, but its role in glomerular development and disease is unknown. Here, we report that mouse glomeruli express far greater amounts of Glcci1 protein compared with the rest of the kidney. RT-PCR and Western blotting demonstrated that mouse glomerular Glcci1 is approximately 60 kD and localizes to the cytoplasm of podocytes in mature glomeruli. In the fetal kidney, intense Glcci1 expression occurs at the capillary-loop stage of glomerular development. Using gene knockdown in zebrafish with morpholinos, morphants lacking Glcci1 function had collapsed glomeruli with foot-process effacement. Permeability studies of the glomerular filtration barrier in these zebrafish morphants demonstrated a disruption of the selective glomerular permeability filter. Taken together, these data suggest that Glcci1 promotes the normal development and maintenance of podocyte structure and function.


Refractoriness in female lizard reproduction: a probable circannual clock.
Postreproductive Cnemidophorus uniparens maintained under free-running conditions of constant darkness for 7 months became reproductive at the same time as controls exposed to a long photoperiod. This lizard exhibits a pause in reproductive activity (refractory period) commencing in late summer in nature and terminating in mid-December in captivity. Both groups terminated refractoriness and started reproducing simultaneously in December despite maintenance of the experimental group in darkness since September. These results confirm the hypothesis that the refractory period in this lizard is under endogenous control.


Aneurysmal bone cyst primary--about eight pediatric cases: radiological aspects and review of the literature.
The aneurysmal bone cyst is a pseudotumoral lesion that can take several aspects. This is a rare lesion representing 1% of bone tumors. It appears usually during the first 30 years of life. The pathogenesis is that of a process of "dysplasia/hyperplasia", favored by a circulatory deficiency and hemorrhage within the lesion and the phenomena of osteoclasis. The objective of this work is to illustrate with analysis, the specific forms and atypical aneurysmal bone cyst which often pose a diagnostic challenge requiring radiological investigation with histological confirmation. We report eight pediatric cases of aneurysmal cysts collected over a period of 3 years, 3 boys and 5 girls. All patients had standard radiographs. MRI was performed in three patients. The diagnosis was confirmed histologically. The atypia has been in the seat: fibula (1 case), metaphyseal (2 cases), diaphyseal (4 cases) and metatarsal (1 case). Aneurysmal bone cyst is a rare benign tumor with predilection to the metaphysis of long bones. Atypical forms even fewer are dominated by the atypical seat.


Aerobic granule formation in a sequencing batch reactor treating newsprint effluent under low phosphate conditions.
Pulp and paper mills are under increasing pressure to minimize the discharge of phosphate to receiving waters. We investigated the operation of two laboratory sequencing batch reactors (SBR) under low phosphate conditions over a period of eight months. Performance characteristics in terms of COD and TSS removal were similar to the full-scale mill activated sludge operation, but the floc density and structure was improved. Sludge yield as a result of phosphate limitation was routinely lower than 0.15 kg/kg of COD. Aerobic granule formation was established in one of the SBRs by reducing the settling time from 30 min to 2 min and by increasing stirring shear force. Once established, the brown granules which were 1-2 mm in diameter were stable over five months of operation. Extracellular polymeric substance (EPS) analysis of the granules indicated a higher galactose content and lower mannose content than in conventional flocs. The granules generated more quorum sensing compound (acyl homoserine lactone) than conventional flocs, suggesting that quorum sensing could play a role in granule formation. When compared to the conventional SBR, the aerobic granule SBR performed at a higher organic loading, at faster settling velocity, and without filamentous bulking.


Chemical and genetic rescue of an ep300 knockdown model for Rubinstein Taybi Syndrome in zebrafish.
EP300 is a member of the EP300/CBP family of lysine acetyltransferases (KATs) with multiple roles in development and physiology. Loss of EP300/CBP activity in humans causes a very rare congenital disorder called Rubinstein Taybi Syndrome (RSTS). The zebrafish genome has two co-orthologs of lysine acetyltransferase EP300 (KAT3B) in zebrafish viz. ep300a and ep300b. Chemical inhibition of Ep300 with C646, a competitive inhibitor and morpholino-based genetic knockdown of ep300a and ep300b cause defects in embryonic development reminiscent of the human RSTS syndrome. Remarkably, overexpression of Ep300a KAT domain results in near complete rescue of the jaw development defects, a characteristic feature of RSTS in human suggesting the dispensability of the protein-interaction and DNA-binding domains for at least some developmental roles of Ep300. We also perform a chemical screen and identify two inhibitors of deacetylases, CHIC35 and HDACi III, that can partially rescue the RSTS-like phenotypes. Thus, modeling rare human genetic disorders in zebrafish allows for functional understanding of the genes involved and can also yield small molecule candidates towards therapeutic goals.


In vivo effects of traditional Ayurvedic formulations in Drosophila melanogaster model relate with therapeutic applications.
Ayurveda represents the traditional medicine system of India. Since mechanistic details of therapy in terms of current biology are not available in Ayurvedic literature, modern scientific studies are necessary to understand its major concepts and procedures. It is necessary to examine effects of the whole Ayurvedic formulations rather than their "active" components as is done in most current studies. We tested two different categories of formulations, a Rasayana (Amalaki Rasayana or AR, an herbal derivative) and a Bhasma (Rasa-Sindoor or RS, an organo-metallic derivative of mercury), for effects on longevity, development, fecundity, stress-tolerance, and heterogeneous nuclear ribonucleoprotein (hnRNP) levels of Drosophila melanogaster using at least 200 larvae or flies for each assay. A 0.5% (weight/volume) supplement of AR or RS affected life-history and other physiological traits in distinct ways. While the size of salivary glands, hnRNP levels in larval tissues, and thermotolerance of larvae/adult flies improved significantly following feeding either of the two formulations, the median life span and starvation resistance improved only with AR. Feeding on AR or RS supplemented food improved fecundity differently. Feeding of larvae and adults with AR increased the fecundity while the same with RS had opposite effect. On the contrary, feeding larvae on normal food and adults on AR supplement had no effect on fecundity but a comparable regime of feeding on RS-supplemented food improved fecundity. RS feeding did not cause heavy metal toxicity. The present study with two Ayurvedic formulations reveals formulation-specific effects on several parameters of the fly's life, which seem to generally agree with their recommended human usages in Ayurvedic practices. Thus, Drosophila, with its very rich genetic tools and well-worked-out developmental pathways promises to be a very good model for examining the cellular and molecular bases of the effects of different Ayurvedic formulations.


The FOXP1 transcription factor is expressed in the majority of follicular lymphomas but is rarely expressed in classical and lymphocyte predominant Hodgkin's lymphoma.
The expression of the FOXP1 forkhead/winged helix transcription factor has been investigated in normal and neoplastic lymphoid tissues using the FOXP1-specific monoclonal antibody, JC12. Using single and double immunoenzymatic staining, FOXP1 expression has been studied in a series of classical and lymphocyte predominant Hodgkin's lymphomas, follicle centre lymphomas and Hodgkin's lymphoma-derived cell lines. Neoplastic cells in the majority of classical and lymphocyte predominant Hodgkin's lymphoma were FOXP1-negative. In two cases of classical Hodgkin's lymphoma, the tumour cells showed mislocalisation of FOXP1 to the cytoplasm, while in one case of lymphocyte predominant Hodgkin's lymphoma, and in the Hodgkin's lymphoma cell line KMH2, scattered tumour cells showed nuclear expression of FOXP1. In contrast, the tumour cells in the majority of follicle centre lymphomas showed strong nuclear FOXP1 reactivity. Double labelling studies of lymphoid tissue indicated that a variable proportion of CD20-positive germinal centre B cells express FOXP1 while the vast majority of CD30-positive cells are FOXP1-negative. The heterogeneity of FOXP1 expression in germinal centre-derived lymphomas, may have more to do with the transforming events underlying these distinct types of lymphoma than with their common origin.


C-reactive protein does not relax vascular smooth muscle: effects mediated by sodium azide in commercially available preparations.
C-reactive protein (CRP), an acute-phase protein and newly recognized indicator of cardiovascular risk, may have direct actions on the vascular wall. Previous studies suggest that CRP is a vasodilator that activates smooth muscle K(+) channels. We examined the reported vasoactive properties of CRP and further explored its mechanisms of action. CRP decreased blood pressure in rats and increased coronary flow in open-chest dogs at a constant coronary perfusion pressure. CRP relaxed rat aortic rings and mesenteric small arteries that were contracted with phenylephrine. Relaxation was not affected by endothelial denudation or inhibition of nitric oxide (NO) synthase but was blocked by inhibition of soluble guanylate cyclase or K(+) channels. CRP solutions remained effective, i.e., elicited vasodilation, even after boiling or enzymatic digestion, which suggests the presence of a nonprotein contaminant. Sodium azide (NaN(3), 0.1%) is the preservative used for commercially available CRP and a potential source of NO. NaN(3) elicited the same cardiovascular effects as CRP preparations at equal concentrations, and its actions were blocked by inhibition of guanylate cyclase and K(+) channels. NaN(3)-free CRP, prepared by gel-filtration centrifugation and confirmed by electrophoresis, had no effect on vascular tone. Inhibition of vascular smooth muscle catalase with 3-amino-1,2,4-triazole completely prevented the effects of NaN(3) and NaN(3)-containing CRP solutions. We demonstrate that the acute vasoactive properties of commercially available CRP preparations are attributable to NaN(3) (and subsequent production of NO by catalase); therefore, this study suggests a reappraisal of the acute role of CRP in regulating vascular tone.


Prognostic value of p21(WAF1) and p53 expression in breast carcinoma: an immunohistochemical study in 261 patients with long-term follow-up.
p21 protein (p21) inhibitor of cyclin-dependent kinases is a critical downstream effector in the p53-specific pathway of growth control and can also be induced by p53-independent pathways in relation to terminal differentiation. We investigated p21 immunoreactivity in 261 breast carcinomas (141 node negative and 120 node positive) with long-term follow-up (median, 73 months; range, 37-119). p21 was seen in 214 (82%) infiltrating tumors, staining was nuclear and heterogeneous, and the p21 labeling index ranged from 0 to 90%. Sixty-eight (32%) patients showed p21 overexpression (>10% of reactive tumor cells). p21 overexpression was associated with large tumor size, positive nodal status, high histological grade, and high mitotic count and was related to short disease-free survival (DFS) in the whole series of patients (P = 0.04), in the node-negative subgroup (P = 0.004), and in the group of patients who did not undergo systemic adjuvant therapy (P = 0.003). In patients treated with systemic adjuvant therapy, bivariate analysis of the combined p21 and p53 phenotypes showed that p21+/p53+ tumors were associated with long DFS and overall survival (OS), whereas p21-/p53+ tumors had the worst prognosis. In treated patients, multivariate analysis showed that the p21-/53+ phenotype was independently associated with short DFS and OS. Our present data support the hypothesis that p21/p53 heterogeneous expression may be of clinical relevance for the therapeutic response to chemotherapy/hormonotherapy. The p21-/p53+ phenotype could correspond to a situation where p53 overexpression really reflects complete abrogation of p53 function. These cases with disrupted p53 function should have impaired the G1 checkpoint and may not be able to activate the apoptotic cascade in response to DNA-damaging drugs.


Comparison of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis in Kenya.
To compare the use of generic and proprietary sodium stibogluconate for the treatment of visceral leishmaniasis (kala-azar). A total of 102 patients with confirmed kala-azar were treated in a mission hospital in West Pokot region, Kenya, with sodium stibogluconate (20 mg/kg/day for 30 days)--either as Pentostam (PSM) or generic sodium stibogluconate (SSG); 51 patients were allocated alternately to each treatment group. There were no significant differences in baseline demographic characteristics or disease severity, or in events during treatment. There were 3 deaths in the PSM group and 1 in the SSG group; 2 patients defaulted in each group. Only 1 out of 80 test-of-cure splenic aspirates was positive for Leishmania spp.; this patient was in the SSG group. Follow-up after > or = 6 months showed that 6 out of 58 patients had relapsed, 5 in the SSG group and 1 in the PSM group. No outcome variable was significantly different between the two groups. The availability of cheaper generic sodium stibogluconate, subject to rigid quality controls, now makes it possible for the health authorities in kala-azar endemic areas to provide treatment to many more patients in Africa.


The political management of managed care: explaining variations in state health maintenance organization regulations.
In the 1990s, strong incentives for managed care organizations to control costs, once regarded as a fortuitous confluence of interests, came to be seen as antithetical to consumers' interests in quality of care. In response to this change in political climate, many states have greatly increased their regulatory control of managed care organizations since the mid-1990s. This activity is surprising in an era when public policy on health care issues is usually described as frozen, gridlocked, and/or stalemated as a result of intense activity on the part of organized interests. We take advantage of the variation in state regulations of health maintenance organizations (HMOs) to discover why some governments are able to address policy problems that are often perceived as intractable in a political if not in a true policy sense. From the history of HMOs, the backlash against managed care, and state responses to that backlash, we first extract a number of hypotheses about state regulatory activity. We then test these hypotheses with data on regulatory adoptions by states during the late 1990s and the early 2000s. Last, we discuss the findings with special attention to the role of politics in health care.


Negative regulation of lncRNA GAS5 by miR-21.
In addition to protein-coding genes, the human genome makes a large amount of noncoding RNAs, including microRNAs and long noncoding RNAs (lncRNAs). Both microRNAs and lncRNAs have been shown to have a critical role in the regulation of cellular processes such as cell growth and apoptosis, as well as cancer progression and metastasis. Although it is well known that microRNAs can target a large number of protein-coding genes, little is known whether microRNAs can also target lncRNAs. In the present study, we determine whether miR-21 can regulate lncRNA expression. Using the lncRNA RT-PCR (reverse transcription-polymerase chain reaction) array carrying 83 human disease-related lncRNAs, we show that miR-21 is capable of suppressing the lncRNA growth arrest-specific 5 (GAS5). This negative correlation between miR-21 and GAS5 is also seen in breast tumor specimens. Of interest, GAS5 can also repress miR-21 expression. Whereas ectopic expression of GAS5 suppresses, GAS5-siRNA increases miR-21 expression. Importantly, there is a putative miR-21-binding site in exon 4 of GAS5; deletion of the miR-21-binding site abolishes this activity. Experiments with in vitro cell culture and xenograft mouse model suggest that GAS5 functions as a tumor suppressor. We further show that the biotin-labeled GAS5-RNA probe is able to pull down the key component (AGO2) of the RNA-induced silencing complex (RISC) and we subsequently identify miR-21 in this GAS5-RISC complex, implying that miR-21 and GAS5 may regulate each other in a way similar to the microRNA-mediated silencing of target mRNAs. Together, these results suggest that miR-21 targets not only tumor-suppressive protein-coding genes but also lncRNA GAS5.


NF-κB Activation Promotes Alphavirus Replication in Mature Neurons.
Alphaviruses are enveloped, positive-sense RNA viruses that are important causes of viral encephalomyelitis. Sindbis virus (SINV) infects the neurons of rodents and is a model for studying factors that regulate infection of neuronal cells. The outcome of alphavirus infection of the central nervous system is dependent on neuronal maturation status. Differentiated mature neurons survive and control viral replication better than undifferentiated immature neurons. The cellular factors involved in age-dependent susceptibility include higher levels of antiapoptotic and innate immune factors in mature neurons. Because NF-κB pathway activation is required for the initiation of both apoptosis and the host antiviral response, we analyzed the role of NF-κB during SINV infection of differentiated and undifferentiated rat neuronal cells. SINV infection induced canonical NF-κB activation, as evidenced by the degradation of IκBα and the phosphorylation and nuclear translocation of p65. Inhibition or deletion of the upstream IκB kinase substantially reduced SINV replication in differentiated but not in undifferentiated neuronal cells or mouse embryo fibroblasts. NF-κB inhibition did not affect the establishment of infection, replication complex formation, the synthesis of nonstructural proteins, or viral RNA synthesis in differentiated neurons. However, the translation of structural proteins was impaired, phosphorylation of the α subunit of eukaryotic translation initiation factor 2 (eIF2α) was decreased, and host protein synthesis was maintained, suggesting that NF-κB activation was involved in the regulation of translation during infection of mature neurons. Inhibition or deletion of double-stranded RNA-activated protein kinase (PKR) also decreased eIF2α phosphorylation, the translation of viral structural proteins, and virus production. Therefore, canonical NF-κB activation synergizes with PKR to promote SINV replication in differentiated neurons by facilitating viral structural protein translation.IMPORTANCE Mosquito-borne alphaviruses are a significant and growing cause of viral encephalomyelitis worldwide. The outcome of alphaviral neuronal infections is host age dependent and greatly affected by neuronal maturation status, with differentiated, mature neurons being more resistant to infection than undifferentiated, immature neurons. The biological factors that change during neuronal maturation and that influence the outcome of viral infection are currently only partially defined. These studies investigated the role of NF-κB in determining the outcome of alphaviral infection in mature and immature neurons. Inhibition of canonical NF-κB activation decreased alphavirus replication in mature neurons by regulating protein synthesis and limiting the production of the viral structural proteins but had little effect on viral replication in immature neurons or fibroblasts. Therefore, NF-κB is a signaling pathway that influences the maturation-dependent outcome of alphaviral infection in neurons and that highlights the importance of cellular context in determining the effects of signal pathway activation.


Sex difference in race performance and age of peak performance in the Ironman Triathlon World Championship from 1983 to 2012.
The fastest Ironman race times in 'Ironman Hawaii' were achieved in very recent years. This study investigated the change in sex difference in both race performance and the age of peak performance across years in the top ten athletes for split disciplines and overall race time in the 'Ironman Hawaii' between 1983 and 2012. Changes in split times, overall race times, and age of athletes across years for the top ten overall and the fastest swimmers, cyclists, and runners were investigated using regression analyses and analyses of variance. Between 1983 and 2012, the overall top ten men and women finishers improved their swimming (only men), cycling, running, and overall race times. The sex difference in overall race time decreased significantly (p = 0.01) from 15.2% to 11.3% across time. For the split disciplines, the sex difference remained unchanged (p > 0.05) for swimming (12.5 ± 3.7%) and cycling (12.5 ± 2.7%) but decreased for running from 13.5 ± 8.1% to 7.3 ± 2.9% (p = 0.03). The time performance of the top ten swimmers remained stable (p > 0.05), while those of the top ten cyclists and top ten runners improved (p < 0.01). The sex difference in performance remained unchanged (p > 0.05) in swimming (8.0 ± 2.4%), cycling (12.7 ± 1.8%), and running (15.2 ± 3.0%). Between 1983 and 2012, the age of the overall top ten finishers and the fastest swimmers, cyclists, and runners increased across years for both women and men (p < 0.01). To summarize, for the overall top ten finishers, the sex difference decreased across years for overall race time and running, but not for swimming and cycling. For the top ten per discipline, the sex difference in performance remained unchanged. The athletes improved their performances across years although the age of peak performance increased.


Retinal Nerve Fiber Layer Measures and Cognitive Function in the EPIC-Norfolk Cohort Study.
We examined the relationship between retinal nerve fiber layer (RNFL) thickness and cognitive function in a population of older British adults. Participants of the European Prospective Investigation of Cancer (EPIC) Norfolk cohort study underwent ophthalmic and cognitive assessment. Measurements of RNFL thickness were made using the Heidelberg Retina Tomograph (HRT). Cognitive testing included a short form of the Mini-Mental State Examination (SF-MMSE), an animal naming task, a letter cancellation task, the Hopkins Verbal Learning Test (HVLT), the National Adult Reading Test (NART), and the Paired Associates Learning Test. Multivariable linear regression models were used to assess associations of RNFL thickness with cognitive test scores, adjusted for age, sex, education level, social class, visual acuity, axial length, and history of cataract surgery. Data were available from 5563 participants with a mean age of 67 years. A thicker HRT-derived RNFL thickness was associated with better scores for the SF-MMSE (0.06; 95% confidence interval [CI], [0.02, 0.10], P = 0.005), HVLT (0.16, 95% CI [0.03, 0.29]; P = 0.014), and NART (-0.24, 95% CI [-0.46, -0.02], P = 0.035). The associations of RNFL thickness with SF-MMSE and HVLT remained significant following further adjustment for NART. We found a significant association between HRT-derived RNFL thickness and scores from cognitive tests assessing global function, recognition, learning, episodic memory, and premorbid intelligence. However, the associations were weak and not currently of predictive value. Further research is required to confirm and clarify the nature of these associations, and identify biological mechanisms.


Coherence between brain cortical function and neurocognitive performance during changed gravity conditions.
Previous studies of cognitive, mental and/or motor processes during short-, medium- and long-term weightlessness have only been descriptive in nature, and focused on psychological aspects. Until now, objective observation of neurophysiological parameters has not been carried out--undoubtedly because the technical and methodological means have not been available--, investigations into the neurophysiological effects of weightlessness are in their infancy (Schneider et al. 2008). While imaging techniques such as positron emission tomography (PET) and magnetic resonance imaging (MRI) would be hardly applicable in space, the non-invasive near-infrared spectroscopy (NIRS) technique represents a method of mapping hemodynamic processes in the brain in real time that is both relatively inexpensive and that can be employed even under extreme conditions. The combination with electroencephalography (EEG) opens up the possibility of following the electrocortical processes under changing gravity conditions with a finer temporal resolution as well as with deeper localization, for instance with electrotomography (LORETA). Previous studies showed an increase of beta frequency activity under normal gravity conditions and a decrease under weightlessness conditions during a parabolic flight (Schneider et al. 2008a+b). Tilt studies revealed different changes in brain function, which let suggest, that changes in parabolic flight might reflect emotional processes rather than hemodynamic changes. However, it is still unclear whether these are effects of changed gravity or hemodynamic changes within the brain. Combining EEG/LORETA and NIRS should for the first time make it possible to map the effect of weightlessness and reduced gravity on both hemodynamic and electrophysiological processes in the brain. Initially, this is to be done as part of a feasibility study during a parabolic flight. Afterwards, it is also planned to use both techniques during medium- and long-term space flight. It can be assumed that the long-term redistribution of the blood volume and the associated increase in the supply of oxygen to the brain will lead to changes in the central nervous system that are also responsible for anaemic processes, and which can in turn reduce performance (De Santo et al. 2005), which means that they could be crucial for the success and safety of a mission (Genik et al. 2005, Ellis 2000). Depending on these results, it will be necessary to develop and employ extensive countermeasures. Initial results for the MARS500 study suggest that, in addition to their significance in the context of the cardiovascular and locomotor systems, sport and physical activity can play a part in improving neurocognitive parameters. Before this can be fully established, however, it seems necessary to learn more about the influence of changing gravity conditions on neurophysiological processes and associated neurocognitive impairment.


Doctors who are using e-mail with their patients: a qualitative exploration.
Despite the potential for rapid, asynchronous, documentable communication, the use of e-mail for physician-patient communication has not been widely adopted. To survey physicians currently using e-mail with their patients daily to understand their experiences. In-depth phone interviews of 45 physicians currently using e-mail with patients were audio taped and transcribed verbatim. Two investigators independently qualitatively coded comments. Differences were adjudicated by group consensus. Almost all of the 642 comments from these physicians who currently use e-mail with patients daily could be grouped into 1 of 4 broad domains: (1) e-mail access and content, (2) effects of e-mail on the doctor-patient relationship, (3) managing clinical issues by e-mail, and (4) integrating e-mail into office processes. The most consistent theme was that e-mail communication enhances chronic-disease management. Many physicians also reported improved continuity of care and increased flexibility in responding to nonurgent issues. Integration of e-mail into daily workflow, such as utilization of office personnel, appears to be a significant area of concern for many of the physicians. For other issues, such as content, efficiency of e-mail, and confidentiality, there were diverging experiences and opinions. Physicians appear to be selective in choosing which patients they will communicate with via e-mail, but the criteria for selection is unclear. These physician respondents did perceive benefits to e-mail with a select group of patients. Several areas, such as identifying clinical situations where e-mail communication is effective, incorporating e-mail into office flow, and being reimbursed for online medical care/communication, need to be addressed before this mode of communication diffuses into most practices.


International survey of neuromuscular monitoring in two European countries: a questionnaire study among Hungarian and Romanian anaesthesiologists.
Accumulating evidence indicates that objective neuromuscular monitoring and pharmacological reversal of neuromuscular block reduces the occurrence of residual muscle paralysis in the acute postoperative phase. However, objective neuromuscular monitoring is not a routine habit in anaesthesia. In order to change this situation, we wished to find out, as a first step to improvement, the current use of neuromuscular monitors and the custom of anaesthetists for reversal of neuromuscular block before tracheal extubation. A ten-point questionnaire was available via the Surveymonkey website and the link was sent to 2202 Hungarian and Romanian anaesthetists by email. Three hundred and two (13.7%) of the 2202 registered anaesthetists responded. Less than 10% of them regularly use neuromuscular monitors. They underestimated the occurrence of residual block; only 2.2% gave a correct answer. Neuromuscular monitors are available in 74% of hospitals but are scarcely used. One third of anaesthetists rarely or never use reversal; approximately 20% regularly reverse before extubation. The responders typically believe that clinical signs of residual block are reliable. Instead of monitoring, they use the "timing methods" for tracheal extubation such as time elapsed from last dose, the duration of action of relaxant, the number of top-up doses, the cumulative dose, the return of adequate respiratory tidal volume and the ability to sustain a 5 s head lift. We concluded that neuromuscular monitoring in these two European countries is suboptimal as is the reversal strategy. Given the fact that monitors are available in the hospitals, the mentality should be changed towards evidence based practice.


Is it really useful the Harmonic scalpel in axillary dissection for locally advanced breast cancer? A case series.
The seroma is one of the most common complications in the axillary lymph nodal dissection (different surgical approaches have been tried to reduce the seroma incidence). In our study we evaluate the outcome of patients using or not the ultrasonic scalpel (Harmonic scalpel) according to a standardized surgical technique. From January 2011 to December 2015 120 patients underwent axillary dissection for breast cancer. Patients were divided in two groups: patients belonging to the first group underwent Harmonic scalpel dissection and patients belonging to the second group underwent classical dissection. Each group consisted of 60 patients. Quadrantectomy (QUAD) was performed in 54 patients, 66 women underwent mastectomy. In all patients axillary dissection included the I, II and III level. We compared two groups in terms of: time of surgery, hematoma, drainage volume, days of sealing drainage, seroma formation, number of post-seroma aspirations, upper limb lymphedema, wound infections, post-operative pain. Statistically significant results were obtained in terms of the total volume of the breast and axillary drainage in the two techniques. There were no significant differences in the two samples in terms of operative time incidence of seroma, post-operative hematoma, wound infection, and lymphedema of the upper limb. The small number of cases did not allow us to reach definitive conclusions. The use of Harmonic scalpel seems to show smaller incidence of seroma and reduction of the amount of both breast and axillary drainages. Further studies are needed to define the real advantage in terms of cost benefit of using these devices in the axillary surgery.


Tregs and rethinking cancer immunotherapy.
Tumors express antigens that should induce immune-mediated rejection, but spontaneous rejection of established tumors is rare. Recent work demonstrates that one reason for the lack of tumor rejection is that tumors actively defeat host immunity. This concept forces us to rethink current approaches to harnessing potent, specific host immunity to battle cancer, most of which are based on the paradigm that inducing more antitumor immune cells alone is therapeutic. However, as I discuss in this Personal Perspective, a newer paradigm predicts that reducing tumor-driven immune suppression will be clinically beneficial. CD4+CD25+ Tregs are one mechanism of tumor-driven immune evasion that provide prototypical targets for testing novel anticancer treatment strategies within the newer paradigm.


Leg skin temperature with body-weight-supported treadmill and tilt-table standing training after spinal cord injury.
Randomized crossover. Effects of body-weight-supported treadmill (BWST) and tilt-table standing (TTS) training on skin temperature and blood flow after spinal cord injury (SCI). McMaster University, Canada. Seven individuals with SCI participated in BWST and TTS training (3 times per week for 4 weeks, 4-week detraining between protocols). Skin temperature was measured before and after a single session of BWST or TTS, pre- and post-training. Leg blood flow was measured at rest pre- and post-training. Resting skin temperature decreased at four sites after 4 weeks of BWST training in comparison with the pre-training. Four weeks of TTS training resulted in resting skin temperature decreases post-training at the right thigh only. Both BWST and TTS training resulted in altered reactivity of skin temperature at all sites except the right calf in response to a single session of BWST and TTS. Post-BWST training, a single session of BWST stimulated increased temperature at all sites, whereas after TTS training a single session of TTS resulted in temperature decreases at two of the six sites. No changes were observed in resting blood flow with either BWST or TTS training. Increased resting skin temperature and decreased skin temperature reactivity have been linked to the development of pressure sores. BWST and TTS may stimulate different skin temperature responses and the impact on pressure sore development warrants further investigation.


Random-effects meta-analysis of the clinical utility of tests and prediction models.
The use of data from multiple studies or centers for the validation of a clinical test or a multivariable prediction model allows researchers to investigate the test's/model's performance in multiple settings and populations. Recently, meta-analytic techniques have been proposed to summarize discrimination and calibration across study populations. Here, we rather consider performance in terms of net benefit, which is a measure of clinical utility that weighs the benefits of true positive classifications against the harms of false positives. We posit that it is important to examine clinical utility across multiple settings of interest. This requires a suitable meta-analysis method, and we propose a Bayesian trivariate random-effects meta-analysis of sensitivity, specificity, and prevalence. Across a range of chosen harm-to-benefit ratios, this provides a summary measure of net benefit, a prediction interval, and an estimate of the probability that the test/model is clinically useful in a new setting. In addition, the prediction interval and probability of usefulness can be calculated conditional on the known prevalence in a new setting. The proposed methods are illustrated by 2 case studies: one on the meta-analysis of published studies on ear thermometry to diagnose fever in children and one on the validation of a multivariable clinical risk prediction model for the diagnosis of ovarian cancer in a multicenter dataset. Crucially, in both case studies the clinical utility of the test/model was heterogeneous across settings, limiting its usefulness in practice. This emphasizes that heterogeneity in clinical utility should be assessed before a test/model is routinely implemented.


Partial denervation affects both denervated and innervated fibers in the mammalian skeletal muscle.
Partial denervation of the rat extensor digitorum longus muscle was performed by sectioning only one of the sciatic nerve roots. Measurements of spike resistance to tetrodotoxin in individual muscle fibers revealed denervation changes not only in the denervated fibers but also in the adjacent innervated ones. The results support the concept that products of nerve degeneration play a role in the origin of muscle changes induced by denervation.


Reliability and agreement of intramuscular coherence in tibialis anterior muscle.
Neuroplasticity drives recovery of walking after a lesion of the descending tract. Intramuscular coherence analysis provides a way to quantify corticomotor drive during a functional task, like walking and changes in coherence serve as a marker for neuroplasticity. Although intramuscular coherence analysis is already applied and rapidly growing in interest, the reproducibility of variables derived from coherence is largely unknown. The purpose of this study was to determine the test-retest reliability and agreement of intramuscular coherence variables obtained during walking in healthy subjects. Ten healthy participants walked on a treadmill at a slow and normal speed in three sessions. Area of coherence and peak coherence were derived from the intramuscular coherence spectra calculated using rectified and non-rectified M. tibialis anterior Electromyography (EMG). Reliability, defined as the ability of a measurement to differentiate between subjects and established by the intra-class correlation coefficient, was on the limit of good for area of coherence and peak coherence when derived from rectified EMG during slow walking. Yet, the agreement, defined as the degree to which repeated measures are identical, was low as the measurement error was relatively large. The smallest change to exceed the measurement error between two repeated measures was 66% of the average value. For normal walking and/or other EMG-processing settings, not rectifying the EMG and/or high-pass filtering with a high cutoff frequency (100 Hz) the reliability was only moderate to poor and the agreement was considerably lower. Only for specific conditions and EMG-processing settings, the derived coherence variables can be considered to be reliable measures. However, large changes (>66%) are needed to indicate a real difference. So, although intramuscular coherence is an easy to use and a sufficiently reliable tool to quantify intervention-induced neuroplasticity, the large effects needed to reveal a real change limit its practical use.


Climate change impacts on marine biodiversity, fisheries and society in the Arabian Gulf.
Climate change-reflected in significant environmental changes such as warming, sea level rise, shifts in salinity, oxygen and other ocean conditions-is expected to impact marine organisms and associated fisheries. This study provides an assessment of the potential impacts on, and the vulnerability of, marine biodiversity and fisheries catches in the Arabian Gulf under climate change. To this end, using three separate niche modelling approaches under a 'business-as-usual' climate change scenario, we projected the future habitat suitability of the Arabian Gulf (also known as the Persian Gulf) for 55 expert-identified priority species, including charismatic and non-fish species. Second, we conducted a vulnerability assessment of national economies to climate change impacts on fisheries. The modelling outputs suggested a high rate of local extinction (up to 35% of initial species richness) by 2090 relative to 2010. Spatially, projected local extinctions are highest in the southwestern part of the Gulf, off the coast of Saudi Arabia, Qatar and the United Arab Emirates (UAE). While the projected patterns provided useful indicators of potential climate change impacts on the region's diversity, the magnitude of changes in habitat suitability are more uncertain. Fisheries-specific results suggested reduced future catch potential for several countries on the western side of the Gulf, with projections differing only slightly among models. Qatar and the UAE were particularly affected, with more than a 26% drop in future fish catch potential. Integrating changes in catch potential with socio-economic indicators suggested the fisheries of Bahrain and Iran may be most vulnerable to climate change. We discuss limitations of the indicators and the methods used, as well as the implications of our overall findings for conservation and fisheries management policies in the region.


Dissecting Fission Yeast Shelterin Interactions via MICro-MS Links Disruption of Shelterin Bridge to Tumorigenesis.
Shelterin, a six-member complex, protects telomeres from nucleolytic attack and regulates their elongation by telomerase. Here, we have developed a strategy, called MICro-MS (Mapping Interfaces via Crosslinking-Mass Spectrometry), that combines crosslinking-mass spectrometry and phylogenetic analysis to identify contact sites within the complex. This strategy allowed identification of separation-of-function mutants of fission yeast Ccq1, Poz1, and Pot1 that selectively disrupt their respective interactions with Tpz1. The various telomere dysregulation phenotypes observed in these mutants further emphasize the critical regulatory roles of Tpz1-centered shelterin interactions in telomere homeostasis. Furthermore, the conservation between fission yeast Tpz1-Pot1 and human TPP1-POT1 interactions led us to map a human melanoma-associated POT1 mutation (A532P) to the TPP1-POT1 interface. Diminished TPP1-POT1 interaction caused by hPOT1-A532P may enable unregulated telomere extension, which, in turn, helps cancer cells to achieve replicative immortality. Therefore, our study reveals a connection between shelterin connectivity and tumorigenicity.


Comparison of shoulder range of motion, strength, and playing time in uninjured high school baseball pitchers who reside in warm- and cold-weather climates.
There is an assumption that baseball athletes who reside in warm-weather climates experience larger magnitude adaptations in throwing shoulder motion and strength compared with their peers who reside in cold-weather climates. (1) The warm-weather climate (WWC) group would exhibit more pronounced shoulder motion and strength adaptations than the cold-weather climate (CWC) group, and (2) the WWC group would participate in pitching activities for a greater proportion of the year than the CWC group, with the time spent pitching predicting throwing shoulder motion and strength in both groups. Cross-sectional study; Level of evidence, 3. One hundred uninjured high school pitchers (50 each WWC, CWC) were recruited. Rotational shoulder motion and isometric strength were measured and participants reported the number of months per year they pitched. To identify differences between groups, t tests were performed; linear regression was used to determine the influence of pitching volume on shoulder motion and strength. The WWC group pitched more months per year than athletes from the CWC group, with the number of months spent pitching negatively related to internal rotation motion and external rotation strength. The WWC group exhibited greater shoulder range of motion in all planes compared with the CWC group, as well as significantly lower external rotation strength and external/internal rotation strength ratios. There was no difference in internal rotation strength between groups, nor a difference in the magnitude of side-to-side differences for strength or motion measures. Athletes who reside in cold- and warm-weather climates exhibit differences in throwing shoulder motion and strength, related in part to the number of months spent participating in pitching activities. The amount of time spent participating in pitching activities and the magnitude of range of motion and strength adaptations in athletes who reside in warm-weather climates may make these athletes more susceptible to throwing-related injuries.


Cost-of-Illness Trends Associated with Thyroid Disease in Korea.
The purpose of this study is to analyze the scale of and trends associated with the cost-of-illness of thyroid disease in Korea at 2-year intervals during the last 10 years for which data are available. Cost-of-illness was estimated in terms of direct and indirect costs. Direct costs include direct medical costs due to hospitalization, outpatient and pharmacy sectors, transportation, and care-giver costs. Indirect costs include future income loss due to premature death and loss of productivity as a result of absence from work. The cost-of-illness of thyroid disease in Korea was estimated at 224.2 billion won in 2002, 303.4 billion won in 2004, 400.3 billion won in 2006, 570.4 billion won in 2008, and 762.2 billion won in 2010. For example, the cost-of-illness of thyroid disease in 2010 was 3.4 times greater compared to 2002. The direct cost of the total cost-of-illness was 69.7%, which accounted for the highest proportion of costs. Cost-of-illness for individuals between the ages of 30 and 50 accounted for the greatest share of costs. The cost-of-illness of thyroid disease was relatively large in economically active age groups, and demonstrated a very rapid growth rate compared to other major diseases in Korea. Therefore, we suggest nationwide recognition of the importance of prevention and management of thyroid disease and prioritization of the management of thyroid disease among current and future health promotion policies in Korea.


Effects of River Hydrology and Physicochemistry on Anchovy Abundance and Cymothoid Isopod Parasitism.
The flow regime of a river is an important driver of many ecosystem components. However, few studies explore how differences in flow rates and water chemistry can influence communities of parasites and their hosts. Here, we investigate the impact of dissolved oxygen, pH, salinity, water temperature, and river flow on the abundance and prevalence of cymothoid isopod parasitism (Lironeca ovalis) of the Bay Anchovy (Anchoa mitchilli) in the Alafia and Hillsborough rivers of Tampa Bay (Florida). We also explore seasonality by comparing monthly samples preserved throughout 2005-2007. Although both the Alafia and Hillsborough rivers had similar average water temperatures and salinity, and similar wet and dry season cycles, the upstream damming of the Hillsborough River had numerous negative effects on water flow rate, dissolved oxygen content, and acidity. This disruption in water quality corresponded with a lower abundance of anchovy hosts, fewer free-swimming cymothoids, and low prevalence of anchovy parasitism. Anchovies were much more abundant in the Alafia River, but flow negatively affected abundance-a negative effect that could be mitigated by positive changes in water temperature, salinity, and pH. Flow rates also negatively affected free-swimming cymothoid abundance; however, water flow was less important in predicting their parasitism of anchovies. In Alafia, fewer anchovies were parasitized when dissolved oxygen was high and water acidity was low, but more were parasitized during the wet season. These findings corroborate predictions that flow can moderate habitat stability and complexity which, in turn, can impact opportunities for parasitism of host communities.


Lifetime indirect cost of childhood overweight and obesity: A decision analytic model.
To estimate the indirect lifetime cost of childhood overweight and obesity for Germany. The lifetime cohort model consisted of two parts: (a) Model I used data from the German Interview and Examination Survey for Children on prevalence of BMI categories during childhood to evaluate BMI trajectories before the age of 18; and (b) Model II estimated lifetime excess indirect cost based on the history of childhood BMI. Indirect costs were defined as the opportunity cost of lost productivity due to mortality and morbidity and were identified through a systematic literature review. Our analysis showed that the majority of children with overweight and obesity remained in the same BMI category during their adult life, resulting in significant indirect lifetime costs. We estimated that overweight and obesity during childhood resulted in an excess lifetime cost per person of €4,209 (men) and €2,445 (women). For the current prevalent German population, the excess lifetime cost was €145 billion. Our study showed that childhood obesity results in significant economic burden on the society. Therefore, cost-effective strategies targeted at reducing the prevalence of obesity during the early years of life can significantly reduce both healthcare and nonhealthcare costs over the lifetime.


Differential recognition and scavenging of native and truncated macrophage-derived chemokine (macrophage-derived chemokine/CC chemokine ligand 22) by the D6 decoy receptor.
The promiscuous D6 receptor binds several inflammatory CC chemokines and has been recently proposed to act as a chemokine-scavenging decoy receptor. The present study was designed to better characterize the spectrum of CC chemokines scavenged by D6, focusing in particular on CCR4 ligands and analyzing the influence of NH(2)-terminal processing on recognition by this promiscuous receptor. Using D6 transfectants, it was found that D6 efficiently bound and scavenged most inflammatory CC chemokines (CCR1 through CCR5 agonists). Homeostatic CC chemokines (CCR6 and CCR7 agonists) were not recognized by D6. The CCR4 agonists CC chemokine ligand 17 (CCL17) and CCL22 bound to D6 with high affinity. CCL17 and CCL22 have no agonistic activity for D6 (chemotaxis and calcium fluxes), but were rapidly scavenged, resulting in reduced chemotactic activity on CCR4 transfectants. CD26 mediates NH(2) terminus processing of CCL22, leading to the production of CCL22 (3-69) and CCL22 (5-69) that do not interact with CCR4. These NH(2)-terminal truncated forms of CCL22 were not recognized by D6. The results presented in this study show that D6 recognizes and scavenges a wide spectrum of inflammatory CC chemokines, including the CCR4 agonists CCL22 and CCL17. However, this promiscuous receptor is not engaged by CD26-processed, inactive, CCL22 variants. By recognizing intact CCL22, but not its truncated variants, D6 expressed on lymphatic endothelial cells may regulate the traffic of CCR4-expressing cells, such as dendritic cells.


Application of a novel score test for genetic association incorporating gene-gene interaction suggests functionality for prostate cancer susceptibility regions.
We introduce an innovative multilocus test for disease association. It is an extension of an existing score test that gains power over alternative methods by incorporating a parsimonious one-degree-of-freedom model for interaction. We use our method in applications designed to detect interactions that generate hypotheses about the functionality of prostate cancer (PRCA) susceptibility regions. Our proposed score test is designed to gain additional power through the use of a retrospective likelihood that exploits an assumption of independence between unlinked loci in the underlying population. Its performance is validated through simulation. The method is used in conditional scans with data from stage II of the Cancer Genetic Markers of Susceptibility PRCA genome-wide association study. Our proposed method increases power to detect susceptibility loci in diverse settings. It identified two high-ranking, biologically interesting interactions: (1) rs748120 of NR2C2 and subregions of 8q24 that contain independent susceptibility loci specific to PRCA and (2) rs4810671 of SULF2 and both JAZF1 and HNF1B that are associated with PRCA and type 2 diabetes. Our score test is a promising multilocus tool for genetic epidemiology. The results of our applications suggest functionality for poorly understood PRCA susceptibility regions. They motivate replication study.


Sox6 up-regulation by macrophage migration inhibitory factor promotes survival and maintenance of mouse neural stem/progenitor cells.
Macrophage migration inhibitory factor (MIF) has important roles in supporting the proliferation and/or survival of murine neural stem/progenitor cells (NSPCs), but downstream effectors remain unknown. We show here that MIF robustly increases the expression of Sox6 in NSPCs in vitro. During neural development, Sox6 is expressed in the ventricular zone of the ganglionic eminence (GE) of mouse brains at embryonic day 14.5 (E14.5), cultured NSPCs from E14.5 GE, and NSPCs in the subventricular zone (SVZ) around the lateral ventricle (LV) of the adult mouse forebrain. Retroviral overexpression of Sox6 in NSPCs increases the number of primary and secondary neurospheres and inhibits cell differentiation. This effect is accompanied with increased expression of Hes1 and Bcl-2 and Akt phosphorylation, thus suggesting a role for Sox6 in promoting cell survival and/or self-renewal ability. Constitutive activation of the transcription factor Stat3 results in up-regulation of Sox6 expression and chromatin immunoprecipitation analysis showed that MIF increases Stat3 binding to the Sox6 promoter in NSPCs, indicating that Stat3 stimulates Sox6 expression downstream of MIF. Finally, the ability of MIF to increase the number of primary and secondary neurospheres is inhibited by Sox6 gene silencing. Collectively, our data identify Sox6 as an important downstream effector of MIF signaling in stemness maintenance of NSPCs.


Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury.
Retrospective, longitudinal analysis of motor recovery data from individuals with cervical (C4-C7) sensorimotor complete spinal cord injury (SCI) according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). To analyze the extent and patterns of spontaneous motor recovery over the first year after traumatic cervical sensorimotor complete SCI. Datasets from the European multicenter study about SCI (EMSCI) and the Sygen randomized clinical trial were examined for conversion of American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, change in upper extremity motor score (UEMS) or motor level, as well as relationships between these measures. There were no overall differences between the EMSCI and Sygen datasets in motor recovery patterns. After 1 year, up to 70% of subjects spontaneously recovered at least one motor level, but only 30% recovered two or more motor levels, with lesser values at intermediate time points. AIS grade conversion did not significantly influence motor level changes. At 1 year, the average spontaneous improvement in bilateral UEMS was 10-11 motor points. There was only moderate relationship between a change in UEMS and a change in cervical motor level (r(2)=0.30, P<0.05). Regardless of initial cervical motor level, most individuals recover a similar number of motor points or motor levels. Careful tracking of cervical motor recovery outcomes may provide the necessary sensitivity and accuracy to reliably detect a subtle, but meaningful treatment effect after sensorimotor complete cervical SCI. The distribution of the UEMS change may be more important functionally than the total UEMS recovered.


Prognostic factors for recurrences in neck pain patients up to 1 year after chiropractic care.
Information about recurrence and prognostic factors is important for patients and practitioners to set realistic expectations about the chances of full recovery and to reduce patient anxiety and uncertainty. Therefore, the purpose of this study was to assess recurrence and prognostic factors for neck pain in a chiropractic patient population at 1 year from the start of the current episode. Within a prospective cohort study, 642 neck pain patients were recruited by chiropractors in Switzerland. After a course of chiropractic therapy, patients were followed up for 1 year regarding recurrence of neck pain. A logistic regression analysis was used to assess prognostic factors for recurrent neck pain. The independent variables age, pain medication usage, sex, work status, duration of complaint, previous episodes of neck pain and trauma onset, numerical rating scale, and Bournemouth questionnaire for neck pain were analyzed. Prognostic factors that have been identified in previous studies to influence recovery of neck pain are psychologic distress, poor general health at baseline, and a previous history of pain elsewhere. Five hundred forty five patients (341 females), with a mean age of 42.1 years (SD, 13.1) completed the 1-year follow-up period. Fifty-four participants (11%) were identified as "recurrent." Prognostic factors associated with recurrent neck pain were previous episodes of neck pain and increasing age. The results of this study suggest that recurrence of neck pain within 1 year after chiropractic intervention in Swiss chiropractic patients presenting from varied onsets is low. This study found preliminary findings that older age and a previous episode of neck may be useful predictors of neck pain recurrence within 1 year.


Platelet rich therapies for long bone healing in adults.
The morbidity and socioeconomic costs associated with long bone healing are considerable. Platelet-rich therapies are autologous blood products with a greater concentration of platelets than physiological whole blood. Despite promising results from a number of in-vitro animal studies, clinical evidence to support the use of platelet-rich therapy in long bone healing is unclear. To assess the effects (benefits or harms) of platelet-rich therapies for treating long bone osteotomies, acute fractures, un-united fractures and defects in adults. We searched the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register (8 November 2011), the Cochrane Central Register of Controlled Trials (The Cochrane Library, 2011 Issue 4), MEDLINE (1948 to November Week 1 2011) and EMBASE (1980 to Week 44 2011). Trial registers and reference lists of articles were also searched. Randomised and quasi-randomised controlled clinical trials evaluating any type of platelet-rich therapy compared with either no additional treatment or a placebo in the management of long bone osteotomies, acute fractures, un-united fractures and defects in adults. Studies including participants over 18 years of age; reporting functional outcomes, time to union, non-union, secondary procedures such as for fixation failure or delayed or non-union, adverse effects, pain or costs were included. Two authors independently selected the studies for inclusion in the review. Studies were assessed for the risk of bias using The Cochrane Collaboration's 'Risk of bias' tool. Treatment effects for dichotomous outcomes were expressed with risk ratios (RR) and continuous measures with mean differences, together with 95% confidence intervals (CI). Only one eligible study, involving 21 participants, was included. The study compared platelet-rich therapy and allogenic bone graft with allogenic bone graft alone in patients undergoing corrective osteotomy for medial compartment osteoarthrosis of the knee. The risk of bias associated with this study was substantial. There was no significant difference in patient-reported or clinician-assessed functional outcome scores between groups at one year. There was a statistically significant benefit from platelet-rich therapy in the proportion of bones that were united at one year (8/9 versus 3/9; RR 2.67; 95% CI 1.03 to 6.91). This benefit, however, was not maintained when assuming poor outcomes for participants who were lost to follow-up (8/11 versus 3/10; RR 2.42; 95% CI 0.88 to 6.68). One adverse event was reported in a participant receiving platelet-rich therapy.One other eligible study involving hip fracture patients is currently underway. While a potential benefit of platelet-rich therapies to augment long bone healing in adults cannot be ruled out, the currently available evidence from a single trial is insufficient to support the routine use of this intervention in clinical practice. Future trials should focus on reporting patient-reported functional outcomes from all trial participants for a minimum follow-up of one year.


Renal function following three distinct weight loss dietary strategies during 2 years of a randomized controlled trial.
This study addressed the long-term effect of various diets, particularly low-carbohydrate high-protein, on renal function on participants with or without type 2 diabetes. In the 2-year Dietary Intervention Randomized Controlled Trial (DIRECT), 318 participants (age, 51 years; 86% men; BMI, 31 kg/m(2); mean estimated glomerular filtration rate [eGFR], 70.5 mL/min/1.73 m(2); mean urine microalbumin-to-creatinine ratio, 12:12) with serum creatinine <176 μmol/L (eGFR ≥ 30 mL/min/1.73 m(2)) were randomized to low-fat, Mediterranean, or low-carbohydrate diets. The 2-year compliance was 85%, and the proportion of protein intake significantly increased to 22% of energy only in the low-carbohydrate diet (P < 0.05 vs. low-fat and Mediterranean). We examined changes in urinary microalbumin and eGFR, estimated by Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formulas. Significant (P < 0.05 within groups) improvements in eGFR were achieved in low-carbohydrate (+5.3% [95% CI 2.1-8.5]), Mediterranean (+5.2% [3.0-7.4]), and low-fat diets (+4.0% [0.9-7.1]) with similar magnitude (P > 0.05) across diet groups. The increased eGFR was at least as prominent in participants with (+6.7%) or without (+4.5%) type 2 diabetes or those with lower baseline renal function of eGFR <60 mL/min/1.73 m(2) (+7.1%) versus eGFR ≥ 60 mL/min/1.73 m(2) (+3.7%). In a multivariable model adjusted for age, sex, diet group, type 2 diabetes, use of ACE inhibitors, 2-year weight loss, and change in protein intake (confounders and univariate predictors), only a decrease in fasting insulin (β = -0.211; P = 0.004) and systolic blood pressure (β = -0.25; P < 0.001) were independently associated with increased eGFR. The urine microalbumin-to-creatinine ratio improved similarly across the diets, particularly among participants with baseline sex-adjusted microalbuminuria, with a mean change of -24.8 (P < 0.05). A low-carbohydrate diet is as safe as Mediterranean or low-fat diets in preserving/improving renal function among moderately obese participants with or without type 2 diabetes, with baseline serum creatinine <176 μmol/L. Potential improvement is likely to be mediated by weight loss-induced improvements in insulin sensitivity and blood pressure.


Determination of bone mineral content in cadaveric test specimens.
This study was designed to determine the best method for presenting the bone mineral content of cadaveric test specimens. A total of 59 bone samples were taken from the humeri, radii, and ulnae of 14 female cadavers. For each sample, the bone mineral content was determined with a dual-energy x-ray absorptiometry scanner, and the ash-weight ratio was calculated manually. A linear regression analysis was performed to compare the ash-weight ratio to the 3 methods for reporting bone mineral content as measured by a dual-energy x-ray absorptiometry scanner: by bone mineral content divided by sample length (in g/cm), by projected area (in g/cm2), or by sample volume (in g/cm3). The analysis revealed that the ash-weight ratio correlates best with the volumetric representation. Based on these data, a volumetric representation is suggested as the best representation of bone mineralization, due to its correlation with ash-weight ratio.


Paediatric talus fracture.
Paediatric talus fractures are rare injuries resulting from axial loading of the talus against the anterior tibia with the foot in dorsiflexion. Skeletally immature bone is less brittle, with higher elastic resistance than adult bone, thus the paediatric talus can sustain higher forces before fractures occur. However, displaced paediatric talus fractures and those associated with high-energy trauma have been associated with complications including avascular necrosis, arthrosis, delayed union, neurapraxia and the need for revision surgery. The authors present the rare case of a talar neck fracture in a skeletally immature young girl, initially missed on radiological review. However, clinical suspicion on the part of the emergency physician, repeat examination and further radiographic imaging revealed this rare paediatric injury.


Arterial stiffness and hypertension in a large population of untreated individuals: the Rotterdam Study.
We studied whether arterial stiffness measured as aortic pulse wave velocity (aPWV) and carotid distensibility was associated with different subtypes of hypertension in a large population of untreated middle-aged and elderly men and women. The study was conducted within the framework of the population-based Rotterdam Study. We included 4088 individuals with information on aPWV, with 3554 individuals with carotid distensibility measurements without use of antihypertensive medication. Isolated systolic hypertension (ISH) was defined as SBP at least 140 mmHg and DBP less than 90 mmHg. Combined systolic and diastolic hypertension (Sys/Dia hypertension) was defined as SBP at least 140 mmHg and DBP at least 90 mmHg. Analysis of covariance was used to compare means of arterial stiffness for the different subtypes of hypertension. Multinomial logistic regression analysis was performed to investigate the association of arterial stiffness and the subtypes of hypertension in models adjusted for age, sex, mean arterial pressure, heart rate and cardiovascular risk factors. The mean age of the individuals was 68 years: 45.3% were men, 1597 individuals had ISH and 441 individuals had Sys/Dia hypertension. aPWV was higher (13.2 vs. 12.9 m/s; P = 0.008) in individuals with ISH compared to those with Sys/Dia hypertension. Multivariate odds ratios and corresponding 95% confidence interval of aPWV for ISH were 1.53 (1.38-1.71) and 1.28 (1.09-1.53) for Sys/Dia hypertension. Corresponding odds ratios associated with carotid distensibility were 0.84 (0.75-0.94) and 0.66 (0.54-0.81), respectively. Age significantly modified the association of aPWV with subtypes of hypertension (P < 0.001). In a large untreated population, we found significant associations of both aPWV and carotid distensibility with ISH and Sys/Dia hypertension. individuals with ISH had higher values of aortic stiffness when compared to individuals with Sys/Dia hypertension, a difference that was most pronounced at older age. The results suggest that aortic stiffness contributes to ISH in older individuals without treatment for hypertension.


Thickness determination of a water film on dye-doped ice by fluorescence spectroscopy.
A new method for measuring the thickness of a micrometer-thin water film on ice is presented. The method is based on confocal detection of fluorescence light, emitted by a special coumarin dye dissolved in ice as well as in water. The spectral position of the fluorescence maximum depends strongly on the matrix surrounding the dye molecules. Thus the analysis of the spectra obtained while the focal position perpendicular to the liquid-ice interface is scanned provides the possibility of measuring the thickness of the water film with the vertical resolution of the confocal system. We demonstrate this principle by a model system.


Evaporation of Lennard-Jones fluids.
Evaporation and condensation at a liquid/vapor interface are ubiquitous interphase mass and energy transfer phenomena that are still not well understood. We have carried out large scale molecular dynamics simulations of Lennard-Jones (LJ) fluids composed of monomers, dimers, or trimers to investigate these processes with molecular detail. For LJ monomers in contact with a vacuum, the evaporation rate is found to be very high with significant evaporative cooling and an accompanying density gradient in the liquid domain near the liquid/vapor interface. Increasing the chain length to just dimers significantly reduces the evaporation rate. We confirm that mechanical equilibrium plays a key role in determining the evaporation rate and the density and temperature profiles across the liquid/vapor interface. The velocity distributions of evaporated molecules and the evaporation and condensation coefficients are measured and compared to the predictions of an existing model based on kinetic theory of gases. Our results indicate that for both monatomic and polyatomic molecules, the evaporation and condensation coefficients are equal when systems are not far from equilibrium and smaller than one, and decrease with increasing temperature. For the same reduced temperature T/T(c), where T(c) is the critical temperature, these two coefficients are higher for LJ dimers and trimers than for monomers, in contrast to the traditional viewpoint that they are close to unity for monatomic molecules and decrease for polyatomic molecules. Furthermore, data for the two coefficients collapse onto a master curve when plotted against a translational length ratio between the liquid and vapor phase.


Pharyngeal pituitary non-functioning adenoma with normal intra-sellar gland: massive tumor shrinkage on octreotide therapy.
Functioning or non-functioning ectopic tumors may develop from pharyngeal pituitary remnants. They constitute <1% of all obstructive pharyngeal masses and they have a strong tendency to bleed. We report a case of a non-functioning ectopic pituitary adenoma of the rhino-pharynx studied over a long-term somatostatin analog treatment. PATIENT AND TREATMENT: A 60-Year-old woman presented with severe posterior epistaxis. She had complained of nasal obstruction for the past 2 Years. Magnetic resonance imaging (MRI) and endoscopic examination revealed a 2 cm exophytic, bleeding mass in the cavum, which was judged inoperable, and a biopsy was performed. On immunostaining, tumor cells were positive for pancytokeratins MNF 116 and C11, epithelial membrane antigen, chromogranin and neuron-specific enolase (NSE), and negative for synaptophysin, desmin, actin, estrogen and progesterone receptors, all anterior pituitary hormones and human chorionic gonadotropin. Blood levels of the above hormones and tumor markers were normal, except for a moderate elevation of NSE (33.8 microg/l, normal value <12 microg/l). It was concluded that this was a non-functioning pituitary adenoma of the rhino-pharynx. MRI showed a normal intra-sellar pituitary gland, including the normal bright signal of the posterior lobe. Somatostatin receptor scintigraphy (SRS) disclosed intense tracer uptake in the tumor, indicating high somatostatin receptor content. There was also an intense uptake in the intra-sellar pituitary. Therapy with long-acting octreotide was started, 20 mg per Month i.m. The patient has been on octreotide for the last 12 Months. Nasal obstruction rapidly subsided and bleeding did not recur. Repeated endoscopic examinations showed rapid tumor reduction, the mass shrinkage being almost complete at 3 Months. This was confirmed by MRI, while SRS showed markedly decreased uptake in the residual tumor and the intra-sellar pituitary, and NSE became normal. Pharyngeal pituitary remnant adenomas are rare, but they must be considered in the differential diagnosis of bleeding or obstructive masses of the rhino-pharynx. In this case, the positive SRS influenced the choice of octreotide, as an alternative to surgery. As we show for the first time in this location, octreotide can exert prolonged and marked anti-tumoral effects in non-functioning adenoma.


Human pancreatic acinar cells lack functional responses to cholecystokinin and gastrin.
Pancreatic acinar cells from various species express cholecystokinin (CCK) A, CCK-B, or a combination of these CCK receptor subtypes. The presence and functional roles of CCK receptors on human acinar cells remain unclear. Acini isolated from human pancreas were treated with CCK receptor agonists, CCK-8 and gastrin, and an agonist for m3 muscarinic acetylcholine receptors (m3 AchR), carbachol. Functional parameters measured included intracellular [Ca(2+)], amylase secretion, and ERK phosphorylation. Binding studies were performed using (125)I-CCK-8. Expression of messenger RNAs (mRNAs) was determined using real-time quantitative reverse-transcription polymerase chain reaction (RT-PCR) and localized by in situ hybridization. Human acini did not respond to CCK agonists. In contrast, they responded to carbachol with robust increases in each of the functional parameters. Moreover, the cells responded to CCK agonists after adenoviral-mediated gene transfer of CCK-A or CCK-B receptors. A low level of specific and a high level of nonspecific binding of (125)I-CCK-8 were observed. Quantitative RT-PCR indicated that the message levels for CCK-A receptors were approximately 30-fold lower than those of CCK-B receptors, which were approximately 10-fold lower than those of m3 Ach receptors. In situ hybridization indicated the presence of m3 Ach receptor and insulin mRNA but not CCK-A or CCK-B receptor mRNAs in adult human pancreas. These data indicate that human pancreatic acinar cells do not respond to CCK receptor agonists in terms of expected functional parameters and show that this is due to an insufficient level of receptor expression.


The Development of a Machine Learning Inpatient Acute Kidney Injury Prediction Model.
To develop an acute kidney injury risk prediction model using electronic health record data for longitudinal use in hospitalized patients. Observational cohort study. Tertiary, urban, academic medical center from November 2008 to January 2016. All adult inpatients without pre-existing renal failure at admission, defined as first serum creatinine greater than or equal to 3.0 mg/dL, International Classification of Diseases, 9th Edition, code for chronic kidney disease stage 4 or higher or having received renal replacement therapy within 48 hours of first serum creatinine measurement. None. Demographics, vital signs, diagnostics, and interventions were used in a Gradient Boosting Machine algorithm to predict serum creatinine-based Kidney Disease Improving Global Outcomes stage 2 acute kidney injury, with 60% of the data used for derivation and 40% for validation. Area under the receiver operator characteristic curve (AUC) was calculated in the validation cohort, and subgroup analyses were conducted across admission serum creatinine, acute kidney injury severity, and hospital location. Among the 121,158 included patients, 17,482 (14.4%) developed any Kidney Disease Improving Global Outcomes acute kidney injury, with 4,251 (3.5%) developing stage 2. The AUC (95% CI) was 0.90 (0.90-0.90) for predicting stage 2 acute kidney injury within 24 hours and 0.87 (0.87-0.87) within 48 hours. The AUC was 0.96 (0.96-0.96) for receipt of renal replacement therapy (n = 821) in the next 48 hours. Accuracy was similar across hospital settings (ICU, wards, and emergency department) and admitting serum creatinine groupings. At a probability threshold of greater than or equal to 0.022, the algorithm had a sensitivity of 84% and a specificity of 85% for stage 2 acute kidney injury and predicted the development of stage 2 a median of 41 hours (interquartile range, 12-141 hr) prior to the development of stage 2 acute kidney injury. Readily available electronic health record data can be used to predict impending acute kidney injury prior to changes in serum creatinine with excellent accuracy across different patient locations and admission serum creatinine. Real-time use of this model would allow early interventions for those at high risk of acute kidney injury.


Signaling-Biased and Constitutively Active Dopamine D2 Receptor Variant.
A dopamine D2 receptor mutation was recently identified in a family with a novel hyperkinetic movement disorder. Compared to the wild type D2 receptor, the novel allelic variant D2-I212F activates a Gαi1β1γ2 heterotrimer with higher potency and modestly enhanced basal activity in human embryonic kidney (HEK) 293 cells and has decreased capacity to recruit arrestin3. We now report that omitting overexpressed G protein-coupled receptor kinase-2 (GRK2) decreased the potency and efficacy of quinpirole for arrestin recruitment. The relative efficacy of quinpirole for arrestin recruitment to D2-I212F compared to D2-WT was considerably lower without overexpressed GRK2 than with added GRK2. D2-I212F exhibited higher basal activation of GαoA than Gαi1 but little or no increase in the potency of quinpirole relative to D2-WT. Other signs of D2-I212F constitutive activity for G protein-mediated signaling, in addition to basal activation of Gαi/o, were enhanced basal inhibition of forskolin-stimulated cyclic AMP accumulation that was reversed by the inverse agonists sulpiride and spiperone and a ∼4-fold increase in the apparent affinity of D2-I212F for quinpirole, determined from competition binding assays. In mouse midbrain slices, inhibition of tonic current by the inverse agonist sulpiride in dopamine neurons expressing D2-I212F was consistent with our hypothesis of enhanced constitutive activity and sensitivity to dopamine relative to D2-WT. Molecular dynamics simulations with D2 receptor models suggested that an ionic lock between the cytoplasmic ends of the third and sixth α-helices that constrains many G protein-coupled receptors in an inactive conformation spontaneously breaks in D2-I212F. Overall, these results confirm that D2-I212F is a constitutively active and signaling-biased D2 receptor mutant and also suggest that the effect of the likely pathogenic variant in a given brain region will depend on the nature of G protein and GRK expression.


Psoralen-ultraviolet A vs. narrow-band ultraviolet B phototherapy for the treatment of vitiligo.
Although many treatment modalities have been tried for the treatment of vitiligo, none is uniformly effective. Psoralen phototherapy (psoralen ultraviolet A (PUVA)) is established as efficacious treatment for vitiligo. Recently, narrow-band UVB (NBUVB) has been reported to be an effective and safe therapeutic option in patients with vitiligo. To compare the efficacy of PUVA and NBUVB in the treatment of vitiligo. Retrospective analysis of 69 patients with vitiligo who were treated either with PUVA or NBUVB at the pigmentary clinic of the Dermatology Department of the Postgraduate Institute of Medical Education and Research, Chandigarh, India. The following variables were compared between the two groups of patients: repigmentation status, number of treatments for marked to complete repigmentation in existing lesions, appearance of new lesions or increase in size of existing lesions, adverse effect of therapy, stability of repigmentation and colour match. In PUVA-treated group, 9 patients showed marked to complete repigmentation (23.6%) and 14 patients showed moderate improvement (36.8%), whereas in NBUVB-treated group, 13 patients showed marked to complete repigmentation (41.9%) and 10 patients showed moderate improvement (32.2%). A statistically significantly better stability and colour match of repigmentation with surrounding skin was seen in NBUVB-treated patients. We showed that NBUVB is more effective than PUVA and repigmentation induced with NBUVB is statistically significantly more stable.


GIP-overexpressing mice demonstrate reduced diet-induced obesity and steatosis, and improved glucose homeostasis.
Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that potentiates glucose-stimulated insulin secretion during a meal. Since GIP has also been shown to exert β-cell prosurvival and adipocyte lipogenic effects in rodents, both GIP receptor agonists and antagonists have been considered as potential therapeutics in type 2 diabetes (T2DM). In the present study, we tested the hypothesis that chronically elevating GIP levels in a transgenic (Tg) mouse model would increase adipose tissue expansion and exert beneficial effects on glucose homeostasis. In contrast, although GIP Tg mice demonstrated enhanced β-cell function, resulting in improved glucose tolerance and insulin sensitivity, they exhibited reduced diet-induced obesity. Adipose tissue macrophage infiltration and hepatic steatosis were both greatly reduced, and a number of genes involved in lipid metabolism/inflammatory signaling pathways were found to be down-regulated. Reduced adiposity in GIP Tg mice was associated with decreased energy intake, involving overexpression of hypothalamic GIP. Together, these studies suggest that, in the context of over-nutrition, transgenic GIP overexpression has the potential to improve hepatic and adipocyte function as well as glucose homeostasis.


Survival and Energy Producing Strategies of Alkane Degraders Under Extreme Conditions and Their Biotechnological Potential.
Many petroleum-polluted areas are considered as extreme environments because of co-occurrence of low and high temperatures, high salt, and acidic and anaerobic conditions. Alkanes, which are major constituents of crude oils, can be degraded under extreme conditions, both aerobically and anaerobically by bacteria and archaea of different phyla. Alkane degraders possess exclusive metabolic pathways and survival strategies, which involve the use of protein and RNA chaperones, compatible solutes, biosurfactants, and exopolysaccharide production for self-protection during harsh environmental conditions such as oxidative and osmotic stress, and ionic nutrient-shortage. Recent findings suggest that the thermophilic sulfate-reducing archaeon Archaeoglobus fulgidus uses a novel alkylsuccinate synthase for long-chain alkane degradation, and the thermophilic Candidatus Syntrophoarchaeum butanivorans anaerobically oxidizes butane via alkyl-coenzyme M formation. In addition, gene expression data suggest that extremophiles produce energy via the glyoxylate shunt and the Pta-AckA pathway when grown on a diverse range of alkanes under stress conditions. Alkane degraders possess biotechnological potential for bioremediation because of their unusual characteristics. This review will provide genomic and molecular insights on alkane degraders under extreme conditions.


Joint wavelet transform correlation with separated target and reference planes.
In recent years, we realize the usefulness of feature extraction for optical correlator and hereby, we investigate the capability of Laplace operator in feature extraction of multiple targets. The first-order terms and the false alarm terms in the correlation output would be removed using electronic power spectrum subtraction technique. Most importantly, the entire magneto-optic SLM is completely utilized for displaying only targets in the input scene. A new cost efficient hardware implementation is proposed and aforementioned result of the proposed system is evaluated through computer simulation.