Hepatic fibrosis in patients with chronic hepatitis C assessed by transient elastography: implications for determining the efficacy of antiviral therapy.
The efficacy of combination therapy with peginterferon plus ribavirin to eradicate viral infection in patients with chronic hepatitis C (CHC) is well established; moreover, it is able to arrest or even reverse liver fibrosis. To analyze the measurements of hepatic stiffness as an index of liver fibrosis using transient elastography (TE) in patients who underwent a sustained virological response (SVR) during long-term follow-up; comparing the changes in the severity of fibrosis with non-responders patients. After hepatic fibrosis was studied in three patients with CHC who underwent a SVR during long-term follow up, a prospective study was initiated in 24 patients with CHC who received combination therapy to compare the evolution of fibrosis in those with SVR and those who were non-responders. The genotype of hepatitis C virus (HCV) and the degree of viremia were determined. METAVIR scoring system was used for liver fibrosis. Hepatic stiffness was measured by TE. Of the initial three patients pre-treatment liver biopsies revealed active disease and fibrosis (stage 3) in two and mild fibrosis (stage 1) in one. After several years of follow up serum AST/ALT levels were normal and HCV RNA was undetectable in each case; in contrast to the baseline histological assessments of fibrosis, values for hepatic stiffness (3.4-6.9 KPa) were compatible with an absence of any appreciable hepatic fibrosis. In the prospective study, 8 patients underwent a SVR and 16 were non-responders. TE indicated that the severity of hepatic fibrosis in the SVR group improved in 7 (88%) patients, whereas in the non-responder it improved in only 4 (25%) (p < 0.05). The difference between development of severe fibrosis (F > or = 3) in responders and non-responders was not significant (p = 0.23), possibly due to the small sample size. Regression of hepatic fibrosis appears to be common in patients with CHC who undergo a SVR. TE is a simple non-invasive technique that enables multiple assessments of the severity of hepatic fibrosis to be made efficiently during long-term follow-up of patients with CHC who receive combination antiviral therapy.


Streptococcus agalactiae in adults at Chiang Mai University Hospital: a retrospective study.
Infection caused by Streptococcus agalactiae, a Group B streptococcus, is an emerging disease in non-pregnant adults. This study describes the epidemiological, clinical, and microbiological characteristics of S. agalactiae infection in adult patients in northern Thailand. A retrospective study was conducted between January 1, 2006 and December 31, 2009 at Chiang Mai University Hospital among patients aged ≥15 years, whose clinical specimens obtained from normally sterile sites grew S. agalactiae. One-hundred and eighty-six patients and 197 specimens were identified during the 4-year period. Among 186 patients, 82 were documented as having invasive infection; 42 patients were male (51.2%) with the mean age of 48.5 ± 19.4 years (range 17, 83). Fifty-three patients (64.6%) had underlying medical conditions; 17 patients (20.7%), 10 (12.2%), 8 (9.7%) had diabetes, chronic renal diseases, and malignancy, respectively. Among 40 patients (48.8%) with bloodstream infection, no other site of infection was determined in 29 (35.4%) patients. In the remaining 11 patients, 5 patients (6.1%), 5 (6.1%), and 1 (1.2%) had meningitis, arthritis, and meningitis with arthritis, respectively. Forty-two patients (51.2%) presented with localized infection, i.e., subcutaneous abscess (19 patients, 23.2%), chorioamnionitis (10 patients, 12.2%), urinary tract infection (5 patients, 6.1%), arthritis (3 patients, 3.7%), meningitis (2 patients, 2.4%), and spontaneous bacterial peritonitis, uveitis, and tracheobronchitis (1 patient each, 1.2%). The overall mortality was 14.6% (12 patients). S. agalactiae infection is a growing problem in non-pregnant patients, particularly in those with underlying medical conditions. Physicians should add S. agalactiae infection in the list of differential diagnoses in patients with meningitis and/or septicemia.


Dynamic modeling of temperature change in outdoor operated tubular photobioreactors.
In this study, a one-dimensional transient model was developed to analyze the temperature variation of tubular photobioreactors operated outdoors and the validity of the model was tested by comparing the predictions of the model with the experimental data. The model included the effects of convection and radiative heat exchange on the reactor temperature throughout the day. The temperatures in the reactors increased with increasing solar radiation and air temperatures, and the predicted reactor temperatures corresponded well to the measured experimental values. The heat transferred to the reactor was mainly through radiation: the radiative heat absorbed by the reactor medium, ground radiation, air radiation, and solar (direct and diffuse) radiation, while heat loss was mainly through the heat transfer to the cooling water and forced convection. The amount of heat transferred by reflected radiation and metabolic activities of the bacteria and pump work was negligible. Counter-current cooling was more effective in controlling reactor temperature than co-current cooling. The model developed identifies major heat transfer mechanisms in outdoor operated tubular photobioreactors, and accurately predicts temperature changes in these systems. This is useful in determining cooling duty under transient conditions and scaling up photobioreactors. The photobioreactor design and the thermal modeling were carried out and experimental results obtained for the case study of photofermentative hydrogen production by Rhodobacter capsulatus, but the approach is applicable to photobiological systems that are to be operated under outdoor conditions with significant cooling demands.


The localization of phytate in tofu curd formation and effects of phytate on tofu texture.
The localization of phytate on tofu making and its effects on tofu texture were investigated. Thirty-eight percent and 3% of phytate in soymilk were bound to soluble protein and particulate protein, respectively, and the others were in free form. In the early stage of curd formation, phytate bound to particulate proteins and then a large part of phytate was taken into the tofu curd. Increase of phytate contents in soymilk resulted in the increase of coagulant requirement to make firm tofu. Optimal coagulant concentration (OCC) for making tofu was influenced by phytate contents. The increase of phytate in tofu caused decrease of hardness at OCC and resulted in the increase of brittleness and viscosity of tofu. We concluded that the phytate content is one important factor that contributes to tofu texture.


[Effect of chronic epaden administration on the tissue plasminogen activator activity in rabbits].
The chronic oral administration of epaden (a concentrate of n-3 polyunsaturated fatty acids, n-3 PUFA) to rabbits leads to a decrease in activity of the tissue type plasminogen activator (t-PA) in the blood plasma. In order to elucidate the mechanism of this phenomenon, the epinephrine (adrenaline) stimulated t-PA release in rabbits pretreated with epaden for 4 weeks was compared to that in the control (untreated) group. The epinephrine injections led to a reliable, albeit short-time, increase in the t-PA activity in both test and control groups. Although the base activity of t-PA in the epaden-treated group was lower than that in the control group, the t-PA release in the former group was more pronounced. In addition, the t-PA production was induced by the immobilization shock model in rabbits one month after beginning of the epaden administration (animals in the control group were subject to the shock without epaden pretreatment). In this test, the t-PA release was also more intense in the epaden-treated animals. These results indicate that the dietary epaden administration per os reduces the basal t-PA level, but increases the agonist-induced plasminogen activator production.


HIV-1 reverse transcriptase purified from a recombinant strain of Escherichia coli.
A better understanding of the structure and biochemical properties of the replicative machinery of human immunodeficiency virus type 1 (HIV-1) may be useful in the screening and design of drugs that could be used to treat AIDS. We have previously described a recombinant strain of Escherichia coli that produces HIV-1 reverse transcriptase (RT). Fermentation conditions for the large-scale growth of the bacterial strain and a protocol for the purification of an enzymatically active 66-Kd form of the RT have been developed. The purified RT has all of the appropriate enzymatic functions and properties. The recombinant protein can be substituted for the viral enzyme in structural and biochemical studies and used in screens for drugs that could inhibit HIV replication.


Cross-reactions in cell mediated immunity induced by atypical mycobacteria.
Cross-reactivity in the delayed hypersensitivity response to mycobacteria of different Runyon groups was tested in Swiss white mice immunised with live mycobacteria. All the strains tested gave cross-reactions and, generally, slow growers gave stronger cross-reactions with other slow growers than with rapid growers and vice versa. Sonicates of cross-reacting mycobacteria were also tested for their ability to generate activated macrophages in mice immunised with Mycobacterium avium. All the mycobacterial sonicates generated activated macrophages but a sonicate of Salmonella typhi did not. The sonicate of M. tuberculosis H37Rv also generated activated macrophages, which indicates that there might be protective cross-reactions between M. tuberculosis and atypical mycobacteria.


[Summary of the practice guideline 'Thyroid disorders' (first revision) from the Dutch College of General Practitioners].
--The practice guideline 'Thyroid disorders' developed by the Dutch College of General Practitioners replaces the practice guideline 'Functional thyroid disorders' from 1996. Recommendations for palpable thyroid disorders have been added. --Hypothyroidism can often be treated by the general practitioner. The guideline offers specific recommendations for substitution therapy based on the 'start low, go slow'-principle. --Pharmacological treatment of hyperthyroidism is described as an optional activity for general practitioners. --A conservative approach is taken to the treatment of subclinical thyroid dysfunction. The development of symptoms may justify treatment initiation. --Cooperation has improved harmonisation of this practice guideline with the Netherlands Association for Internal Medicine's practice guideline 'Functional thyroid disorders' and the Dutch Institute for Healthcare Improvement's practice guideline 'Thyroid carcinomas'.


Social class and wise reasoning about interpersonal conflicts across regions, persons and situations.
We propose that class is inversely related to a propensity for using wise reasoning (recognizing limits of their knowledge, consider world in flux and change, acknowledges and integrate different perspectives) in interpersonal situations, contrary to established class advantage in abstract cognition. Two studies-an online survey from regions differing in economic affluence (n = 2 145) and a representative in-lab study with stratified sampling of adults from working and middle-class backgrounds (n = 299)-tested this proposition, indicating that higher social class consistently related to lower levels of wise reasoning across different levels of analysis, including regional and individual differences, and subjective construal of specific situations. The results held across personal and standardized hypothetical situations, across self-reported and observed wise reasoning, and when controlling for fluid and crystallized cognitive abilities. Consistent with an ecological framework, class differences in wise reasoning were specific to interpersonal (versus societal) conflicts. These findings suggest that higher social class weighs individuals down by providing the ecological constraints that undermine wise reasoning about interpersonal affairs.


Differential roles of signaling pathways for proliferation and migration of rat pancreatic stellate cells.
Activated pancreatic stellate cells (PSCs) have recently been implicated in the pathogenesis of pancreatic fibrosis and inflammation. Accumulation of PSCs is a fundamental feature of pancreatic fibrosis, and platelet-derived growth factor (PDGF)-BB is the most potent mitogen for PSCs. But, the molecular mechanisms responsible for PDGF's actions in PSCs are largely unknown. In hepatic stellate cells, it has been established that activation of both phosphatidylinositol (PI) 3-kinase and extracellular-signal regulated kinase (ERK) pathways is required for PDGF-BB-induced proliferation and migration. The aim of this study was to elucidate the signaling pathways mediating PDGF-BB's actions in PSCs. PSCs were isolated from rat pancreas tissue and used in their culture-activated, myofibroblast-like phenotype. Culture-activated PSCs expressed PDGF alpha- and beta-receptors. PDGF-BB induced autophosphorylation of its receptor, followed by the activation of PI 3-kinase, Akt, and ERK pathways. Activation of PI 3-kinase was not required for PDGF-BB-induced ERK activation. PDGF-BB induced approximately five-fold increase in proliferation and chemotaxis of PSCs. Inhibition of ERK pathway with PD98059 completely blocked proliferation, whereas PD98059 had a modest inhibitory effect on cell migration (approximately 50%). On the other hand, inhibition of PI 3-kinase pathway with wortmannin or LY294002 almost completely inhibited migration, but did not affect proliferation of PSCs. In conclusion, our results suggest that ERK pathway regulates proliferation and migration in response to PDGF-BB, whereas PI 3-kinase mediates cellular migration, but not proliferation of PSCs.


Rapidly self-renewing human multipotent marrow stromal cells (hMSC) express sialyl Lewis X and actively adhere to arterial endothelium in a chick embryo model system.
There have been conflicting observations regarding the receptors utilized by human multipotent mesenchymal bone marrow stromal cells (hMSC) to adhere to endothelial cells (EC). To address the discrepancies, we performed experiments with cells prepared with a standardized, low-density protocol preserving a sub-population of small cells that are rapidly self-renewing. Sialyl Lewis X (SLeX) and α4 integrin expression were determined by flow cytometry. Fucosyltransferase expression was determined by quantitative realtime RT-PCR. Cell adhesion assays were carried out with a panel of endothelial cells from arteries, veins and the microvasculature in vitro. In vivo experiments were performed to determine single cell interactions in the chick embryo chorioallantoic membrane (CAM). The CAM is a well-characterized respiratory organ allowing for time-lapse image acquisition of large numbers of cells treated with blocking antibodies against adhesion molecules expressed on hMSC. hMSC expressed α4 integrin, SLeX and fucosyltransferase 4 and adhered to human EC from arteries, veins and the microvasculature under static conditions in vitro. In vivo, hMSC rolled on and adhered to arterioles in the chick embryo CAM, whereas control melanoma cells embolized. Inhibition of α4 integrin and/or SLeX with blocking antibodies reduced rolling and adhesion in arterioles and increased embolism of hMSC. The results demonstrated that rapidly self-renewing hMSC were retained in the CAM because they rolled on and adhered to respiratory arteriolar EC in an α4 integrin- and SLeX-dependent manner. It is therefore important to select cells based on their cell adhesion receptor profile as well as size depending on the intended target of the cell and the injection route.


Optimal parallel stack filtering under the mean absolute error criterion.
The authors extend the configuration of stack filtering to develop a new class of stack-type filters called parallel stack filters (PSFs). As a basis for the parallel stack filtering, the block threshold decomposition (BTD) is introduced, and its properties are investigated. The design of optimal PSHs under the mean absolute error (MAE) criterion is shown to be similar to the minimum MAE stack filtering theory. The only difference is that one needs now to design more than one stack filter that together construct an optimal PSF. As a result, while reviewing briefly the optimal stack filtering theory, they will put more efforts to demonstrate, via several examples, the improvement by switching from stack filtering to parallel stack filtering for the task of image noise removal.


U of Manitoba program delivers care to natives, hope to aboriginal students.
In northern Manitoba and the Northwest Territories, aboriginal communities receive their medical care via a network of nursing stations run by the J.A. Hildes Northern Medical Unit at the University of Manitoba. Most care is provided by nurse practitioners and local health care staff, supported by weekly visits from Winnipeg-based physicians and weekend telephone consultations. It is hoped that more aboriginal students will eventually choose medicine as a career and return to live and work in their communities. The CMA helps support this goal through a bursary program for native students.


Observation of generalized Kibble-Zurek mechanism across a first-order quantum phase transition in a spinor condensate.
The Kibble-Zurek mechanism provides a unified theory to describe the universal scaling laws in the dynamics when a system is driven through a second-order quantum phase transition. However, for first-order quantum phase transitions, the Kibble-Zurek mechanism is usually not applicable. Here, we experimentally demonstrate and theoretically analyze a power-law scaling in the dynamics of a spin-1 condensate across a first-order quantum phase transition when a system is slowly driven from a polar phase to an antiferromagnetic phase. We show that this power-law scaling can be described by a generalized Kibble-Zurek mechanism. Furthermore, by experimentally measuring the spin population, we show the power-law scaling of the temporal onset of spin excitations with respect to the quench rate, which agrees well with our numerical simulation results. Our results open the door for further exploring the generalized Kibble-Zurek mechanism to understand the dynamics across first-order quantum phase transitions.


Differential assembly of inwardly rectifying K+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes.
The inwardly rectifying K+ channel subunit Kir5.1 is expressed abundantly in the brain, but its precise distribution and function are still largely unknown. Because Kir5.1 is co-expressed with Kir4.1 in retinal glial Muller cells, we have compared the biochemical and immunological properties of Kir5.1 and Kir4.1 in the mouse brain. Immunoprecipitation experiments suggested that brain expressed at least two subsets of Kir channels, heteromeric Kir4.1/5.1 and homomeric Kir4.1. Immunolabeling using specific antibodies showed that channels comprising Kir4.1 and Kir5.1 subunits were assembled in a region-specific fashion. Heteromeric Kir4.1/5.1 was identified in the neocortex and in the glomeruli of the olfactory bulb. Homomeric Kir4.1 was confined to the hippocampus and the thalamus. Homomeric Kir5.1 was not identified. Kir4.1/5.1 and Kir4.1 expression appeared to occur only in astrocytes, specifically in the membrane domains facing the pia mater and blood vessels or in the processes surrounding synapses. Both Kir4.1/5.1 and Kir4.1 could be associated with PDZ domain-containing syntrophins, which might be involved in the subcellular targeting of these astrocyte Kir channels. Because heteromeric Kir4.1/5.1 and homomeric Kir4.1 have distinct ion channel properties (Tanemoto, M., Kittaka, N., Inanobe, A., and Kurachi, Y. (2000) J. Physiol. (Lond.) 525, 587-592 and Tucker, S. J., Imbrici, P., Salvatore, L., D'Adamo, M. C., and Pessia, M. (2000) J. Biol. Chem. 275, 16404-16407), it is plausible that these channels play differential physiological roles in the K+ -buffering action of brain astrocytes in a region-specific manner.


A novel reassortant influenza A (H1N1) virus infection in swine in Shandong Province, eastern China.
Influenza A (H1N1) viruses are distributed worldwide and pose a threat to public health. Swine, as a natural host and mixing vessel of influenza A (H1N1) virus, play a critical role in the transmission of this virus to humans. Furthermore, swine influenza A (H1N1) viruses have provided all eight genes or some genes to the genomes of influenza strains that historically have caused human pandemics. Hence, persistent surveillance of influenza A (H1N1) virus in swine herds could contribute to the prevention and control of this virus. Here, we report a novel reassortant influenza A (H1N1) virus generated by reassortment between 2009 pandemic H1N1 viruses and swine viruses. We also found that this virus is prevalent in swine herds in Shandong Province, eastern China. Our findings suggest that surveillance of the emergence of the novel reassortant influenza A (H1N1) virus in swine is imperative.


Prognostic impact of pulmonary artery systolic pressure in patients undergoing transcatheter aortic valve replacement for aortic stenosis.
Baseline pulmonary hypertension (PH) is a predictor of poor outcomes in patients with severe aortic stenosis (AS). Surgical aortic valve replacement is thought to alleviate PH. The aim of this study was to determine the prognostic impact of PH in patients who underwent transcatheter aortic valve replacement (TAVR). An observational cohort study was conducted using prospectively collected data on 277 consecutive patients with severe AS who underwent TAVR at the Mayo Clinic (Rochester, Minnesota) from November 1, 2008, to June 31, 2013. Clinical and echocardiographic data, pulmonary function characteristics, and outcomes stratified by tertiles of pulmonary artery systolic pressure (PASP) were analyzed. From 277 patients who underwent TAVR, 251 patients had PASP assessment at baseline. Those in the highest PASP tertile (PASP ≥49 mm Hg) had more severe chronic lung disease and worse diastolic dysfunction. Being in the highest PASP tertile was an independent predictor of long-term mortality (hazard ratio 2.88, 95% confidence interval 1.15 to 7.23). Patients in the highest PASP tertile had longer lengths of hospital stay, while other short-term outcomes (30-day mortality and readmission, stroke, prolonged ventilation, and reoperation for bleeding) were similar across PASP tertiles. TAVR was associated with a decrease in PASP in the highest PASP tertile at 1 week after the procedure (-8 ± 14 mm Hg) and at 3 months (-7 ± 15 mm Hg) compared with baseline. In conclusion, among patients with severe AS who underwent TAVR, higher baseline PASP was strongly associated with diastolic dysfunction and chronic lung disease. Patients with higher baseline PASP tolerated TAVR relatively well in the early postprocedural phase, with diminished long-term survival. PH should not disqualify patients with severe AS from consideration for TAVR.


Application of a Demineralized Cortical Bone Matrix and Bone Marrow-Derived Mesenchymal Stem Cells in a Model of Chronic Rotator Cuff Degeneration.
The success of rotator cuff repair is primarily dependent on tendon-bone healing. Failure is common because weak scar tissue replaces the native enthesis, rendering it prone to reruptures. A demineralized bone matrix (DBM) consists of a network of collagen fibers that provide a sustained release of growth factors such as bone morphogenetic proteins. Previous studies have demonstrated that it can regenerate a fibrocartilaginous enthesis. The use of a DBM and mesenchymal stem cells (MSCs) at the healing enthesis will result in a higher bone mineral density at the tendon insertion and will enhance the regeneration of a morphologically superior enthesis when compared with an acellular human dermal matrix. Controlled laboratory study. Eighteen female Wistar rats underwent unilateral detachment of the supraspinatus tendon. Three weeks later, tendon repair was carried out in animals randomized into 3 groups: group 1 received augmentation of the repair with a cortical allogenic DBM (n = 6); group 2 received augmentation with a nonmeshed, ultrathick, acellular human dermal matrix (n = 6); and group 3 underwent tendon-bone repair without a scaffold (n = 6). All animals received 1 × 106 MSCs delivered in fibrin glue to the repair site. Specimens were retrieved at 6 weeks postoperatively for histological analysis and the evaluation of bone mineral density. All groups demonstrated closure of the tendon-bone gap with a fibrocartilaginous enthesis. Although there were no significant differences in the enthesis maturation and modified Movin scores, repair augmented with a dermal matrix + MSCs exhibited a disorganized enthesis, abnormal collagen fiber arrangement, and greater cellularity compared with other MSC groups. Only repairs augmented with a DBM + MSCs reached a bone mineral density not significantly lower than nonoperated controls. A DBM enhanced with MSCs can augment rotator cuff healing at 6 weeks and restore bone mineral density at the enthesis to its preinjury levels. Biological augmentation of rotator cuff repair with a DBM and MSCs may reduce the incidence of retears, although further studies are required to determine its effectiveness.


[Multiple perceptions of infant mortality in Ceará State, Brazil].
This qualitative study analyzes the perceptions of various social actors towards infant mortality and the program to reduce it in Ceará State, Northeast Brazil. The study compares two municipalities (counties) that showed opposite infant mortality trends from 1993 to 1997, during which time Ceará achieved international visibility for having reduced infant mortality statewide. A total of 48 semi-structured interviews with four groups of key informants health system managers, community health agents, mothers who had lost a child, and neighbor women with children in the same age bracket and content analysis revealed "multiple conflicting voices" on the issue. Although the level of political determination to implement the interventions varied between the two municipalities, the differences in perceptions concerning infant death were more striking between the various groups of social actors, regardless of the municipality. The study revealed a kind of authoritarian educational practice that jeopardizes acceptance of the Community Health Agents Program. Public policies are needed that give voice to the people closest to the experience of infant death.


A projection access order for speedy convergence of ART (algebraic reconstruction technique): a multilevel scheme for computed tomography.
The practical performance of algebraic reconstruction techniques (ART) for computed tomography (CT) depends heavily on the order in which the projections are considered. Complete orthogonalization, notwithstanding its theoretical justification, is not feasible because the computational time is prohibitive. The authors report here a scheme that yields the most efficient reconstruction without orthogonalization: projections are organized and accessed in a nominally multilevel fashion. Each level makes the best use of the image information reconstructed in the preceding levels. If the number of projections is a power of two. Then the access orders are exactly that for the 1D FFT. The authors' scheme can be easily implemented. Using it, one iteration of ART yields a high-quality image. Experimental results of this algorithm are demonstrated and compared with the results from the conventional sequential method and also random ordering. Comparisons show that this scheme is superior. ART is better in image quality than the Fourier back-projection algorithm, at least for a smaller number of projections. Since the authors have made it much more efficient in computational speed, ART could now find widespread use in medical imaging.


Regulation of the transcription factor NF-kappaB1 by microRNA-9 in human gastric adenocarcinoma.
MicroRNAs (miRNAs) are a new class of naturally occurring, small, non-coding RNAs that regulate protein-coding mRNAs by causing mRNA degradation or repressing translation. The roles of miRNAs in lineage determination and proliferation, as well as the localization of several miRNA genes at sites of translocation breakpoints or deletions, have led to speculation that miRNAs could be important factors in the development or maintenance of the neoplastic state. We showed that miR-9 was downregulated in human gastric adenocarcinoma. Overexpression of miR-9 suppressed the growth of human gastric adenocarcinoma cell line MGC803 cell as well as xenograft tumors derived from them in SCID mice. Bioinformatics analysis indicated a putative miR-9 binding site in the 3'-untranslated region (3'UTR) of the tumor-related gene NF-kappaB1 mRNA. In an EGFP reporter system, overexpression of miR-9 downregulated EGFP intensity, and mutation of the miR-9 binding site abolished the effect of miR-9 on EGFP intensity. Furthermore, both the NF-kappaB1 mRNA and protein levels were affected by miR-9. Finally, knockdown of NF-kappaB1 inhibited MGC803 cell growth in a time-dependent manner, while ectopic expression of NF-kappaB1 could rescue MGC803 cell from growth inhibition caused by miR-9. These findings indicate that miR-9 targets NF-kappaB1 and regulates gastric cancer cell growth, suggesting that miR-9 shows tumor suppressive activity in human gastric cancer pathogenesis.


Lymphoplasmacytic chronic cholecystitis and biliary tract disease in patients with lymphoplasmacytic sclerosing pancreatitis.
Lymphoplasmacytic sclerosing pancreatitis (LPSP) represents a distinctive form of chronic pancreatitis characterized by diffuse fibroinflammatory infiltrates that can involve both the pancreatic ducts and acinar parenchyma. Several cases of inflammatory infiltrates within the gallbladder have been reported in association with LPSP, but the spectrum of gallbladder pathology in patients with LPSP has not been systematically reviewed. Many patients with LPSP have distal CBD fibrosis, strictures, and inflammation, features that overlap somewhat with primary sclerosing cholangitis (PSC). In PSC, a pattern of gallbladder pathology termed "diffuse acalculous lymphoplasmacytic chronic cholecystitis" has been previously described as showing a triad of diffuse, mucosal-based, plasma cell-rich inflammatory infiltrates. We studied 20 gallbladders from patients with LPSP and compared them with 20 gallbladders in PSC, 20 gallbladders with chronic cholelithiasis, and 10 gallbladders from patients with benign (non-LPSP) pancreatic disease. The following features were evaluated: degree and composition of mucosal inflammation and deep (mural) inflammation, lymphoid nodules, metaplasia, dysplasia/neoplasia, fibrosis, muscular hypertrophy, Rokitansky-Aschoff sinuses, and cholesterolosis. The majority (60%) of gallbladders in LPSP contained moderate or marked inflammatory infiltrates and lymphoid nodules, frequencies similar to PSC but significantly higher than in chronic cholelithiasis and benign non-LPSP pancreatic disease. LPSP gallbladders received the highest scores for deep inflammation of all groups, and 35% of LPSP gallbladders showed transmural chronic cholecystitis. Overall, "diffuse lymphoplasmacytic chronic cholecystitis" was present in 50% of PSC cases and 25% of LPSP cases, but in only 5% of chronic cholelithiasis and none of non-LPSP benign pancreatic disease. Mucosal inflammation in LPSP gallbladders correlated significantly with the presence of inflammation in the extrapancreatic portion of the CBD. These findings suggest that inflammatory pathology of the gallbladder is frequently associated with LPSP and that it is part of the spectrum of biliary tract disease in these patients, rather than a simple reflection of the pancreatitis itself.


Ten-year absolute fracture risk and hip bone strength in Canadian women with systemic lupus erythematosus.
Women with systemic lupus erythematosus (SLE) are at risk of osteoporosis (OP) and fractures because of SLE or its treatments. We aimed to determine in women with SLE (1) the prevalence of low bone mass (LBM) in those < 50 years of age and OP in those > 50 years of age; (2) the 10-year absolute fracture risk in those > 40 years of age using the Canadian Fracture Risk Assessment Tool (FRAX); (3) bone quality using hip structural analysis (HSA); and (4) the associations between HSA and age, SLE duration, and corticosteroid exposure. Women without prior OP fractures were eligible. Bone mineral densities at the hip, spine, and femoral neck were determined using dual-energy x-ray absorptiometry. OP was determined using World Health Organization definitions for participants aged ≥ 50 years (32.8%), and LBM was defined as Z-scores ≤ -2.0 for those aged < 50 years. For those aged ≥ 40 years (63.5%), the 10-year probabilities of a major fracture (FRAX-Major) and hip fracture (FRAX-Hip) were calculated. FRAX-Major ≥ 20% or Hip ≥ 3% was considered high risk. HSA was done in a subgroup (n = 81) of patients. The study group was 271 women. Mean (SD) age was 43.8 (13.1) years and SLE duration was 11.6 (10.4) years. OP was diagnosed in 14.6% and LBM in 8.8%. FRAX-Major ≥ 20% was seen in 9 patients (5.3%), of whom 6 were taking OP medications. FRAX-Hip ≥ 3% occurred in 16 patients (9.4%), of whom 9 were taking OP medications. Buckling ratio at the left hip narrow neck was positively correlated with FRAX-Major, FRAX-Hip, SLE duration, and duration of corticosteroid use. LBM is prevalent in women with SLE who are < 50 years of age. FRAX may identify those at higher risk of fractures while HSA can assess bone structure noninvasively.


Alcohol, masculinity, honour and male barroom aggression in an Australian sample.
The link between alcohol and men's aggression is well established, although growing evidence also points to individual and learned social factors. The aim of the present study was to investigate the relationships between male alcohol-related aggression (MARA) among young Australian men and heavy episodic drinking, trait aggression, masculinity, concerns about social honour and expected positive consequences of MARA. The total sample comprised 170 men aged 18-25 years who completed an online questionnaire exploring beliefs and attitudes towards MARA. Those who reported heavy episodic drinking were more likely to be involved in an incident of MARA. In addition, those who were involved in MARA had higher levels of trait aggression, concern for social honour and expected positive consequences of aggression in bars than did those without such involvement. The relationship between socially constructed masculinity factors (a combined variable reflecting masculinity, social honour and expected positive consequences) and MARA was mediated by heavy episodic drinking. Social honour accounted for almost all of the predictive power of masculinity factors. Heavy episodic drinking and trait aggression remained significant predictors of MARA in a multivariate model. The findings from the current study may assist in developing preventative techniques for young men which target masculinity concerns and the consequences of participating in MARA.


TRIM3 inhibits P53 signaling in breast cancer cells.
Beast cancer is the most common women cancer worldwide, while two third of them are ER alpha positive breast cancer. Among the ER alpha positive breast cancer, about 80% are P53 wild type, indicating the potential tumor suppression role in ER alpha positive breast cancer. Since P53 is an important safeguard to inhibit cell malignant transformation, reactivating P53 signaling could a plausible approach to treat breast cancer. TRIM3 protein levels were measured by western blot, while the P53 classical target genes were measured by real-time PCR. WST1 assay were used to measure cell proliferation, while cleaved caspase-3 was used to detect cell apoptosis. Protein stability and ubiquitin assay were used to detect the P53 protein ubiquitin and stability. The immuno-precipitation assays were used to detect the protein interactions. Immuno-staining was used to detect the protein localization of P53 and TRIM3, while the ubiquitin-based immuno-precipitation assays were used to detect the specific ubiquitination manner of P53. In our study, we identified TRIM3 as an endogenous inhibitor for P53 signaling. TRIM3 depletion inhibited breast cancer cell proliferation and promoted apoptosis. In addition, TRIM3 depletion increased P53 protein level in breast cancer cell. Further investigation showed that TRIM3 could associate with P53 and promote P53 K48-linked ubiquitination and degradation. Our study identified a novel post-translational modification mechanism between TRIM3 and P53. TRIM3 depletion or blockage could be a promising strategy to rescue P53 signaling and inhibit breast cancer progression.


Synthesis of meso-substituted porphyrins carrying carboranes and oligo(ethylene glycol) units for potential applications in boron neutron capture therapy.
Selective delivery of 10B to tumours is one of the major remaining problems in boron neutron capture therapy (BNCT) of cancer. Porphyrins are selectively accumulated in tumours. Thus two series of carborane-carrying porphyrins were constructed, with additional functionality for attachment of uncharged potentially water-solubilising polyethers. 3-(1,2-Dicarbaclosododecaboran(12)-1-ylmethoxy)benzaldehyde was prepared by protection of the aldehyde of 3-(prop-2-ynyloxy)benzaldehyde as a dithioacetal, treatment with decaborane(14) and deprotection. Condensation with a 3-nitrophenyldipyrromethane gave a separable mixture of meso-(3-nitrophenyl)-meso-(3-carboranylmethoxyphenyl)porphyrins, resulting from extensive scrambling at the porphyrinogen stage. Similarly, condensation of 3-(1,2-dicarbaclosododecaboran(12)-1-yl)benzaldehyde with this dipyrromethane gave an analogous mixture of meso-(3-nitrophenyl)-meso-(3-carboranylphenyl)porphyrins. In this second series, the two regioisomeric bis(nitrophenyl)bis(carboranylphenyl)porphyrins could only be distinguished by X-ray crystallography, their NMR spectra being identical. The nitro groups of the mono(nitrophenyl)porphyrins and the bis(nitrophenyl)-porphyrins were reduced to the corresponding amines with tin(II) chloride and the monoamines were coupled with a omega-methoxy poly(ethylene glycol) chloroformate of mean MW 600 to give the MeOPEGylated tricarboranyl porphyrins.


Heat hardening in a pair of Anolis lizards: constraints, dynamics and ecological consequences.
Heat tolerance plasticity is predicted to be an important buffer against global warming. Nonetheless, basal heat tolerance often correlates negatively with tolerance plasticity ('trade-off hypothesis'), a constraint that could limit plasticity benefits. We tested the trade-off hypothesis at the individual level with respect to heat hardening in two lizard species, Anolis carolinensis and Anolis sagrei. Heat hardening is a rapid increase in heat tolerance after heat shock that is rarely measured in reptiles but is generally considered to be a first line of physiological defense against heat. We also employed a biophysical model of operative habitat temperatures to estimate the performance consequences of hardening under ecologically relevant conditions. Anolis carolinensis hardened by 2 h post-heat shock and maintained hardening for several hours. However, A. sagrei did not harden. Biophysical models showed that hardening in A. carolinensis reduces their overheating risk in the field. Therefore, while not all lizards heat harden, hardening has benefits for species that can. We initially found a negative relationship between basal tolerance and hardening within both species, consistent with the trade-off hypothesis. However, permutation analyses showed that the apparent trade-offs could not be differentiated from statistical artifact. We found the same result when we re-analyzed published data supporting the trade-off hypothesis in another lizard species. Our results show that false positives may be common when testing the trade-off hypothesis. Statistical approaches that account for this are critical to ensure that the hypothesis, which has broad implications for thermal adaptation and responses to warming, is assessed appropriately.


Crystalline structures of particles interacting through the harmonic-repulsive pair potential.
The behavior of identical particles interacting through the harmonic-repulsive pair potential has been studied in 3D using molecular dynamics simulations at a number of different densities. We found that at many densities, as the temperature of the systems decreases, the particles crystallize into complex structures whose formation has not been anticipated in previous studies on the harmonic-repulsive pair potential. In particular, at certain densities, crystallization into the structure Ia3¯d (space group #230) with 16 particles in the unit cell occupying Wyckoff special positions (16b) was observed. This crystal structure has not been observed previously in experiments or in computer simulations of single component atomic or soft matter systems. At another density, we observed a liquid which is rather stable against crystallization. Yet, we observed crystallization of this liquid into the monoclinic C2/c (space group #15) structure with 32 particles in the unit cell occupying four different non-special Wyckoff (8f) sites. In this structure particles located at different Wyckoff sites have different energies. From the perspective of the local atomic environment, the organization of particles in this structure resembles the structure of some columnar quasicrystals. At a different value of the density, we did not observe crystallization at all despite rather long molecular dynamics runs. At two other densities, we observed the formation of the βSn distorted diamond structures instead of the expected diamond structure. Possibly, we also observed the formation of the R3¯c hexagonal lattice with 24 particles per unit cell occupying non-equivalent positions.


Biochar Affects Essential Nutrients of Carrot Taproots and Lettuce Leaves.
Essential nutrient concentrations in crops can affect human health. While biochar has the potential as a soil amendment to improve crop yields, it may also affect the concentrations of nutrients such as Ca, Fe, K, Mg, Mn, and Zn in edible portions of crops. To better characterize effects of biochar on important human nutrients in food crops, we evaluated the effects of biochar on lettuce (Lactuca sativa L. cv. Black-Seeded Simpson) leaf and carrot [Daucus carota subsp. sativus (Hoffm.) Schübl. cv. Tendersweet] developing taproot nutrients. Plants were grown in pots in a greenhouse using sandy loam (Coxville, fine, kaolinitic, thermic Typic Paleaquults) and loamy sand (Norfolk, fine-loamy, kaolinitic, thermic Typic Kandiudults,) series soils, amended with biochar produced from four feedstocks: pine chips (PC), poultry litter (PL), swine solids (SS), and switchgrass (SG); and two blends of PC plus PL [Pc/PL, 50%/50% (55) and 80%/20% (82) by weight]. Biochar was produced at 350, 500, and 700 °C from each feedstock. Lettuce leaf and carrot taproot total nutrient concentrations were determined by inductively coupled plasma analysis. Biochar (especially at least in part manure-based, i.e., PL, SS, 55, and 82 at nearly all temperatures) primarily decreased nutrient concentrations in lettuce leaves, with Ca, Mg, and Zn affected most. Carrot taproot nutrient concentrations also deceased, but to a lesser extent. Some biochars increased leaf or taproot nutrient concentrations, especially K. This study indicated that biochar can both decrease and increase leaf and taproot nutrient concentrations important for human health. Thus, potential effects on nutrients in plants should be carefully considered when biochar is used as a soil amendment with vegetable crops.


Phenotyping of rare circulating cells in the blood of non-metastatic breast cancer patients using microfluidic Labyrinth technology.
Label-free technologies for isolating rare circulating cells in breast cancer patients are widely available; however, they are mostly validated on metastatic patient blood samples. Given the need to use blood-based biomarkers to inform on disease progression and treatment decisions, it is important to validate these technologies in non-metastatic patient blood samples. In this study, we specifically focus on a recently established label-free microfluidic technology Labyrinth and assess its capabilities to phenotype a variety of rare circulating tumor cells indicative of epithelial-to-mesenchymal transition as well as cancer-associated macrophage-like (CAML) cells. We specifically chose a patient cohort that is non-metastatic and selected to undergo neoadjuvant chemotherapy to assess the performance of the Labyrinth technology. We enrolled 21 treatment naïve non-metastatic breast cancer patients of various disease stages. Our results indicate that (i) Labyrinth microfluidic technology is successfully able to isolate different phenotypes of CTCs despite the counts being low. (ii) Invasive phenotypes of CTCs such as transitioning CTCs and mesenchymal CTCs were found to be present in high numbers in stage III patients as compared to stage II patients. (iii) As the total load of CTCs increased, the mesenchymal CTCs were found to be increasing. (iv) Labyrinth was able to isolate CAMLs with the counts being higher in stage III patients as compared to stage II patients. Our study demonstrates the ability of the Labyrinth microfluidic technology to isolate rare cancer-associated cells from the blood of treatment naïve non-metastatic breast cancer patients, laying the foundation for tracking oncogenic spread and immune response in patients undergoing neoadjuvant chemotherapy.


Developmental patterning of carbohydrate antigens during early embryogenesis of the chick: expression of antigens of the poly-N-acetyllactosamine series.
This report describes a striking temporal and spatial patterning of specific carbohydrate sequences in the developing chick embryo. By using oligosaccharide sequence-specific monoclonal antibodies as immunohistochemical reagents in conjunction with neuraminidase, it was possible to visualize the occurrence, as well as the changes in distribution, of oligosaccharides of the poly-N-acetyllactosamine series. These were (a) long-chain unbranched sequences reactive with anti-i Den, (b) long-chain branched sequences reactive with anti-I Step and (c) short-chain branched sequences reactive with anti-I Ma and (d) their sialylated forms. The salient observations with serial sections of embryos from the unincubated to the 17th stage were as follows. (1) A pronounced anteroposterior patterning appeared during neuroectodermal development, such that the long-chain unbranched and long-chain branched sequences, which were abundant on the ectoderm of the earlier stages, were replaced by short-chain branched sialo-oligosaccharides in the developing brain and anterior neural tube. (2) A striking anteroposterior and mediolateral patterning developed in the subectodermal extracellular spaces. The long-chain linear and short-chain non-sialylated sequences demarcated regions favourable for migration of the lateral plate mesoderm. (3) A distinction was made between the dorsal and ventral routes of the trunk neural crest in that the extracellular matrix of the dorsal route only was associated with long-chain linear and short-chain sialylated branched sequences. (4) A circumscribed perinotochordal distribution of the short-chain sialylated branched sequences was observed in the region of the future centra of the vertebrae. (5) An abundance of long-chain linear and long-chain sialylated branched structures was detected in primordial germ cells which permitted their identification during migration. These observations suggest that oligosaccharides of the poly-N-acetyllactosamine series may have roles as short-range, region-specific information factors during morphogenetic events that take place in the developing embryo, and they open the way to the search for recognition proteins (e.g. endogenous lectins) specific for each of these oligosaccharide structures.


The discursive construction of HIV stigma in Irish print media.
As interlocutors in national level discourse with the power to influence public opinion and inform policy, the news media are an important data source in understanding the constitutive roles played by culture and discourse in shaping health experiences and outcomes. This paper reports on a critical discourse analysis of news media coverage of HIV in the Republic of Ireland between 2006 and 2016. This period is significant because of the considerable increase in new HIV diagnoses that occurred in Ireland after the 2008 recession. Analysis of articles (n = 103) demonstrated a pattern of dividing practices whereby people living with or affected by HIV were frequently positioned as somatically and morally deficient via discourses of risk and responsibility. Little focus was given over to examination of the structural drivers of HIV, occluding the social context of the epidemic. The findings suggest that media discourses on HIV have the potential to other people living with HIV and generate stigma by invoking a dynamic of blame and shame frequently implicated in the stigma process.


Identification of MicroRNAs and their Targets Associated with Embryo Abortion during Chrysanthemum Cross Breeding via High-Throughput Sequencing.
MicroRNAs (miRNAs) are important regulators in plant development. They post-transcriptionally regulate gene expression during various biological and metabolic processes by binding to the 3'-untranslated region of target mRNAs to facilitate mRNA degradation or inhibit translation. Chrysanthemum (Chrysanthemum morifolium) is one of the most important ornamental flowers with increasing demand each year. However, embryo abortion is the main reason for chrysanthemum cross breeding failure. To date, there have been no experiments examining the expression of miRNAs associated with chrysanthemum embryo development. Therefore, we sequenced three small RNA libraries to identify miRNAs and their functions. Our results will provide molecular insights into chrysanthemum embryo abortion. Three small RNA libraries were built from normal chrysanthemum ovules at 12 days after pollination (DAP), and normal and abnormal chrysanthemum ovules at 18 DAP. We validated 228 miRNAs with significant changes in expression frequency during embryonic development. Comparative profiling revealed that 69 miRNAs exhibited significant differential expression between normal and abnormal embryos at 18 DAP. In addition, a total of 1037 miRNA target genes were predicted, and their annotations were defined by transcriptome data. Target genes associated with metabolic pathways were most highly represented according to the annotation. Moreover, 52 predicted target genes were identified to be associated with embryonic development, including 31 transcription factors and 21 additional genes. Gene ontology (GO) annotation also revealed that high-ranking miRNA target genes related to cellular processes and metabolic processes were involved in transcription regulation and the embryo developmental process. The present study generated three miRNA libraries and gained information on miRNAs and their targets in the chrysanthemum embryo. These results enrich the growing database of new miRNAs and lay the foundation for the further understanding of miRNA biological function in the regulation of chrysanthemum embryo abortion.


Retinotectal system of the tortoise, Testudo horsfieldi, Gray (morpho-functional study in the norm and after enucleation).
The optic nerve and mesencephalic optic centre (tectum opticum, TO) of the tortoise, Testudo horsfieldi, Gray, in the norm and after the enucleation have been studies using Golgi's method, electron microscopy and the electrophysiological technique. The optic nerve comprises about 400,000 fibres represented by two classes of axons: myelinated (10%) and unmyelinated (90%). The diameters of the former vary within 0.3-3 mum, of the latter within 0.3-1.1 mum. The neurogramms of the optic nerve contain two components corresponding to the two rates of conduction through different groups of fibres (1.3 musec and 0.5 musec). The stratified synaptic organization of the TO has been investigated. The optic terminals are shown to join in complex synaptic formations at certain levels of the upper layers of the TO (Strata I, II and III). The process of degeneration in the optic system of Testudo is drastically stretched in time. It was demonstrated by the electrophysiological control that the TO potentials induced in response to the nerve stimulation were not registered any longer only 6-6.5 months after the enucleation. Certain groups of retinal fibres of the optic nerve and their terminals in the TO are shown to degenerate differently and asynchronously. Earlier unknown types of destructive changes of the terminals (vesicular, neurofilamentous, glycogen and others) are described. It is suggested that the different types of degeneration of the optic fibres and their terminals are the result of possible biochemical heterogeneity of the retinal ganglious cells. The comparison of the terms and types of degeneration of different groups of nervous fibres in the optic nerve and their terminals in the TO has revealed some correlations suggesting that the myelinated optic fibres produce nervous terminals degenerating by the "dark" type, whereas the unmyelinated optic axons may be subdivided into several groups, each producing nervous terminals subjected to a definite type of destruction ("clear", "vesicular", "neurofilamentous" etc.). The localization of certain groups of therminals at certain levels of the cortical plate of the TO confirms the electrophysiological data on the stratified organization of the retino-tectal projections in the TO of lower vertebrates. It has been shown by the comparison of the results obtained with those reported for Emys orbicularis, L. that the two species have marked differences in the morpho-functional characteristics of the retino-tectal system, neuronic composition of the TO, the character of destructive changes of the terminals after the enucleation and the component composition of polysynaptic complexes and glomerules. Probably these differences may come from the peculiarities of the perception and transformation of visual information in the species.


Dying for work: The magnitude of US mortality from selected causes of death associated with occupation.
Deaths due to occupational disease and injury place a heavy burden on society in terms of economic costs and human suffering. We estimate the annual deaths due to selected diseases for which an occupational association is reasonably well established and quantifiable, by calculation of attributable fractions (AFs), with full documentation; the deaths due to occupational injury are then added to derive an estimated number of annual deaths due to occupation. Using 1997 US mortality data, the estimated annual burden of occupational disease mortality resulting from selected respiratory diseases, cancers, cardiovascular disease, chronic renal failure, and hepatitis is 49,000, with a range from 26,000 to 72,000. The Bureau of Labor Statistics estimates there are about 6,200 work-related injury deaths annually. Adding disease and injury data, we estimate that there are a total of 55,200 US deaths annually resulting from occupational disease or injury (range 32,200-78,200). Our estimate is in the range reported by previous investigators, although we have restricted ourselves more than others to only those diseases with well-established occupational etiology, biasing our estimates conservatively. The underlying assumptions and data used to generate the estimates are well documented, so our estimates may be updated as new data emerges on occupational risks and exposed populations, providing an advantage over previous studies. We estimate that occupational deaths are the 8th leading cause of death in the US, after diabetes (64,751) but ahead of suicide (30,575), and greater than the annual number of motor vehicle deaths per year (43,501).


Common and individually specific chromosomal characteristics of cultured human melanoma.
Since individual chromosomes can be accurately identified by new banding techniques, atebrin fluorescence was used for chromosome analysis in six cell lines and two primary outgrowths derived from human malignant melanoma. Gross aneuploidy was seen in all specimens, but each culture contained at least 1 distinctive marker chromosome specific for that cell line in 87 to 100% of metaphases. One of the primary explants contained a marker that was demonstrable in fresh tissue and persisted through 2 weeks of culture. The same marker was found in all metaphases from 2 different metastases, but skin fibroblasts from the same patient had a normal chromosome complement. No common marker for human melanoma was found, but in 6 of the 8 cultures the most frequently found marker was formed by a brightly banded chromatid addition. Relative polysomy for Chromosome 7 was found in 7 of the 8 cultures and, for Chromosome 22, in 8 of the 8 cultures. The frequency of polysomy of Chromosomes 7 and 22 was significant at the 5% level.


Blake outer ridge: development by gravity tectonics.
A continuous seismic profile across the Blake Outer Ridge reveals clear evidence of a structural origin for the ridge. A ridge core separates distinctive regions of structure east and west of the crest and does not support a theory of depositional origin. The presence of horizon A continuously beneath the ridge rules out faulting or folding involving basement rocks. Gravity tectonics are suggested as the mechanism for formation of the ridge after the deposition of the sediments above horizon A.


In vivo neuronal function of the fragile X mental retardation protein is regulated by phosphorylation.
Fragile X syndrome (FXS), caused by loss of the Fragile X Mental Retardation 1 (FMR1) gene product (FMRP), is the most common heritable cause of intellectual disability and autism spectrum disorders. It has been long hypothesized that the phosphorylation of serine 500 (S500) in human FMRP controls its function as an RNA-binding translational repressor. To test this hypothesis in vivo, we employed neuronally targeted expression of three human FMR1 transgenes, including wild-type (hFMR1), dephosphomimetic (S500A-hFMR1) and phosphomimetic (S500D-hFMR1), in the Drosophila FXS disease model to investigate phosphorylation requirements. At the molecular level, dfmr1 null mutants exhibit elevated brain protein levels due to loss of translational repressor activity. This defect is rescued for an individual target protein and across the population of brain proteins by the phosphomimetic, whereas the dephosphomimetic phenocopies the null condition. At the cellular level, dfmr1 null synapse architecture exhibits increased area, branching and bouton number. The phosphomimetic fully rescues these synaptogenesis defects, whereas the dephosphomimetic provides no rescue. The presence of Futsch-positive (microtubule-associated protein 1B) supernumerary microtubule loops is elevated in dfmr1 null synapses. The human phosphomimetic restores normal Futsch loops, whereas the dephosphomimetic provides no activity. At the behavioral level, dfmr1 null mutants exhibit strongly impaired olfactory associative learning. The human phosphomimetic targeted only to the brain-learning center restores normal learning ability, whereas the dephosphomimetic provides absolutely no rescue. We conclude that human FMRP S500 phosphorylation is necessary for its in vivo function as a neuronal translational repressor and regulator of synaptic architecture, and for the manifestation of FMRP-dependent learning behavior.


[The mechanisms regulating the activity of the longitudinal layer of the intestinal smooth muscle in the Dolly Varden trout].
Spontaneous myogenic rhythmic motility of the Salvelinus malma curilus smooth muscle structures was studied. The findings suggested presence of a general tonic inhibitory action of the enteral part of the metasympathetic nervous system on myogenic motility of intestinal longitudinal layer. The splanchnic nerve effect on intestinal motor activity was revealed. Dependence of obvious components of visceromotor response on the stimulation frequency, was shown. Possible origin of these components was discussed on the basis of experimentally obtained characteristics of effects of the transmitter substances on the smooth muscle structure. Functioning of neural muscular structures was compared in the mammalian and fish intestines.


Pathology of premalignant lesions and carcinoma of the prostate in African-American men.
The objective of this study was to summarize data describing the morphological characteristics of the spectrum of prostatic neoplasia in African-American men and compare them to their equivalents in Caucasian men. Studies that have emphasized the documentation of pathological features of prostate cancer or its putative precursors in African Americans are reviewed and are contrasted with comparable data concerning Caucasians. The author's experience is also presented. There is significant overlap between the pathological features of prostate cancer in African Americans and Caucasians in their clinical associations. The main pathological parameter reported with consistency to differ between the two groups is the observation that African-American patients present with a more advanced stage of the disease compared with Caucasian patients. Reports on differences in the grade and volume of the disease are less consistent. Comparative data on "preclinical," autopsy-type cancers and those concerning premalignant lesions indicate a similar prevalence of autopsy cancers between the two races while the prevalence and extent of high-grade prostatic intraepithelial neoplasia is higher in African-American men compared with Caucasian men. The difference is more evident in younger individuals. In conclusion, there are indications that African-American men with clinically localized prostate cancer tend to have a more advanced pathological stage at the time of radical prostatectomy compared with Caucasian men. Our data also indicate a higher prevalence of a putative precursor for clinically evident prostate cancer, high-grade prostatic intraepithelial neoplasia in African-American men. The earlier onset and extensiveness of this lesion may contribute to the higher incidence of clinically evident prostate cancer in African Americans.


Effect of the shipment of cadaveric renal allografts on allograft survival.
Since 1996, the allocation of grafts in France has been based on a hierarchical three-level system: national, regional and local. The objective of this study was to determine whether the shipment of cadaveric kidneys according to these new exchange rules affects allograft outcome in the Eastern region of France. This retrospective study analysed all renal transplants performed in the four centres of the French Eastern region during 3 years (1996 to 1998). All patients were followed up until death, return to dialysis, last information date or the end of June 2003. Information regarding the donors, recipients and treatments, as well as patient and graft outcome, was recorded. Factors associated with graft loss were analysed using Cox proportional hazard methods. 542 transplants were analysed, 287 (53%) kidneys were transplanted locally, 229 (42.2%) kidneys coming from exchanges within the region and 26 (4.8%) from another region. There were statistically significant differences between the four centres for donors' and recipient' characteristics and for immunosuppressive treatment, but there was no difference between centres regarding patient survival (94.4% at 5 years), graft survival (83.7% at 5 years) or death-censored graft survival (87.8% at 5 years). Compared to locally transplanted grafts, shipped grafts had significantly better human leukocyte antigen (HLA) matching (2.5 +/- 1.3 versus 2.1 +/- 1.0 matches, P = 0.0005 but a longer cold ischaemia time (23.2 +/- 7.9 versus 19.2 +/- 7.8 h, P < 0.0001). Three independent factors were associated with a reduced graft survival: at least one acute rejection, delayed graft function and a shipped graft. The results of this study suggest that the shipment of cadaveric renal allografts in a regional distribution system is associated with better HLA matching but is a significant predictor of graft loss at 5 years. It would be advisable to restrict graft sharing to patients whose access to transplantation is limited, taking special care to avoid any additional factors having a detrimental effect on the outcome.


Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments.
The use of flecainide and encainide was terminated in the Cardiac Arrhythmia Suppression Trial because of an excess of sudden cardiac deaths in the active treatment group. Such events might arise from reentrant rhythms initiated by premature stimulation in the presence of anisotropic sodium channel availability. Drugs that bind to sodium channels increase the functional dispersion of refractoriness by slowing (a result of the drug-unbinding process) the transition from an inexcitable state to an excitable state. It is interesting that encainide and flecainide unbind slowly (15-20 seconds), whereas lidocaine and moricizine unbind rapidly (0.2-1.3 seconds). With a computer representation of a cable with Beeler-Reuter membrane properties, we found a small (6 msec) vulnerable window that occurred 338 msec after the last drive stimulus. Premature stimuli falling within the vulnerable window resulted in unidirectional block and reentrant activation. In the presence of a slowly unbinding drug, the window was delayed an additional 341 msec, and its duration was extended to 38 msec. The delay (antiarrhythmic effect) before the onset of the vulnerable window and its duration (proarrhythmic effect) were both dependent on the sodium channel availability and the recovery process. Both effects were also prolonged when sodium channel availability was reduced by membrane depolarization. Defining the proarrhythmic potential as the duration of the vulnerable window, we found that hypothetical use-dependent class I drugs have a greater proarrhythmic potential than non-use-dependent drugs. The antiarrhythmic and proarrhythmic properties of pure sodium channel antagonists are both dependent on sodium channel availability. Consequently, the price for increased antiarrhythmic efficacy (suppressed premature ventricular contractions) is an increased proarrhythmic vulnerability to unsuppressed premature ventricular contractions.


Individual differences in regulatory mode moderate the effectiveness of a pilot mHealth trial for diabetes management among older veterans.
mHealth tools to help people manage chronic illnesses have surged in popularity, but evidence of their effectiveness remains mixed. The aim of this study was to address a gap in the mHealth and health psychology literatures by investigating how individual differences in psychological traits are associated with mHealth effectiveness. Drawing from regulatory mode theory, we tested the role of locomotion and assessment in explaining why mHealth tools are effective for some but not everyone. A 13-week pilot study investigated the effectiveness of an mHealth app in improving health behaviors among older veterans (n = 27) with poorly controlled Type 2 diabetes. We developed a gamified mHealth tool (DiaSocial) aimed at encouraging tracking of glucose control, exercise, nutrition, and medication adherence. Important individual differences in longitudinal trends of adherence, operationalized as points earned for healthy behavior, over the course of the 13-week study period were found. Specifically, low locomotion was associated with unchanging levels of adherence during the course of the study. In contrast, high locomotion was associated with generally stronger adherence although it exhibited a quadratic longitudinal trend. In addition, high assessment was associated with a marginal, positive trend in adherence over time while low assessment was associated with a marginal, negative trend. Next, we examined the relationship between greater adherence and improved clinical outcomes, finding that greater adherence was associated with greater reductions in glycated hemoglobin (HbA1c) levels. Findings from the pilot study suggest that mHealth technologies can help older adults improve their diabetes management, but a "one size fits all" approach may yield suboptimal outcomes.


Cardiac failure in children with pneumonia in Papua New Guinea.
Cardiac failure is suspected of contributing to mortality from pneumonia in children in developing countries, but its role has not been clearly defined. A convenience sample of 47 children admitted to Goroka Hospital in Papua New Guinea was studied prospectively with ultrasound, chest radiographs and assays of creatine kinase and lactate dehydrogenase. Results. Seven (15%) of the 47 children died. Of the 43 children who had a chest radiograph, 31 (72%) had severe or very severe pneumonia. No child had poor contractility of the heart on ultrasound examination or unequivocally raised cardiac isoenzymes; therefore no evidence of myocardial injury from sepsis was found. However, ultrasound examination showed dilatation of the right ventricle or hepatic veins in 12 (26%) of the children (both were dilated in 7 children) and 4 (33%) of these children died; this suggests that right ventricular cardiac failure secondary to pulmonary hypertension was present in 26% (95% confidence interval, 14 to 40%) of these children with severe pneumonia. Tachycardia was not associated with right ventricular dilatation on ultrasound, but 3 of the 4 children with more than 3 cm of liver palpable in the abdomen had right ventricular dilatation. Only 4 of the 12 children with right heart failure had hepatomegaly, tachycardia, raised jugular venous pressure or peripheral edema. Right ventricular failure is common in children with severe pneumonia, and it is probably caused by pulmonary hypertension rather than septic toxemia. The clinical signs of heart failure are unreliable. There is no evidence that digoxin is effective treatment for right ventricular failure secondary to pulmonary hypertension.


Combination of serum CST1 and HE4 for early diagnosis of endometrial cancer.
Optimal serological biomarkers have been absent for the early diagnosis of endometrial cancer, to date. In this study, we aimed to define the diagnostic performances of individual and combined detection of serum cysteine protease inhibitor 1 (CST1) with traditional tumor markers, including glycated antigen 125 (CA125) and human epididymis protein 4 (HE4), in patients with early-stage endometrial cancer (EC). The performances of individual and combined detection of serum CST1, HE4, and CA125 were evaluated by enzyme-linked immunosorbent assay (ELISA) and chemiluminescent immunoassay, respectively. A training data set of 67 patients with early EC, 67 patients with endometrial benign lesion (EBL), and 67 healthy controls (HC) was used to develop a predictive model for early EC diagnosis, which was validated by an independent validation data set. In the training data set, serum CST1 and HE4 levels in the early EC group were significantly higher than in EBL/HC groups (P < 0.05), while there was no significant difference of serum CA125 level between the early EC and EBL/HC groups (P > 0.05). Serum CST1 and HE4 exhibited areas under the curve (AUC) of 0.715 with 31.3% sensitivity at 90.3% specificity, and 0.706 with 23.9% sensitivity at 95.5% specificity, respectively. Combined detection of serum CST1 and HE4 exhibited an AUC of 0.788 with 49.3% sensitivity at 92.5% specificity. The combination of serum CST1 and HE4 showed promise in diagnosis. CST1 is a prospective serological biomarker for early EC diagnosis, and the combination of CST1 and HE4 contributes to the further improvement in the diagnosis of patients with early-stage EC.


Genetic variation in Hyperpolarization-activated cyclic nucleotide-gated channels and its relationship with neuroticism, cognition and risk of depression.
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are encoded by four genes (HCN1-4) and, through activation by cyclic AMP (cAMP), represent a point of convergence for several psychosis risk genes. On the basis of positive preliminary data, we sought to test whether genetic variation in HCN1-4 conferred risk of depression or cognitive impairment in the Generation Scotland: Scottish Family Health Study. HCN1, HCN2, HCN3, and HCN4 were genotyped for 43 haplotype-tagging SNPs and tested for association with DSM-IV depression, neuroticism, and a battery of cognitive tests assessing cognitive ability, memory, verbal fluency, and psychomotor performance. No association was found between any HCN channel gene SNP and risk of depression, neuroticism, or on any cognitive measure. The current study does not support a genetic role for HCN channels in conferring risk of depression or cognitive impairment in individuals from the Scottish population.


When a feature detector becomes a feature generator.
The neural network approach is reviewed in the context of studies in the animal and human visual systems. An attempt is made to explain perception, memory, and learning as a feedback loop similar to the one used in the ALOPEX optimization concept. Applications in pattern recognition and image processing are discussed. Experiments using visual evoked potentials in humans are described.


Comparison of agents producing a neutrophilic leukocytosis in man. Hydrocortisone, prednisone, endotoxin, and etiocholanolone.
To study the potential application of glucocorticosteroid administration for the measurement of the bone marrow neutrophil reserve response, blood neutrophil count changes were measured in normal subjects after the administration of intravenous hydrocortisone (25, 50, 100, 200, and 400 mg) and oral prednisone (5, 10, 20, 40, and 80 mg). The upper three doses of both steroids increased the blood neutrophil count by approximately 4,000 cells/mm3. The neutrophilia occurring after hydrocortisone (200 mg) and/or prednisone (40 mg) was compared with that observed after endotoxin (0.8 ng/kg) and etiocholanolone (0.1 mg/kg) in 14 normal subjects, 7 patients with Wegener's granulomatosis on cyclophosphamide therapy and 10 patients with chronic idiopathic neutropenia. The normal responses (mean increase of blood neutrophils/mm3 above base line +/- 1 SEM) were: hydrocortisone 4,220 +/- 320, prednisone 4,610 +/- 360, endotoxin 6,060 +/- 880, and etiocholanolone 3,780 +/- 440. In the patient studies, etiocholanolone gave the smallest mean responses, but, in general, the results were similar for all agents. These data indicate that these glucocorticosteroids can be used as equivalent agents to endotoxin and etiocholanolone for measuring the neutrophil reserve response.


The Solanum glaucophyllum Desf. extract reduces mineralized matrix synthesis in osteogenically differentiated rat mesenchymal stem cells in vitro.
The Solanum glaucophyllum Desf. has been used to treat and prevent diseases in human and veterinary medicine. On the other hand, plant poisoning causes several bone diseases, among them osteoporosis, which is characterized by osteoblastic hypoplasia. Because the osteoblast is a cell derived from the differentiation of mesenchymal stem cells (MSCs) from bone marrow, the hypothesis is that the plant reduces the osteogenic differentiation of MSCs. The objective of this study was to evaluate the effects of S. glaucophyllum Desf. extract on MSCs cultured in osteogenic differentiation medium. We determined by liquid chromatography that 1 ml of plant extract contained 3.8 μl of 1,25(OH)2 D3 (calcitriol). Four groups of MSCs cultivated in osteogenic medium were evaluated as follows: (a) treated with 100 μl of extract/L containing 0.4 μg/L of calcitriol; (b) treated with 1 ml of extract/L containing 4 μg/L of calcitriol; (c) treated with 5 ml of extract/L containing 20 μg/L of calcitriol; and (d) a control group without extract. We performed alkaline phosphatase activity assay, analysis of MTT conversion to formazan, and evaluated the percentage of cells, and number and diameter of mineralization nodules. The expression of gene transcripts for osteopontin, bone sialoprotein and BMP-2 was analysed by RT-qPCR. After 21 days, there was a significant reduction in MTT conversion to formazan in treated groups, of the cellularity in the group with 5 ml of extract/L, and in the number and size of mineralization nodules in the groups treated with 1 and 5 ml of extract/L. The 5 ml extract/L concentration also reduced transcript expression of osteopontin. It is concluded that S. glaucophyllum Desf. at concentrations of 1 and 5 ml extract/L reduced mineralized matrix synthesis in MSCs cultivated in osteogenic differentiation medium, which suggests that this is one of the mechanisms by which osteoporosis occurs in intoxicated animals.


Recent progess in phosphoinositide 3-kinases: oncogenic properties and prognostic and therapeutic implications.
Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that coordinate various fundamental cellular responses including mitogenic signaling, cell survival and proliferation, vesicular trafficking, cytoskeletal rearrangement and metabolism. Overexpression caused by genetic alterations such as the amplification or gain of copy numbers was frequently observed for various PI3Ks in different human cancers. In recent years, the high-frequency somatic mutations of PIK3CA observed in different human cancers further strengthen the notion that PI3Ks are optimal targets for therapeutic intervention. In this review, I summarize current experimental evidence about the transformation capability and oncogenic properties of different PIK3CA mutations identified in human cancers. I also discuss the association of PIK3CA mutations with other genetic markers, as well as the prognostic value of PIK3CA somatic mutations in human cancers. Finally, I discuss the application of PI3Ks as therapeutic targets in human cancers, including targeted and combinational therapies and the potential challenges that confront their clinical applications.


Investigation of modified graphene for energy storage applications.
Lithium-ion batteries (LIB) have been receiving extensive attention because of the high specific energy density for wide applications such as electronic vehicles, commercial mobile electronics, and military applications. In LIB, graphite is the most commonly used anode material; however, lithium-ion intercalation in graphite is limited, hindering the battery charge rate and capacity. To overcome this obstacle, nanostructured anode assembly has been extensively studied to increase the lithium-ion diffusion rate. Among these approaches, high specific surface area metal oxide nanowires connecting nanostructured carbon materials accumulation have shown propitious results for enhanced lithium intercalation. Recently, nanowire/graphene hybrids were developed for the enhancement of LIB performance; however, almost all previous efforts employed nanowires on graphene in a random fashion, which limited lithium-ion diffusion rate. Therefore, we demonstrate a new approach by hydrothermally growing uniform nanowires on graphene aerogel to further improve the performance. This nanowire/graphene aerogel hybrid not only uses the high surface area of the graphene aerogel but also increases the specific surface area for electrode-electrolyte interaction. Therefore, this new nanowire/graphene aerogel hybrid anode material could enhance the specific capacity and charge-discharge rate. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) are used for materials characterization. Battery analyzer and potentio-galvanostat are used for measuring the electrical performance of the battery. The testing results show that nanowire graphene hybrid anode gives significantly improved performance compared to graphene anode.


IAEA-HypoX. A randomized multicenter study of the hypoxic radiosensitizer nimorazole concomitant with accelerated radiotherapy in head and neck squamous cell carcinoma.
To test the hypothesis that radiotherapy (RT) of head and neck squamous cell carcinoma (HNSCC) can be improved by hypoxic modification using nimorazole (NIM) in association with accelerated fractionation. The protocol was activated in March 2012 as an international multicenter randomized trial in patients with HNSCC. Tumors were treated to a dose of 66-70Gy, 33-35 fractions, 6 fractions per week. NIM was administered in a dose of 1.2gperm(2), 90min before the first daily RT fraction. The primary endpoint was loco-regional failure. The trial was closed prematurely by June 2014 due to poor recruitment. An associated quality assurance program was performed to ensure the consistency of RT with the protocol guidelines. The trial was dimensioned to include 600 patients in 3years, but only 104 patients were randomized between March 2012 and May 2014 due to the inability to involve three major centers and the insufficient recruitment rate from the other participating centers. Twenty patients from two centers had to be excluded from the analysis due to the unavailability of the follow-up data. Among the remaining 84 patients, 82 patients were evaluable (39 and 43 patients in the RT+NIM and the RT-alone arms, respectively). The treatment compliance was good with only six patients not completing the full planned RT course, and 31 patients (79%) out of 39 allocated for NIM, achieving at least 90% of the prescribed drug dose. At the time of evaluation, 40 patients had failed to achieve persistent loco-regional tumor control, and a total of 45 patients had died. The use of NIM improved the loco-regional tumor control with an 18month post-randomization cumulative failure rate of 33% versus 51% in the control arm, yielding a risk difference of 18% (CI -3% to 39%; P=0.10). The corresponding values for overall death was 43% versus 62%, yielding a risk difference of 19% (CI -3% to 42%; P=0.10). Sixteen patients, out of 55 patients analyzed for hypoxic gene expression, were classified as having more hypoxic tumors. Such patients, if treated with RT alone, had a higher loco-regional tumor failure rate as compared to the rest of the patients with known hypoxic status (P=0.05). Although the trial was incomplete and suffered from a small number of patients, the results suggested an improvement in loco-regional tumor control and overall survival in patients with advanced HNSCC given the hypoxic modifier NIM in addition to accelerated fractionation RT. However, the trial also revealed that conducting multicenter and multinational study combining drug and RT in developing countries may suffer from uncontrolled and unsolvable problems.


Overlapping neural response to the pain or harm of people, animals, and nature.
Interpersonal pain perception is a fundamental and evolutionarily beneficial social process. While critical for navigating the social world, whether or not people rely on similar processes to perceive and respond to the harm of the non-human biological world remains largely unknown. Here we investigate whether neural reactivity toward the suffering of other people is distinct from or overlapping with the neural response to pain and harm inflicted upon non-human entities, specifically animals and nature. We used fMRI to measure neural activity while participants (n=15) perceived and reported how badly they felt for the pain or harm of humans, animals, and nature, relative to neutral situations. Neural regions associated with perceiving the pain of other people (e.g. dorsal anterior cingulate cortex, bilateral anterior insula) were similarly recruited when perceiving and responding to painful scenes across people, animals, and nature. These results suggest that similar brain responses are relied upon when perceiving the harm of social and non-social biological entities, broadly construed, and that activity within the dorsal anterior cingulate cortex and bilateral anterior insula in response to pain-relevant stimuli is not uniquely specific to humans.


[A renocolic fistula diagnosed by retrograde pyelography].
To describe a case of renocolic fistula diagnosed by retrograde pyelography. A case of renocolic fistula associated with pyonephrosis and left pleural empyema in a 48-year-old female with a history of recurrent pyelonephritis is presented. The ultrasound findings were suggestive of pyonephrosis and an excretory urogram showed a non-functioning left kidney. Retrograde pyelography showed passage of contrast medium into the descending colon. Surgical treatment consisted of nephrectomy, exteriorization of the compromised colon and pleurotomy. The patient died from septic shock. The utility of retrograde pyelography in the diagnosis of renocolic fistula is demonstrated in the case described herein.


Lyotropic anions. Na channel gating and Ca electrode response.
The effects of external anions on gating of Na channels of frog skeletal muscle were studied under voltage clamp. Anions reversibly shift the voltage dependence of peak sodium permeability and of steady state sodium inactivation towards more negative potentials in the sequence: methanesulfonate less than or equal to Cl- less than or equal to acetate less than Br- less than or equal to NO-3 less than or equal to SO2-4 less than benzenesulfonate less than SCN- less than ClO-4; approximately the lyotropic sequence. Voltage shifts are graded with mole fraction in mixtures and are roughly additive to calcium shifts. The peak PNa is not greatly affected. Except for SO2-4, these anions did not change the Ca++ activity of the solutions as measured with the dye murexide. Shifts of gating can be explained as the electrostatic effect of anion adsorption to the Na channel or to nearby lipid. Such adsorption is expected to follow the lyotropic series. Anions also interfere significantly with the response of a Ca-sensitive membrane electrode following the same sequence of effectiveness as the shifts of gating. The lyotropic anions decrease the Ca++ sensitivity and cause anomalously negative responses of the Ca electrode because these anions are somewhat permeant in the hydrophobic detector membrane.


Differentiating human bone from animal bone: a review of histological methods.
This review brings together a complex and extensive literature to address the question of whether it is possible to distinguish human from nonhuman bone using the histological appearance of cortical bone. The mammalian species included are rat, hare, badger, racoon dog, cat, dog, pig, cow, goat, sheep, deer, horse, water buffalo, bear, nonhuman primates, and human and are therefore not exhaustive, but cover those mammals that may contribute to a North American or Eurasian forensic assemblage. The review has demonstrated that differentiation of human from certain nonhuman species is possible, including small mammals exhibiting Haversian bone tissue and large mammals exhibiting plexiform bone tissue. Pig, cow, goat, sheep, horse, and water buffalo exhibit both plexiform and Haversian bone tissue and where only Haversian bone tissue exists in bone fragments, differentiation of these species from humans is not possible. Other primate Haversian bone tissue is also not distinguishable from humans. Where differentiation using Haversian bone tissue is undertaken, both the general microstructural appearance and measurements of histological structures should be applied. Haversian system diameter and Haversian canal diameter are the most optimal and diagnostic measurements to use. Haversian system density may be usefully applied to provide an upper and lower limit for humans.


Factors influencing functional outcome and discharge disposition after thoracic spinal cord injury.
The purpose of this retrospective study was to describe the relationships among level of injury, completeness of impairment, age, complexity of coexistent disease, functional outcomes, and discharge disposition in persons with traumatic thoracic spinal cord injury (SCI). The sample consisted of 41 persons with acute traumatic thoracic SCI discharged from a 48-bed rehabilitation unit between 1992 and 1997. Persons with complete SCI had significantly lower Functional Independence Measure scores than persons with incomplete SCI (p < .05). The effect of the completeness of injury did not persist to discharge FIM scores. Persons discharged to home without a home-health referral (HHR) had higher FIM scores than those discharged to home with one. Persons discharged to home with an HHR had higher FIM scores than those discharged to skilled nursing facility units, although these were not statistically significant. The findings of this study suggest that rehabilitation goals and discharge disposition planning for persons with traumatic thoracic SCI cannot be based on level and completeness of injury alone. The interdisciplinary team must understand the abilities, needs, and disposition of this population to develop rehabilitation goals and interventions that are feasible and realistic.


Intentions vs. resemblance: understanding pictures in typical development and autism.
Research has debated whether children reflect on artists' intentions when comprehending pictures, or instead derive meaning entirely from resemblance. We explore these hypotheses by comparing how typically developing toddlers and low-functioning children with autism (a population impaired in intentional reasoning) interpret abstract pictures. In Experiment 1, both groups mapped familiar object names onto abstract pictures, however, they related the same representations to different 3-D referents. Toddlers linked abstract pictures with intended referents they did not resemble, while children with autism mapped picture-referent relations based on resemblance. Experiment 2 showed that toddlers do not rely upon linguistic cues to determine intended referential relations. Experiment 3 confirmed that the responding of children with autism was not due to perseveration or associative word learning, and also provided independent evidence of their intention-reading difficulties. We argue that typically developing children derive meaning from the social-communicative intentions underlying pictures when resemblance is an inadequate cue to meaning. By contrast, children with autism do not reflect on artists' intentions and simply relate pictures to whatever they happen to resemble.


Studies on Ca channels in intact cardiac cells: voltage-dependent effects and cooperative interactions of dihydropyridine enantiomers.
We have investigated the effects of two oppositely acting enantiomers of the 1,4-dihydropyridine derivative 202-791 on voltage-dependent Ca channels by combining electrophysiological techniques and binding studies. The (S)-enantiomer of 202-791 promoting prolonged openings of single Ca channels, and thereby increasing transmembrane Ba currents, was classified as channel activator. The (R)-enantiomer favoring a closed state of the channel, and thereby reducing Ba currents, was classified as a channel blocker. Both compounds shifted the steady state current inactivation curve toward more negative potentials. At holding potentials positive to -20 mV, the Ca channel-activating effect of the (S)-enantiomer turned over into a blocking effect. In cells with normal resting potential the combination of the two enantiomers revealed a possible positive cooperative effect resulting in an enhancement of the open state probability of the channels. At depolarized holding potentials the activator enhanced the inhibitory effect of the blocker. Binding studies in intact cells were performed by using the radiolabeled channel-blocking dihydropyridine 3H-(+)-PN 200-110. The results showed a strong increase in binding affinity but no change in binding capacity when the cells were depolarized. Analysis of the interactions of (S)- and (R)-202-791 with this radioligand indicated stimulation of 3H-(+)-PN 200-110 binding by the (S)-enantiomer in polarized cells (membrane potential -38 +/- 4 mV). This effect could be attributed to an increase in binding affinity. The (R)-enantiomer had no such positive cooperative effect, but acted as a purely competitive ligand. Depolarization to 0 mV increased the apparent affinity of both enantiomers by factors of 38 (blocker) and 12 (activator), but abolished the cooperative effect of (S)-202-791 on the binding of the radioligand. Ca ions had little effect on the binding of 3H-(+)-PN 200-110 in polarized cells. However, in the presence of the activating (S)-enantiomer, Ca transformed the usual hyperbolic binding isotherm of the radioligand into a strongly sigmoid curve. Sigmoidicity was minimal with 3-5 microM Ca and maximal with 0.5 mM Ca. Together these data demonstrate homotropic and heterotropic cooperative interactions between channel activator and channel blocker. They indicate that at least two high affinity binding sites for dihydropyridines are associated with voltage-dependent Ca channels. Voltage dependence of both--binding affinity and cooperativity--suggests that these binding sites are located close to a structural component of the channel which is involved in the potential-sensitive gating process.


Fish oil regulates adiponectin secretion by a peroxisome proliferator-activated receptor-gamma-dependent mechanism in mice.
Adiponectin has insulin-sensitizing, antiatherogenic, and anti-inflammatory properties, but little is known about factors that regulate its secretion. To examine the effect of fish oil on adiponectin secretion, mice were fed either a control diet or isocaloric diets containing 27% safflower oil or 27, 13.5, and 8% menhaden fish oil. Within 15 days, fish oil feeding raised plasma adiponectin concentrations two- to threefold in a dose-dependent manner, and the concentrations remained approximately twofold higher for 7 days when the fish oil diet was replaced by the safflower oil diet. Within 24 h, fish oil markedly induced transcription of the adiponectin gene in epididymal adipose tissue but not in subcutaneous fat. The increase of plasma adiponectin by fish oil was completely blocked by administration of the peroxisome proliferator-activated receptor (PPAR)gamma inhibitor bisphenol-A-diglycidyl ether. In contrast, there was no effect of fish oil feeding on adiponectin secretion in PPARalpha-null mice. These data suggest that fish oil is a naturally occurring potent regulator of adiponectin secretion in vivo and that it does so through a PPARgamma-dependent and PPARalpha-independent manner in epididymal fat.


Tailoring the material properties of gelatin hydrogels by high energy electron irradiation.
Natural hydrogels such as gelatin are highly desirable biomaterials for application in drug delivery, biosensors, bioactuators and extracellular matrix components due to strong biocompatibility and biodegradability. Typically, chemical crosslinkers are used to optimize material properties, often introducing toxic byproducts into the material. In this present work, electron irradiation is employed as a reagent-free crosslinking technique to precisely tailor the viscoelasticity, swelling behavior, thermal stability and structure of gelatin. With increasing electron dose, changes in swelling behavior and rheology indicate increasing amounts of random coils and dangling ends as opposed to helical content, a result confirmed through Fourier transform infrared spectroscopy. Gel fraction, rheology and swelling measurements at 37 °C were used to verify thermal stability in biological conditions. Scanning electron microscopy images of dried gelatin samples support these conclusions by revealing a loss of free volume and apparent order in the fracture patterns. The degree of crosslinking and mesh size are quantified by rubber elasticity theory and the Flory-Rehner equation. Overall, precise control of material properties is demonstrated through the interplay of concentration and irradiation dose, while providing an extensive parameter-property database suitable for optimized synthesis.


Friends also matter: Examining friendship adjustment indices as moderators of anxious-withdrawal and trajectories of change in psychological maladjustment.
The present study evaluated whether 3 indices of friendship adjustment (mutual friendship involvement, friendship stability, friendship quality) are important, but overlooked, moderators of the impact of anxious-withdrawal on trajectories of psychological maladjustment during early adolescence. Participants included 271 young adolescents (51% boys; Mage = 11.83 years; 42% ethnic minority) who completed peer nomination and self-report measures at 3 waves in a longitudinal study. In line with hypotheses, growth curve analyses revealed that anxious-withdrawal predicted less negative psychological adjustment trajectories for friended young adolescents, albeit somewhat differently for boys and girls. Understanding the unique significance of friendships in the lives of anxious-withdrawn young adolescents could improve interventions as their friendships may be more successfully targeted than their group-level peer difficulties. (PsycINFO Database Record


Strategic Targeting of Multiple BMP Receptors Prevents Trauma-Induced Heterotopic Ossification.
Trauma-induced heterotopic ossification (tHO) is a condition of pathologic wound healing, defined by the progressive formation of ectopic bone in soft tissue following severe burns or trauma. Because previous studies have shown that genetic variants of HO, such as fibrodysplasia ossificans progressiva (FOP), are caused by hyperactivating mutations of the type I bone morphogenetic protein receptor (T1-BMPR) ACVR1/ALK2, studies evaluating therapies for HO have been directed primarily toward drugs for this specific receptor. However, patients with tHO do not carry known T1-BMPR mutations. Here we show that, although BMP signaling is required for tHO, no single T1-BMPR (ACVR1/ALK2, BMPR1a/ALK3, or BMPR1b/ALK6) alone is necessary for this disease, suggesting that these receptors have functional redundancy in the setting of tHO. By utilizing two different classes of BMP signaling inhibitors, we developed a translational approach to treatment, integrating treatment choice with existing diagnostic options. Our treatment paradigm balances either immediate therapy with reduced risk for adverse effects (Alk3-Fc) or delayed therapy with improved patient selection but greater risk for adverse effects (LDN-212854).