Working memory in spelling: Evidence from backward typing.
Theories of spelling (Margolin, 1984; Nolan & Caramazza, 1983) propose a working memory system for storing order and identity information of letters during the spelling process. Capacity limitations related to the use of such a graphemic buffer were explored. Participants had to type words backwards. Longer pauses between key presses were assumed to signal points at which graphemic buffer contents were refreshed. Five- and six-letter words were divided by a major pause into chunks of two and three letters, partly coinciding with syllables. Articulatory suppression had no effect on performance. Increasing the length of the stimuli to seven to eight letters resulted in major pauses occurring at syllable boundaries, and performance becoming vulnerable to articulatory suppression but not foot tapping. Forward typing resulted in a similar pause pattern. The results suggest that chunks of approximately three letters can be handled at any one time. For short words the task seems to rely on non-phonological modes of coding, whereas longer words appear to require the use of a phonological code, possibly for keeping track of progress through the word.


Morphological and mechanical determinants of cellular uptake of deformable nanoparticles.
Understanding the interactions of nanoparticles (NPs) with cell membranes and regulating their cellular uptake processes are of fundamental importance to the design of drug delivery systems with minimum toxicity, high efficiency and long circulation time. Employing the procedure of coarse-graining, we built an elastically deformable NP model with tunable morphological and mechanical properties. We found that the cellular uptake of deformable NPs depends on their shape: an increase in the particle elasticity significantly slows the uptake rate of spherical NPs, slightly retards that of prolate NPs, and promotes the uptake of oblate NPs. The intrinsic mechanisms have been carefully investigated through analysis of the endocytic mechanisms and free energy calculations. These findings provide unique insights into how deformable NPs penetrate across cell membranes and offer novel possibilities for designing effective NP-based carriers for drug delivery.


[Tuberculosis in Salvador, Bahia, Brazil, in the 1990s].
The characteristics of tuberculosis (TB) cases and deaths were analyzed in order to characterize the epidemiological profile of TB (incidence and mortality) in Salvador, Bahia, Brazil, in the 1990s. Annual incidence and mortality rates were calculated by gender, age bracket, and clinical forms of the disease using databases from the Tuberculosis Information System of the Bahia State Health Secretariat and the Mortality Information System of the Brazilian Ministry of Health. TB spatial distribution was analyzed according to health district. Cases and deaths were predominantly in males in the 15 to 39 year group. The pulmonary form showed the highest incidence and mortality. The existing data did not corroborate the hypothesis that AIDS/TB co-infection might contribute to maintaining the high mortality rates. The greater occurrence of tuberculosis in certain health districts may be associated with population density and unfavorable living conditions.


Delirium after surgical and transcatheter aortic valve replacement is associated with increased mortality.
The purpose of this study was to determine the incidence and clinical significance of postoperative delirium (PD) in patients with aortic stenosis undergoing surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR). Between 2010 and 2013, 427 patients underwent TAVR (n = 168) or SAVR (n = 259) and were screened for PD using the Confusion Assessment Method for the Intensive Care Unit. The incidence of PD in both treatment groups was determined and its association with morbidity and mortality was retrospectively compared. PD occurred in 135 patients (32%) with a similar incidence between SAVR (33% [86 out of 259]) and TAVR (29% [49 out of 168]) (P = .40). TAVR by transfemoral approach had the lowest incidence of PD compared with SAVR (18% vs 33%; P = .025) or TAVR when performed by alternative access techniques (18% vs 35%; P = .02). Delirium was associated with longer initial intensive care unit stay (70 vs 27 hours), intensive care unit readmission (10% [14 out of 135] vs 2% [6 out of 292]), and longer hospital stay (8 vs 6 days) (P < .001 for all). PD was associated with increased mortality at 30 days (7% vs 1%; P < .001) and 1 year (21% vs 8%; P < .001). After multivariable adjustment, PD remained associated with increased 1-year mortality (hazard ratio, 3.02; 95% confidence interval, 1.75-5.23; P < .001). There was no interaction between PD and aortic valve replacement approach with respect to 1-year mortality (P = .12). Among propensity-matched patients (n = 170), SAVR-treated patients had a higher incidence of PD than TAVR-treated patients (51% vs 29%; P = .004). PD occurs commonly after SAVR and TAVR and is associated with increased morbidity and mortality. Given the high incidence of PD and its associated adverse outcomes, further studies are needed to minimize PD and potentially improve patient outcomes.


The presence of D-fagomine in the human diet from buckwheat-based foodstuffs.
Buckwheat (Fagopyrum esculentum Moench) groats contain the iminosugar D-fagomine as a minor component that might contribute to the alleged health benefits of this pseudo-cereal. This study presents analysis of D-fagomine in buckwheat-based foodstuffs by liquid chromatography coupled to mass spectrometry and an estimation of its presence in the human diet based on a published population-based cross-sectional nutrition survey. D-fagomine is present in common buckwheat-based foodstuffs in amounts ranging from 1 to 25 mg/kg or mg/L, it is stable during boiling, baking, frying and fermentation, and it is biosynthesised upon sprouting. The estimated total intake of D-fagomine resulting from a diet that includes such foodstuffs would be between 3 and 17 mg per day (mean for both genders; range from P5 to P95). A diet rich in buckwheat products would provide a daily amount of D-fagomine that may in part explain the beneficial properties traditionally attributed to buckwheat consumption.


Identification of novel human GH-1 gene polymorphisms that are associated with growth hormone secretion and height.
Height, which is partially determined by GH secretion, is genetically influenced. The purpose of this study was to identify polymorphisms in the GH-1 gene, which are associated with altered GH production. The subjects included prepubertal short children with GH insufficiency without gross pituitary abnormalities (n = 43), short children with normal GH secretion (n = 46), and normal adults (n = 294). A polymorphism in intron 4 (P-1, A or T at base 1663) was identified. Two additional polymorphic sites (P-2, T or G at base 218, and P-3, G or T at base 439) in the promoter region of the GH-1 gene were also identified and matched with the P-1 polymorphism (A or T, respectively) in more than 90% of the subjects. P-1, P-2, and P-3 were considered to be associated with GH production, and the results of P-2 are explained as a representative in this abstract. For example, the allele frequency of T at P-2 in prepubertal short children with GH insufficiency without gross pituitary abnormalities (58.1%) was significantly different from that in short children with normal GH secretion and normal adults (37.0% and 43.5%, respectively; P < 0.001). Furthermore, significant differences were observed in maximal GH peaks in provocative tests (11.1 vs. 18.2 ng/mL, P = 0.006), insulin-like growth factor I SD scores (SDS) (-2.4 vs. -0.8, P < 0.0001), and height (Ht) SDS (-3.7 vs. -3.0, P = 0/001) in children with the T/T or G/G genotypes at P-2, respectively. In the entire study group, significant differences in insulin-like growth factor SDS (T/T, -0.9; G/G, -0.2; P = 0.0009) and Ht SDS (T/T, -1.0; G/G, -0.4; P = 0.022) were observed between the T/T and G/G genotypes at P-2. These data indicate that GH secretion is partially determined by polymorphisms in the GH-1 gene, which explain some of the variations in GH secretion and Ht.


Improving pregnant women's diet and physical activity behaviours: the emergent role of health identity.
Women who gain too much weight in pregnancy are at increased risk of disease and of having children with increased risk. Interventions to improve health behaviours are usually designed for a general population of pregnant women, and trial outcomes show an average impact that does not represent the differences between individuals. To inform the development of future interventions, this study explored the factors that influenced women's diet and physical activity during pregnancy and aimed to identify the needs of these women with regards to lifestyle support. Women who completed a trial of vitamin D supplementation and nurse support in pregnancy were invited to take part in an interview. Seventeen women were interviewed about their lifestyles during pregnancy, the support they had, and the support they wanted. Interview transcripts were coded thematically and analysed to understand the factors that influenced the diets and physical activity levels of these women and their engagement with resources that could provide support. Women identified barriers to eating well or being physically active, and pregnancy-specific issues like nausea and pain were common. Women's interest in maintaining a healthy lifestyle and their engagement with lifestyle support was related to the extent to which they self-identified as healthy people. Health-disengaged women were disinterested in talking about their lifestyles while health-focused women did not feel that they needed extra support. Women between these ends of the 'health identity' spectrum were interested in improving their health, and were able to identify barriers as well as sources of support. Lifestyle interventions in pregnancy should be adapted to meet the needs of individuals with different health identities, and encouraging a change in health identity may be one way of supporting sustained change in health behaviours.


Stromal Clues in Endometrial Carcinoma: Loss of Expression of β-Catenin, Epithelial-Mesenchymal Transition Regulators, and Estrogen-Progesterone Receptor.
Epithelial-stroma interactions in the endometrium are known to be responsible for physiological functions and emergence of several pathologic lesions. Periglandular stromal cells act on endometrial cells in a paracrine manner through sex hormones. In this study, we immunohistochemically evaluated the expression of epithelial-mesenchymal transition regulators (SNAIL/SLUG, TWIST, ZEB1), adhesion molecules (β-catenin and E-cadhenin), estrogen (ER)-progesterone (PR) receptor and their correlation with each other in 30 benign, 148 hyperplastic (EH), and 101 endometrioid-type endometrial carcinoma (EC) endometria. In the epithelial component, loss of expression in E-cadherin, ER and PR, and overexpression of TWIST and ZEB1 were significantly higher in EC than in EH (P<0.01). In the periglandular stromal component, β-catenin and SNAIL/SLUG expression were significantly higher in normal endometrium and simple without atypical EH compared with complex atypical EH and EC (P<0.01). In addition, periglandular stromal TWIST expression was significantly higher in EH group compared with EC (P<0.05). There was significantly negative correlation between β-catenin and ER, TWIST and ER, and TWIST and PR in hyperplastic and carcinomatous glandular epithelium, whereas there was a significantly positive correlation between β-catenin and SNAIL-SLUG, β-catenin and TWIST, β-catenin and ER, β-catenin and PR, SNAIL-SLUG and ER, SNAIL-SLUG and PR, TWIST and ER, TWIST and PR, in periglandular/cancer-associated stromal cells (P<0.01). In conclusion, the pattern of positive and negative correlations in the expression of epithelial-mesenchymal transition regulators (SNAIL-SLUG and TWIST), sex hormone receptors (ER and PR), and β-catenin between ECs and hyperplasia, as well as between epithelium and stroma herein, is suggestive of a significant role for these proteins and their underlying molecular processes in the development of endometrial carcinomas.


Life style intervention in moderately overweight individuals is associated with decreased levels of cathepsins L and S in plasma.
Adipose tissue cells produce cathepsins L and S, which have proatherogenic effects. Obesity is strongly linked to atherogenesis, cardiovascular morbidity, and mortality. The aim of the present study was to see if life style interventions/weight reduction could decrease cathepsin L and S levels in blood plasma. Study subjects (n=31) were recruited to a life style intervention program aiming at increased physical activity, more healthy eating habits, and weight reduction for most of the participants. Blood samples were collected at inclusion and after 4 and 8 weeks. Cathepsin L was significantly reduced at 4 weeks (p<0.0001) and 8 weeks (p=0.0004). A similar reduction was also seen for cathepsin S at 4 weeks (p=0.03) and 8 weeks (p=0.008). No significant change in fractalkine values was observed at 4 weeks (p=0.58), but a significant increase was apparent at 8 weeks (p=0.0002). The intervention program resulted in significant reductions of cathepsin L and S levels in plasma after 4 and 8 weeks of intervention.


Fidaxomicin for the treatment of Clostridium difficile infections.
To evaluate the pharmacology, microbiology, safety, and efficacy of fidaxomicin for treatment of Clostridium difficile infections (CDI). Literature was identified through Ovid MEDLINE (1948-December 2011) and International Pharmaceutical Abstracts (1970-December 2011) using the search terms fidaxomicin, OPT-80, PAR-101, OP-118, difimicin, tiacumicin, lipiarmycin, Clostridium difficile, Clostridium difficile infection, Clostridium difficile-associated diarrhea, and cost. Drug monographs were retrieved from manufacturers' Web pages, and the Red Book component of Micromedex was used for cost information. All pertinent Phase 1, 2, and 3 studies published in English were included. Fidaxomicin is a macrocyclic compound bactericidal against C. difficile and inhibits toxin and spore production. It has poor oral absorption with high fecal concentrations. Available Phase 2 and 3 data with fidaxomicin 200 mg orally every 12 hours demonstrate similar effectiveness in treating CDI compared to oral vancomycin. Fidaxomicin was shown to have less frequency of recurrent infections. Adverse effects are uncommon and occur at similar rates as with oral vancomycin. The most frequently reported adverse effects are gastrointestinal, hematologic, and electrolyte disorders. Available data are lacking in several areas, including the efficacy and safety of fidaxomicin compared to established regimens for mild-to-moderate, life-threatening, and recurrent CDIs. The cost of a 10-day course of fidaxomicin is significantly more than that of metronidazole and vancomycin for treatment of mild-to-moderate CDI. Fidaxomicin appears to be an effective and safe alternative to oral vancomycin for treatment of mild-to-moderate and severe CDI. Data on its use compared to guideline-recommended therapies for mild-to-moderate and life-threatening CDI are needed. Further data assessing the cost-effectiveness of fidaxomicin are needed. Currently, it cannot be recommended over vancomycin for treatment of CDI. However, it may be considered for treatment of recurrent infections.


Gender differences in work performance on the Baltimore Therapeutic Equipment work simulator.
The purposes of this study were to (a) establish biomechanical and physiological normative data for healthy young women performing three tasks on the Baltimore Therapeutic Equipment work simulator (BTE): wheel-turn, push-pull, and overhead-reach; and (b) compare these data with previously reported values for healthy men of a similar age group. Twenty women completed five test sessions: (a) task familiarization on the BTE to determine the work intensity that was perceived as hard on the Borg scale, (b) incremental test on an arm crank ergometer to measure peak oxygen uptake (VO2) and peak heart rate (HR), and (c) one of the three tasks in random order for 4 min during the next three sessions. Physiological responses were monitored with a metabolic cart interfaced with an electrocardiogram. Torque, work, and power during the three tasks were significantly higher (p < .05) in men than in women. The absolute VO2 (L.min-1) during these tasks was higher in men, but when the VO2 was calculated relative to body weight (ml.kg-1.min-1), no significant (p > .05) gender differences were observed. Computation of energy expenditure relative to body weight and power output (cal.kg-1.W-1) indicated that women expended significantly (p < .05) more energy than men. No significant (p > .05) gender differences were observed for VO2 and HR when the values were expressed as a percentage of their respective peaks. Findings indicated that (a) the functional work capacity is significantly lower in women than in men, (b) women are less efficient than men when the energy expenditure is expressed per unit of body weight and power output, and (c) the relative physiological stress in men and women is similar under these conditions.


[Use of Solid Intercalary Allografts for Reconstruction Following the Resection of Primary Bone Tumors].
PURPOSE OF THE STUDY There are several treatment options for bone tumors at diaphyseal/metadiaphyseal sites of long bones (with joint preservation) including massive intercalary allografts, autografts (vascularized or non-vascularized fibular autograft, devitalised tumor bearing bone), endoprosthetic replacement (intercalary spacer), cementoplasty with ostheosynthesis and distraction osteogenesis. Reconstruction using massive intercalary bone allografts is for us the method of choice in case of curable primary bone tumors at the diaphyseal/metadiaphyseal region. The purpose of this study is to evaluate our results and complications. MATERIAL AND METHODS Our retrospective study reviewed 41 patients after intercalary allograft reconstruction following the resection of primary bone tumors in the years 2000 - 2014. The group consists of 27 men and 14 women with the mean age at the time of diagnosis 27 years and the mean follow-up (from primary surgery) was 7 years. The patients were diagnosed with the Ewing sarcoma (14), chondrosarcoma (9), osteosarcoma (8), adamantinoma (6), OFD-like adamantinoma (2) and aneurysmatic bone cyst (2). The site of tumor were tibia (18), femur (16), humerus (5), radius (1) and ulna (1). We retrospectively evaluated the results of this intercallary allograft reconstructions, the incidence of failures and complications as well as the role of risk factors. RESULTS 14 patients (34.1%) successfully healed without complications. In the same number of patients (14 patients, 34.1%) the allograft reconstruction failed. 7 of these patients underwent amputation (17.1%), 6 of whom for oncological complications (local recurrence) and only 1 for complications of the reconstruction (infection). Other 7 patients with an allograft-related failure were successfully treated with a limb salvage procedure and underwent a new reconstruction. The remaining 13 patients (31.7%) suffered from complications that did not result in a failure of the reconstruction. The major complications of the reconstruction were the non-union (53.7%), fractures and allograft resorption (14.6%) and infection (7.3%). By statistical evaluation of common risk factors a statistically significant relationship was found between uncomplicated healing and stable bridging osteosynthesis (p = 0.014), between allograft fractures/resorptions and non-bridging osteosynthesis (p = 0.018), and the lowest reoperation rate was connected with plate osteosynthesis (0.037). DISCUSSION AND CONCLUSIONS The intercalary allograft reconstruction is an important biological method in orthopaedic tumor surgery. Even though it is connected with a high rate of complications (non-union, fracture and resorption, infection), in the vast majority of cases they can be solved, while achieving limb-salvage and good function of extremity. The essential prerequisite for successful uncomplicated healing of reconstruction is the stable bridging osteosynthesis, preferably with a plate. In high risk patients with a combination of recognized important risk factors described in literature (adult patients, large resection (more than 15 cm), femoral location and aggressive oncological treatment) we nowadays try to reduce the complication rate with a primary combination of an allograft with vascularized fibular autograft. Key words:biological bone reconstruction, massive intercallary allograft, stable bridging osteosynthesis, primary bone tumors.


Pattern, Timing and Survival in Patients with Recurrent Gastric Cancer.
The aim of this study was to investigate the recurrence patterns, the timing of recurrence, and the survival rate in recurrent cases of gastric cancer. Of 1,029 patients who underwent curative resection for gastric cancer at the Department of Surgery, Korea University Guro Hospital between 2000 and 2006, 146 patients developed recurrence and were included in this study. Timing and patterns of recurrence, the recurrence pattern according to clinicopathological factors, and post-recurrence survival rate were analyzed retrospectively. The mean time to recurrence was 21.2 months. Forty-two patients (28.8%) had recurrence within 1 year, and 54 patients (37.0%) had recurrence 1-2 years after surgery. Single-site recurrence occurred in 72.6% of patients, and multiple-site recurrence in 27.4%. The most frequent pattern of recurrence was peritoneal recurrence in 39.7% of patients, hematogeneous in 24.7%, locoregional in 18.5%, and to a distant lymph node in 17.1%. In cases that showed recurrence within 1 year, the most frequent pattern of recurrence was hematogeneous recurrence, while it was peritoneal in the group with recurrence between 1 and 2 years after surgery. Patterns of recurrence significantly differed according to the sex and gross tumor morphology. The mean post-recurrence survival time was 15.7 months. There was no statistically significant difference in the post-recurrence survival time according to the pattern of recurrence. The most frequent pattern of recurrence was peritoneal recurrence, and recurrence most often occurred within 2 years after curative resection. There was no significant difference in post-recurrence survival time according to the pattern of recurrence.


KCNQ channels in nociceptive cold-sensing trigeminal ganglion neurons as therapeutic targets for treating orofacial cold hyperalgesia.
Hyperexcitability of nociceptive afferent fibers is an underlying mechanism of neuropathic pain and ion channels involved in neuronal excitability are potentially therapeutic targets. KCNQ channels, a subfamily of voltage-gated K(+) channels mediating M-currents, play a key role in neuronal excitability. It is unknown whether KCNQ channels are involved in the excitability of nociceptive cold-sensing trigeminal afferent fibers and if so, whether they are therapeutic targets for orofacial cold hyperalgesia, an intractable trigeminal neuropathic pain. Patch-clamp recording technique was used to study M-currents and neuronal excitability of cold-sensing trigeminal ganglion neurons. Orofacial operant behavioral assessment was performed in animals with trigeminal neuropathic pain induced by oxaliplatin or by infraorbital nerve chronic constrictive injury. We showed that KCNQ channels were expressed on and mediated M-currents in rat nociceptive cold-sensing trigeminal ganglion (TG) neurons. The channels were involved in setting both resting membrane potentials and rheobase for firing action potentials in these cold-sensing TG neurons. Inhibition of KCNQ channels by linopirdine significantly decreased resting membrane potentials and the rheobase of these TG neurons. Linopirdine directly induced orofacial cold hyperalgesia when the KCNQ inhibitor was subcutaneously injected into rat orofacial regions. On the other hand, retigabine, a KCNQ channel potentiator, suppressed the excitability of nociceptive cold-sensing TG neurons. We further determined whether KCNQ channel could be a therapeutic target for orofacial cold hyperalgesia. Orofacial cold hyperalgesia was induced in rats either by the administration of oxaliplatin or by infraorbital nerve chronic constrictive injury. Using the orofacial operant test, we showed that retigabine dose-dependently alleviated orofacial cold hyperalgesia in both animal models. Taken together, these findings indicate that KCNQ channel plays a significant role in controlling cold sensitivity and is a therapeutic target for alleviating trigeminal neuropathic pain that manifests orofacial cold hyperalgesia.


Radioimmunoassay of oxytocin.
The evaluation of a radioimmunoassay of oxytocin is described. The method involved careful collection and transportation of blood at 4 degrees C, acidification of the plasma, extraction with Fuller's earth and radioimmunoassay using antisera raised in rabbits immunized against oxytocin conjugated to bovine serum albumin and 125I-labelled oxytocin. The antisera showed insignificant cross-reaction with a variety of small peptides including vasopressin and vasotocin. The limit of detection of the assay was 2.5 pg with intra-assay and interassay coefficients of variation of 7-15% and 12-18% respectively. Seventy-seven per cent (88 out of 116) of the pregnant women tested had detectable maternal plasma oxytocin. Serial samples of maternal plasma showed a significant increase in oxytocin from the first to the second stage of labour and a significant decrease in the third stage. Oxytocin concentrations in the umbilical arterial plasma were significantly higher in patients in labour. The significance of these findings is discussed.


Neighbourhood vitality and physical activity among the elderly: The role of walkable environments on active ageing in Barcelona, Spain.
This study investigated whether neighbourhood vitality and walkability were associated with active ageing of the elderly. Immobility, activity engagement and physical activity were explored in relation with age, gender and walkability of the built environment. Number of trips per day and minutes spent on walking by the elderly were extracted from a broad travel survey with more than 12,000 CATI interviews and were compared across vital and non-vital urban environments. Results highlight the importance of vital environments for elderly active mobility as subpopulations residing in highly walkable neighbourhoods undertook more trips and spent more minutes walking than their counterparts. The results also suggest that the built environment has different effects in terms of gender, as elderly men were more susceptible to urban vitality than elderly women.


Beyond an Open Future.
Discussions about the ethical permissibility of pediatric cognitive enhancement frequently revolve around arguments about welfare, and often include an appeal to the child's right to an open future. Both proponents and opponents of cognitive enhancement claim that their respective positions best serve the interests of the child by promoting an open future. This article argues that this right to an open future argument only captures some of the risks to the welfare of children, therefore requiring a broader ethical approach. Further, it suggests that a thorough moral assessment of the ends pursued is needed before concluding on the moral permissibility of cognitive enhancement in children, which ultimately hinges on the effect on the overall welfare of the child, beyond an open future.


Comparative mitogenomic analysis of three species of periwinkles: Littorina fabalis, L. obtusata and L. saxatilis.
The flat periwinkles, Littorina fabalis and L. obtusata, offer an interesting system for local adaptation and ecological speciation studies. In order to provide genomic resources for these species, we sequenced their mitogenomes together with that of the rough periwinkle L. saxatilis by means of next-generation sequencing technologies. The three mitogenomes present the typical repertoire of 13 protein-coding genes, 22 transfer RNA genes, two ribosomal RNA genes and a putative control region. Although the latter could not be fully recovered in flat periwinkles using short-reads due to a highly repetitive fragment, in L. saxatilis this problem was overcome with additional long-reads and we were able to assemble the complete mitogenome. Both gene order and nucleotide composition are similar between the three species as well as compared to other Littorinimorpha. A large variance in divergence was observed across mitochondrial regions, with six- to ten-fold difference between the highest and the lowest divergence rates. Based on nucleotide changes on the whole molecule and assuming a molecular clock, L. fabalis and L. obtusata started to diverge around 0.8 Mya (0.4-1.1 Mya). The evolution of the mitochondrial protein-coding genes in the three Littorina species appears mainly influenced by purifying selection as revealed by phylogenetic tests based on dN/dS ratios that did not detect any evidence for positive selection, although some caution is required given the limited power of the dataset and the implemented approaches.


Chemosensitivity in primary liver cancers: evaluation of the correlation between chemosensitivity and clinicopathological factors.
The aim of this study is to investigate the correlation of the chemosensitivity of primary liver cancers and the clinicopathological factors. The correlation of the chemosensitivity was investigated along with the associated clinicopathological factors, using 229 cases with hepatocellular carcinoma (HCC) and 8 with cholangiocellular carcinoma (CCC), ,who all underwent hepatic resection. Chemosensitivity was determined by a succinate dehydrogenase inhibition assay. The overall rate of chemosensitivity among the HCCs was as follows: 34.8% to adriamycin, 40.5% to mitomycin C, 38.2% to cisplatin, respectively, while the resistant rate to all drugs tested was 50.9%. The chemoresistant rate of the HCCs with hepatitis C tended to be higher (62%) than that of the HCCs with hepatitis B (50%). In the HCCs, there was no definite correlation between the chemosensitivity to each drug and the histological findings, while there seemed to be a positive correlation between the chemoresistant rate and the poor prognostic risk factors, such as vascular invasion and intrahepatic metastasis. In CCCs, the chemoresistant rate to all drugs tested was 77.7%, moreover, both the age and the CA 19-9 level in the chemosensitive group were significantly higher than those in the chemoresistant group. HCC with hepatitis C, as well as the higher degree of malignant potentials such as vascular invasion, intrahepatic metastasis and poor differentiation tended to be resistant to all 3 drugs tested. CCC was also highly resistant to all 3 drugs tested. For such resistant tumors, the drug-resistant mechanism urgently needs to be identified as soon as possible.


Isolation and developmental characterization of cerebral cortical multipotent progenitors.
Multipotent neural progenitor species present within developing and adult periventricular generative zones can give rise to all of the major cellular elements of the brain. Although lineage specification during development has been thought to be restricted to these generative zones, we have utilized quantitative immunoselection techniques to isolate an enriched population of multipotent neural progenitor cells that express polysialylated neural cell adhesion molecule (PSA-NCAM) from postnatal day 2 cerebral cortex independent of generative zones. This population of cerebral cortical progenitor cells exhibited robust proliferation in response to epidermal growth factor and subsequently gave rise to clonally derived neurons, astrocytes, and oligodendrocytes. Quantitative regional analysis further demonstrated that while the multipotent cells derived from the cerebral cortex uniformly expressed PSA-NCAM, multipotent cells derived from generative zones contained equal proportions of PSA-NCAM-positive and -negative multipotent progenitor cells. The generation of individual cellular lineages from cortical multipotent progenitors could be enhanced by specific cytokines that are expressed within the cerebral cortex. Further, while oligodendroglial progenitor cells derived from cortical multipotent progenitors exhibited responsiveness to platelet-derived growth factor (PDGF) and neurotrophin-3 (NT-3), primary cultures of cortical oligodendroglial progenitors were responsive to PDGF but not to NT-3. These observations suggest that in addition to glial progenitors that commit to a specific lineage prior to migration from generative zones, there is within the cerebral cortex a separate pool of multipotent cells that are capable of generating mature glial progeny in response to specific environmental cues. Therapeutic interventions aimed at differentiation of endogenous cerebral pools of multipotent progenitors may provide a novel strategy for amelioration of the sequelae of environmental and genetic insults to the postnatal cerebrum.


Photochemical incorporation of silver quantum dots in monodisperse silica colloids for photonic crystal applications.
We developed a novel method to fabricate nanocomposite monodisperse SiO2 spheres (approximately 100 nm) containing homogeneously dispersed Ag quantum dots (approximately 2 to 5 nm). The inclusion morphology is controlled through the timing of the photochemical reduction of silver ions during hydrolysis of tetraethoxysilane in a microemulsion. Depending on the timing, Ag quantum dots can be directed to different annuli within the SiO2 spheres, as well as onto the SiO2 sphere surfaces. The embedded Ag quantum dots show a plasmon resonance absorption band at 438 nm. These Ag@SiO2 particles have significant surface charge and readily self-assemble into crystalline colloidal array (CCA) photonic crystals which Bragg-diffract light in the visible region. The magnitude of the plasmon resonance absorption depends on the CCA Bragg diffraction condition. The negative dielectric constant of the silver nanoparticles may be decreasing the silica-silver nanodot composite refractive index below that of the water medium. We may be observing an analogue of the Borrmann effect previously observed in X-ray scattering, where the incident and diffracted electric field standing wave becomes localized in regions of small CCA crystal absorption.


Prior Percutaneous Coronary Interventions May Be Associated With Increased Mortality After Coronary Bypass Grafting: A Meta-Analysis.
There is conflicting evidence for adverse outcomes after coronary artery bypass surgery (CABG) with prior percutaneous intervention (PCI). A literature search was performed from 1998 to 2017 and articles with primary or secondary outcomes of survival, major adverse cardiovascular events (MACE), and myocardial infarction in CABG patients with prior PCI were included. Forest plots were generated from odds ratios for survival, MACE, and myocardial infarction for unmatched and propensity-matched data. Heterogeneity between studies was assessed for all outcomes using I2. Funnel plots were generated for early survival, survival at 5 years, survival at >5 years, and MACE. Thirty-one studies were included over 18 years with 194,544 patients without PCI prior to CABG and 23,519 patients (12.09%) with prior PCI. Prior PCI did not adversely affect survival among the included studies (inverse rate ratio: 1.12, 95% confidence interval: 0.98-1.27, P = 0.110. MACE was significantly worse for those with prior PCI (odds ratio: 1.26, confidence interval: 1.02-1.55, P = 0.03). The relative risk of mortality associated with prior PCI has decreased significantly over the last 2 decades. Studies with higher percentage of prior PCI patients had higher relative mortalities. There was significant heterogeneity between studies for the treatment effects. PCI prior to CABG in recent times does not adversely affect survival despite adverse early and late MACE rates. However, high institutional rates of prior PCI may be associated with increasing mortality after CABG.


Effect of Comorbidity on Lung Cancer Diagnosis Timing and Mortality: A Nationwide Population-Based Cohort Study in Taiwan.
The effect of comorbidity on lung cancer patients' survival has been widely reported. The aim of this study was to investigate the effects of comorbidity on the establishment of the diagnosis of lung cancer and survival in lung cancer patients in Taiwan by using a nationwide population-based study design. This study collected various comorbidity patients and analyzed data regarding the lung cancer diagnosis and survival during a 16-year follow-up period (1995-2010). In total, 101,776 lung cancer patients were included, comprising 44,770 with and 57,006 without comorbidity. The Kaplan-Meier analyses were used to compare overall survival between lung cancer patients with and without comorbidity. In our cohort, chronic bronchitis patients who developed lung cancer had the lowest overall survival in one (45%), five (28.6%), and ten years (26.2%) since lung cancer diagnosis. Among lung cancer patients with nonpulmonary comorbidities, patients with hypertension had the lowest overall survival in one (47.9%), five (30.5%), and ten (28.2%) years since lung cancer diagnosis. In 2010, patients with and without comorbidity had 14.86 and 9.31 clinical visits, respectively. Lung cancer patients with preexisting comorbidity had higher frequency of physician visits. The presence of comorbid conditions was associated with early diagnosis of lung cancer.


Hemispheric black carbon increase after the 13th-century Māori arrival in New Zealand.
New Zealand was among the last habitable places on earth to be colonized by humans1. Charcoal records indicate that wildfires were rare prior to colonization and widespread following the 13th- to 14th-century Māori settlement2, but the precise timing and magnitude of associated biomass-burning emissions are unknown1,3, as are effects on light-absorbing black carbon aerosol concentrations over the pristine Southern Ocean and Antarctica4. Here we used an array of well-dated Antarctic ice-core records to show that while black carbon deposition rates were stable over continental Antarctica during the past two millennia, they were approximately threefold higher over the northern Antarctic Peninsula during the past 700 years. Aerosol modelling5 demonstrates that the observed deposition could result only from increased emissions poleward of 40° S-implicating fires in Tasmania, New Zealand and Patagonia-but only New Zealand palaeofire records indicate coincident increases. Rapid deposition increases started in 1297 (±30 s.d.) in the northern Antarctic Peninsula, consistent with the late 13th-century Māori settlement and New Zealand black carbon emissions of 36 (±21 2 s.d.) Gg y-1 during peak deposition in the 16th century. While charcoal and pollen records suggest earlier, climate-modulated burning in Tasmania and southern Patagonia6,7, deposition in Antarctica shows that black carbon emissions from burning in New Zealand dwarfed other preindustrial emissions in these regions during the past 2,000 years, providing clear evidence of large-scale environmental effects associated with early human activities across the remote Southern Hemisphere.


Development of human hepatocellular carcinoma in X-linked severe combined immunodeficient pigs: An orthotopic xenograft model.
Hepatocellular carcinoma (HCC) is the fifth most common primary tumor and the third leading cause of cancer-related deaths worldwide. Rodent models of HCC have contributed to the advancement of studies investigating liver carcinogenesis, tumor-host interactions, and drug screening. However, their small size renders them unsuitable for surgical or clinical imaging studies, necessitating the development of larger-size HCC models. Here, we developed a xenograft model of human HCC in X-linked interleukin-2 receptor gamma chain gene (Il2rg)-targeted severe combined immunodeficient (SCID) pigs. HepG2 cell suspension in serum-free medium containing 50% membrane matrix was directly injected into the liver parenchyma of eight X-linked Il2rg-targeted SCID pigs (6.6-15.6 kg) via ultrasonography-guided percutaneous puncture. Tumor engraftment was evaluated weekly using ultrasonography, and cone-beam computed tomography was performed during arterial portography (CTAP) and hepatic arteriography (CTHA) to evaluate the hemodynamics of engrafted tumors. The engrafted tumors were histologically analyzed following necropsy and assessed for pathological similarities to human HCCs. Macroscopic tumor formation was observed in seven of the eight pigs (simple nodular tumors in three and multinodular tumors in four). Engrafted tumors were identified as low-echoic upon ultrasonography and as perfusion-defect nodules on the CTAP images. Meanwhile, CTHA showed that the tumors were hyperattenuating. Further, histopathological findings of the engrafted tumors were consistent with those of human HCC. In conclusion, the porcine model of human HCC, successfully generated herein, might help develop more effective therapeutic strategies for HCC.


Common determinants of body size and eye size in chickens from an advanced intercross line.
Myopia development is characterised by an increased axial eye length. Therefore, identifying factors that influence eye size may provide new insights into the aetiology of myopia. In humans, axial length is positively correlated to height and weight, and in mice, eye weight is positively correlated with body weight. The purpose of this study was to examine the relationship between eye size and body size in chickens from a genetic cross in which alleles with major effects on eye and body size were segregating. Chickens from a cross between a layer line (small body size and eye size) and a broiler line (large body and eye size) were interbred for 10 generations so that alleles for eye and body size would have the chance to segregate independently. At 3 weeks of age, 510 chicks were assessed using in vivo high resolution A-scan ultrasonography and keratometry. Equatorial eye diameter and eye weight were measured after enucleation. The variations in eye size parameters that could be explained by body weight (BW), body length (BL), head width (HW) and sex were examined using multiple linear regression. It was found that BW, BL and HW and sex together predicted 51-56% of the variation in eye weight, axial length, corneal radius, and equatorial eye diameter. By contrast, the same variables predicted only 22% of the variation in lens thickness. After adjusting for sex, the three body size parameters predicted 45-49% of the variation in eye weight, axial length, corneal radius, and eye diameter, but only 0.4% of the variation in lens thickness. In conclusion, about half of the variation in eye size in the chickens of this broiler-layer advanced intercross line is likely to be determined by pleiotropic genes that also influence body size. Thus, mapping the quantitative trait loci (QTL) that determine body size may be useful in understanding the genetic determination of eye size (a logical inference of this result is that the 20 or more genetic variants that have recently been shown to influence human height may also be found to influence axial eye length). Furthermore, adjusting for body size will be essential in mapping pure eye size QTL in this chicken population, and may also have value in mapping eye size QTL in humans.


Differential regulation of hepatic organic cation transporter 1, organic anion-transporting polypeptide 1a4, bile-salt export pump, and multidrug resistance-associated protein 2 transporter expression in lymphocyte-deficient mice associates with interleukin-6 production.
Cholestasis results from interrupted bile flow and is associated with immune-mediated liver diseases. It is unclear how inflammation contributes to cholestasis. The aim of this study was to determine whether T and B cells contribute to hepatic transporter expression under basal and inflammatory conditions. C57BL/6J wild-type mice or strains lacking T, B, or both T and B cells were exposed to lipopolysaccharide (LPS) or saline, and livers were collected 16 hours later. Branched DNA signal amplification was used to assess mRNA levels of organic anion-transporting polypeptides (Oatp) 1a1, 1a4, and 1b2; organic cation transporter (Oct) 1; canalicular bile-salt export pump (Bsep); multidrug resistance-associated proteins (Mrp) 2 and 3; and sodium-taurocholate cotransporting polypeptide (Ntcp). Real-time polymerase chain reaction analysis was used to correlate changes of transporter expression with interleukin-1b (IL-1b), IL-6, IL-17A, IL-17F, tumor necrosis factor-α (TNF-α), and interferon-γ expression in the liver. LPS treatment inhibited Bsep and Oct1 mRNA expression, and this was abrogated with a loss of T cells, but not B cells. In addition, the absence of T cells increased Mrp2 mRNA expression, whereas B cell deficiency attenuated Oatp1a4 mRNA in LPS-treated mice. Oatp1a1, Oatp1b2, Ntcp, and Mrp3 were largely unaffected by T or B cell deficiency. Lymphocyte deficiency altered basal and inflammatory IL-6, but not TNF-α or IL-1b, mRNA expression. Taken together, these data implicate lymphocytes as regulators of basal and inflammatory hepatic transporter expression and suggest that IL-6 signaling may play a critical role.


Can health care teams improve primary care practice?
In health care settings, individuals from different disciplines come together to care for patients. Although these groups of health care personnel are generally called teams, they need to earn true team status by demonstrating teamwork. Developing health care teams requires attention to 2 central questions: who is on the team and how do team members work together? This article chiefly focuses on the second question. Cohesive health care teams have 5 key characteristics: clear goals with measurable outcomes, clinical and administrative systems, division of labor, training of all team members, and effective communication. Two organizations are described that demonstrate these components: a private primary care practice in Bangor, Me, and Kaiser Permanente's Georgia region primary care sites. Research on patient care teams suggests that teams with greater cohesiveness are associated with better clinical outcome measures and higher patient satisfaction. In addition, medical settings in which physicians and nonphysician professionals work together as teams can demonstrate improved patient outcomes. A number of barriers to team formation exist, chiefly related to the challenges of human relationships and personalities. Taking small steps toward team development may improve the work environment in primary care practices.


Antigenic relatedness of selected flaviviruses: study with homologous and heterologous immune mouse ascitic fluids.
The antigenic relationship of 9 flaviviruses, Yellow fever (YF), Wesselsbron (WSL), Uganda S (UGS), Potiskum (POT), West Nile (WN), Banzi (BAN), Zika (ZK), Dengue type 1 (DEN-1) and Dengue type 2 (DEN-2), was assessed by cross-haemagglutination-inhibition (Cross-HI) and cross-complement fixation (Cross-CF) reactions between each of the viruses and their homologous immune mouse ascitic fluids. Titre ratios were calculated using the heterologous and homologous titres. Cross-CF reactions revealed wider antigenic variations among viruses than Cross-HI reactions. There was no significant antigenic variation between WSL, POT and YF viruses using either of those methods. However, definite differences in antigenicity were observed between them and UGS, BAN and ZK viruses. There were no significant differences between UGS, BAN and ZK or between DEN-1 and DEN-2. The serological relationship among flaviviruses is important in establishing diagnosis and epidemiology of these infections in Africa.


High-performance perovskite light-emitting diodes via morphological control of perovskite films.
Solution-processable perovskite materials have garnered tremendous attention because of their excellent charge carrier mobility, possibility of a tunable optical bandgap, and high photoluminescence quantum efficiency (PLQE). In particular, the uniform morphology of a perovskite film is the most important factor in realizing perovskite light-emitting diodes (PeLEDs) with high efficiency and full-coverage electroluminescence (EL). In this study, we demonstrate highly efficient PeLEDs that contain a perovskite film with a uniform morphology by introducing HBr into the perovskite precursor. The introduction of HBr into the perovskite precursor results in a perovskite film with a uniform, continuous morphology because the HBr increases the solubility of the inorganic component in the perovskite precursor and reduces the crystallization rate of the perovskite film upon spin-coating. Moreover, PeLEDs fabricated using perovskite films with a uniform, continuous morphology, which were deposited using 6 vol% HBr in a dimethylformamide (DMF)/hydrobromic acid (HBr) cosolvent, exhibited full coverage of the green EL emission. Finally, the optimized PeLEDs fabricated with perovskite films deposited using the DMF/HBr cosolvent exhibited a maximum luminance of 3490 cd m(-2) (at 4.3 V) and a luminous efficiency of 0.43 cd A(-1) (at 4.3 V).


An operational model for implementing conservation action.
The preoccupation of many conservation planners with the refinement of systematic assessment techniques has manifested an "implementation crisis" in conservation planning. This preoccupation has provided systematic assessments with well-tested tools (e.g., area selection algorithms) and principles (e.g., representation, complementarity), but our understanding of these techniques currently far exceeds our ability to apply them effectively to pragmatic conservation problems. The science is informative about where one needs to do conservation, but silent on how to achieve it. Operational models, defined as simplified conceptualizations of processes for implementing conservation action at priority conservation areas, are essential for guiding conservation planning initiatives because they assist understanding of how these processes function. Operational models developed to date have largely been linear, simplistic, and focused on the systematic assessment of biological entities. Experience in the real world indicates that operational models for conducting conservation planning initiatives should explicitly complement a systematic conservation assessment with activities that empower individuals and institutions (enabling) and explicitly aim to secure conservation action (implementation). Specifically, implementing effective conservation action requires that systematic assessments be integrated functionally with a process for developing an implementation strategy and processes for stakeholder collaboration while maintaining a broad focus on the implementation of conservation action. A suite of hallmarks define effective operational models (e.g., stakeholder collaboration, links with land-use planning, social learning, and action research). Greater development and testing of the practical application of operational models should lead to higher levels of effective implementation and alleviate the implementation crisis. Social learning institutions are essential for ensuring ongoing improvement in the development and application of operational models that deliver effective conservation action.


Serology Assays Used in SARS-CoV-2 Seroprevalence Surveys Worldwide: A Systematic Review and Meta-Analysis of Assay Features, Testing Algorithms, and Performance.
Background: Many serological assays to detect SARS-CoV-2 antibodies were developed during the COVID-19 pandemic. Differences in the detection mechanism of SARS-CoV-2 serological assays limited the comparability of seroprevalence estimates for populations being tested. Methods: We conducted a systematic review and meta-analysis of serological assays used in SARS-CoV-2 population seroprevalence surveys, searching for published articles, preprints, institutional sources, and grey literature between 1 January 2020, and 19 November 2021. We described features of all identified assays and mapped performance metrics by the manufacturers, third-party head-to-head, and independent group evaluations. We compared the reported assay performance by evaluation source with a mixed-effect beta regression model. A simulation was run to quantify how biased assay performance affects population seroprevalence estimates with test adjustment. Results: Among 1807 included serosurveys, 192 distinctive commercial assays and 380 self-developed assays were identified. According to manufacturers, 28.6% of all commercial assays met WHO criteria for emergency use (sensitivity [Sn.] >= 90.0%, specificity [Sp.] >= 97.0%). However, manufacturers overstated the absolute values of Sn. of commercial assays by 1.0% [0.1, 1.4%] and 3.3% [2.7, 3.4%], and Sp. by 0.9% [0.9, 0.9%] and 0.2% [−0.1, 0.4%] compared to third-party and independent evaluations, respectively. Reported performance data was not sufficient to support a similar analysis for self-developed assays. Simulations indicate that inaccurate Sn. and Sp. can bias seroprevalence estimates adjusted for assay performance; the error level changes with the background seroprevalence. Conclusions: The Sn. and Sp. of the serological assay are not fixed properties, but varying features depending on the testing population. To achieve precise population estimates and to ensure the comparability of seroprevalence, serosurveys should select assays with high performance validated not only by their manufacturers and adjust seroprevalence estimates based on assured performance data. More investigation should be directed to consolidating the performance of self-developed assays.


Does the addition of fundoplication to repair the intra-thoracic stomach improve quality of life?
The role of fundoplication in addition to hiatal hernia repair has been controversial. The aim of this study was to compare quality of life related to gastroesophageal reflux disease (GERD) in patients who underwent intra-thoracic stomach repair with and without fundoplication. We proposed that the group without a fundoplication would have poorer quality of life due to continued symptoms. All patients undergoing foregut surgery at the Creighton University Esophageal Center are entered in a prospectively maintained database. The database was queried to identify patients who underwent surgery for a near complete (>75 % of stomach in chest) intra-thoracic stomach with gastric volvulus between 2004 and 2013. A questionnaire was derived from the Quality of Life in Reflux and Dyspepsia and Frequency Scale for Symptoms of GERD questionnaires to assess for symptoms related to reflux, and this questionnaire was administered by phone. A total of 150 patients underwent repair of ITS during the study period. A total of 109 patients had ITS repair with fundoplication, while 41 had only ITS repair. Follow-up was available in 54 % of patients in the fundoplication group (median follow-up of 5.2 years) and in 49 % of patients in the non-fundoplication group (median follow-up of 4 years). Significantly, more patients woke up at night (p < 0.01) and found themselves coughing around mealtime (p < 0.01) in the fundoplication group. Patients in the non-fundoplication group had significantly more daytime reflux (p = 0.02). Despite these symptoms, only one patient in the fundoplication group and no patients in the non-fundoplication group admitted that these symptoms were severe enough to severely affect their quality of life. All other patients contacted felt satisfied, and >80 % rated their quality of life as either good or excellent. We conclude that there is not a significant difference in quality-of-life parameters on long-term follow-up between patients undergoing ITS repair with or without fundoplication.


Antiparkinsonian Effects of a Metabotropic Glutamate Receptor 4 Agonist in MPTP-Treated Marmosets.
Increased firing across glutamatergic synapses may contribute to both the motor dysfunction and L-DOPA-induced dyskinesia seen in Parkinson's disease. Given their ability to reduce glutamate release, activation of group III metabotropic glutamate receptors such as metabotropic glutamate receptor 4 may prove effective against both motor dysfunction and dyskinesia in Parkinson's disease. We hypothesised that activation of metabotropic glutamate receptor 4 by an orthosteric agonist ((2S)-2-amino-4-(hydroxy(hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl)phosphoryl)butanoic acid, LSP1-2111) would produce antiparkinsonian activity and reduce expression of dyskinesia in a 1-methyl-4-phenyl,1,2,3,6-tetrahydropyridine (MPTP)-treated marmoset model of Parkinson's disease. Common marmosets were previously treated with MPTP and pre-primed with L-DOPA for up to 28 days to express dyskinesia. LSP1-2111 (1, 3, or 6 mg/kg s.c.) or vehicle (0.9% saline s.c.) were administered immediately prior to L-DOPA (8 mg/kg + benserazide (10 mg/kg) p.o.) or vehicle (10% sucrose p.o.). Locomotor activity was measured in automated test cages and animals were scored for dyskinesia and disability. As expected, L-DOPA reversed motor disability and induced moderate dyskinesia. By contrast, LSP1-2111 alone significantly reduced the motor disability without any accompanying expression of dyskinesia. When administered in combination with L-DOPA, LSP1-2111 did not significantly reduce the severity of L-DOPA-induced dyskinesia. Systemic administration of LSP1-2111 reduces motor disability without causing dyskinesia in MPTP-treated marmosets, supporting a role for metabotropic glutamate receptor 4 orthosteric agonists as promising monotherapy for PD. Conversely, this study found no evidence to support their use as antidyskinetic agents within the dose range tested.


Effect of initial treatment strategy on survival of patients with advanced-stage Hodgkin's lymphoma: a systematic review and network meta-analysis.
Several treatment strategies are available for adults with advanced-stage Hodgkin's lymphoma, but studies assessing two alternative standards of care-increased dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated), and doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)-were not powered to test differences in overall survival. To guide treatment decisions in this population of patients, we did a systematic review and network meta-analysis to identify the best initial treatment strategy. We searched the Cochrane Library, Medline, and conference proceedings for randomised controlled trials published between January, 1980, and June, 2013, that assessed overall survival in patients with advanced-stage Hodgkin's lymphoma given BEACOPPbaseline, BEACOPPescalated, BEACOPP variants, ABVD, cyclophosphamide (mechlorethamine), vincristine, procarbazine, and prednisone (C[M]OPP), hybrid or alternating chemotherapy regimens with ABVD as the backbone (eg, COPP/ABVD, MOPP/ABVD), or doxorubicin, vinblastine, mechlorethamine, vincristine, bleomycin, etoposide, and prednisone combined with radiation therapy (the Stanford V regimen). We assessed studies for eligibility, extracted data, and assessed their quality. We then pooled the data and used a Bayesian random-effects model to combine direct comparisons with indirect evidence. We also reconstructed individual patient survival data from published Kaplan-Meier curves and did standard random-effects Poisson regression. Results are reported relative to ABVD. The primary outcome was overall survival. We screened 2055 records and identified 75 papers covering 14 eligible trials that assessed 11 different regimens in 9993 patients, providing 59 651 patient-years of follow-up. 1189 patients died, and the median follow-up was 5·9 years (IQR 4·9-6·7). Included studies were of high methodological quality, and between-trial heterogeneity was negligible (τ(2)=0·01). Overall survival was highest in patients who received six cycles of BEACOPPescalated (HR 0·38, 95% credibility interval [CrI] 0·20-0·75). Compared with a 5 year survival of 88% for ABVD, the survival benefit for six cycles of BEACOPPescalated is 7% (95% CrI 3-10)-ie, a 5 year survival of 95%. Reconstructed individual survival data showed that, at 5 years, BEACOPPescalated has a 10% (95% CI 3-15) advantage over ABVD in overall survival. Six cycles of BEACOPPescalated significantly improves overall survival compared with ABVD and other regimens, and thus we recommend this treatment strategy as standard of care for patients with access to the appropriate supportive care.


Urinary albumin excretion as a marker of endothelial dysfunction in migraine sufferers: the HUNT study, Norway.
To investigate urine albumin leakage as a marker of endothelial dysfunction in migraine patients. A population-based health study. 303 patients with migraine, 1009 patients with non-migraine headache and 5287 headache-free controls. The association between urine albumin- to-creatine ratio (ACR) and headache status was investigated in the Nord-Trøndelag Health Study (HUNT-2). Patients were selected in two strata, based on either (1) self-reported hypertension/diabetes (morbid sample) or (2) a random sample. Analyses were performed using analysis of covariance. There was no association between headache status and ACR in the study population (p=0.23, mean ACR for migraine 1.66, 95% CI 1.31 to 2.01, for non-migraine headache 1.90, 95% CI 1.71 to 2.09 and for no headache 1.73, 95% CI 1.64 to 1.81) after relevant adjustments. Similarly, no association between headache status and ACR was seen when the analysis was stratified for morbid and random samples, or for migraine with and without aura. We found no evidence of increased urine albumin leakage in migraine sufferers when compared with headache-free controls. This could indicate that systemic endothelial dysfunction is not a prominent feature of migraine.


Retroperitoneal ganglioneuroma with lymphnode metastasis: a case report.
Ganglioneuroma is a benign, most differentiated tumor of neural crest origin. These tumors though benign, can very rarely metastasize to regional lymphnodes or to distant sites. We report a case of a 52 year old lady who presented to the surgical OPD with dyspeptic symptoms of 2 months duration. Ultrasonography and CT scan of the abdomen showed a homogenous mass in the region of the right adrenal gland, extending between the inferior vena cava and the aorta. A clinical and radiological diagnosis of an adrenal tumor was made. Microscopically, the tumor histology was that of a ganglioneuroma (schwannian stroma-dominant) mature type. The lymph node attached to the tumor showed metastasis, the metastatic foci having the same morphology as the primary tumor. The right adrenal gland was free of tumor. The case is illustrative due to its clinical presentation mimicking an adrenal incidentaloma, and a rare phenomenon of a benign tumor exhibiting completely differentiated lymph node metastasis.


[Frozen shoulder: A long-lasting and misunderstood clinical problem].
Frozen shoulder (FS), also known as adhesive capsulitis, is a painful inflammatory fibrotic disease of the glenohumeral joint capsule. While it's frequently self-limiting, patients can be symptomatic for years. The clinical course is often divided into three phases: the freezing phase with predominantly pain, the frozen phase with mainly stiffness, and the thawing phase during which the complaints slowly resolve. Diagnosing FS can be challenging during the freezing phase as the symptoms in this phase are similar to other common shoulder conditions (such as subacromial pain syndrome). Treatment options include analgesia, physical therapy, corticosteroid injections, hydrodilatation, manipulation under anaesthesia, and arthroscopic release. Despite the many treatment options, there is no clear treatment guideline. Based on recent literature, conservative management is indicated as it can provide temporary symptom reduction. Due to significant risk of complications, surgical management should only be considered if patients retain complaints despite long-term conservative therapy.


Surviving apoptosis: life-death signaling in single cells.
Tissue development and homeostasis are regulated by opposing pro-survival and pro-death signals. An interesting feature of the Tumor Necrosis Factor (TNF) family of ligands is that they simultaneously activate opposing signals within a single cell via the same ligand-receptor complex. The magnitude of pro-death events such as caspase activation and pro-survival events such as Nuclear Factor (NF)-κB activation vary not only from one cell type to the next but also among individual cells of the same type due to intrinsic and extrinsic noise. The molecules involved in these pro-survival and/or pro-death pathways, and the different phenotypes that result from their activities, have been recently reviewed. Here we focus on the impact of cell-to-cell variability in the strength of these opposing signals on shaping cell fate decisions.


Six challenges in modelling for public health policy.
The World Health Organisation's definition of public health refers to all organized measures to prevent disease, promote health, and prolong life among the population as a whole (World Health Organization, 2014). Mathematical modelling plays an increasingly important role in helping to guide the most high impact and cost-effective means of achieving these goals. Public health programmes are usually implemented over a long period of time with broad benefits to many in the community. Clinical trials are seldom large enough to capture these effects. Observational data may be used to evaluate a programme after it is underway, but have limited value in helping to predict the future impact of a proposed policy. Furthermore, public health practitioners are often required to respond to new threats, for which there is little or no previous data on which to assess the threat. Computational and mathematical models can help to assess potential threats and impacts early in the process, and later aid in interpreting data from complex and multifactorial systems. As such, these models can be critical tools in guiding public health action. However, there are a number of challenges in achieving a successful interface between modelling and public health. Here, we discuss some of these challenges.


Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial.
Invasive aspergillosis is an important cause of morbidity and mortality in immunocompromised patients. Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species. We investigated the efficacy and safety of posaconazole oral suspension (800 mg/day in divided doses) as monotherapy in an open-label, multicenter study in patients with invasive aspergillosis and other mycoses who were refractory to or intolerant of conventional antifungal therapy. Data from external control cases were collected retrospectively to provide a comparative reference group. Cases of aspergillosis deemed evaluable by a blinded data review committee included 107 posaconazole recipients and 86 control subjects (modified intent-to-treat population). The populations were similar and balanced with regard to prespecified demographic and disease variables. The overall success rate (i.e., the data review committee-assessed global response at the end of treatment) was 42% for posaconazole recipients and 26% for control subjects (odds ratio, 4.06; 95% confidence interval, 1.50-11.04; P=.006). The differences in response between the modified intent-to-treat treatment groups were preserved across additional, prespecified subsets, including infection site (pulmonary or disseminated), hematological malignancy, hematopoietic stem cell transplantation, baseline neutropenia, and reason for enrollment (patient was refractory to or intolerant of previous antifungal therapy). An exposure-response relationship was suggested by pharmacokinetic analyses. Although the study predates extensive use of echinocandins and voriconazole, these findings demonstrate that posaconazole is an alternative to salvage therapy for patients with invasive aspergillosis who are refractory to or intolerant of previous antifungal therapy.


Orderly recruitment among motoneurons supplying different muscles.
Virtually all movements involve the recruitment of motor units from multiple muscles. Given the functional diversity of motor units (motoneurons and the muscle fibers they supply), the effective production of specific movements undoubtedly depends upon some principle(s) to organize the ensemble of active motor units. The principle acting to organize the recruitment of motor units within muscles is the size principle, whereby the first motor units to be recruited have the smallest values for axonal conduction velocity and contractile force, and are the slowest to contract and fatigue. Here we consider the possibility that the size principle applies in the recruitment of motor units across muscles, i.e., that regardless of their muscles of origin, active motor units are recruited in rank order, for example, from low to high conduction velocity. The benefits of orderly recruitment across muscles could be similar to the acknowledged advantages of orderly recruitment within muscles. One benefit is that the neural process involved in organizing active motor units would be simplified. In a muscle-based scheme, the size principle would organize only those motor units within individual muscles, leaving the nervous system with the additional task of coordinating the relative activities of motor units from different muscles. By contrast, in an ensemble-based scheme, orderly recruitment of all motor units according to the size principle would automatically coordinate motor units both within and across motor nuclei. Another potential benefit is the provision for movements with smooth trajectory, the result of interleaving the divergent torque contributions made by motor units from muscles that differ in their orientations about joints. Otherwise, if order were restricted within muscles, the torque trajectory of a joint would change unevenly as participating muscles begin contracting at different times and grade activity at different rates. These considerations support speculation that motor units recruited from co-contracting muscles are collectively recruited according to the size principle.


Role of the HLA class II: HCV-related disorders.
The paper highlights the role of different HLA class II molecules in hepatic and lymphoproliferative HCV-related disorders. HLA molecules have been reviewed, according to an in silico cluster classification, based on the sequence, the biochemical structure of the pockets, and the functional characteristics of the HLA II molecules. Thus, by reducing the complexity of HLA II polymorphism, characteristics that unite different HLA molecules with specific HCV-associated pathologies may be recognized with greater case. Results show that HLA clusters associated with better dlimination of the virus are protective against HCC development, while the same clusters are associated with a higher risk of developing cryoglobulinemic syndrome and the concomitant NHL. These data added further acknowledgements on pathogenetic mechanisms associated with HCV infection. Results also highlight differences of NHL occurring in HCV-positive subjects, with or without a concomitant type II autoimmune cryoglobulinemic syndrome, suggesting that cryoglobulinemic background associated with NHL should be considered in the evaluation of the effectiveness of new therapies in the course of HCV-associated NHLs.


Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
Both lipid-modifying therapy and antioxidant vitamins are thought to have benefit in patients with coronary disease. We studied simvastatin-niacin and antioxidant-vitamin therapy, alone and together, for cardiovascular protection in patients with coronary disease and low plasma levels of HDL. In a three-year, double-blind trial, 160 patients with coronary disease, low HDL cholesterol levels and normal LDL cholesterol levels were randomly assigned to receive one of four regimens: simvastatin plus niacin, vitamins, simvastatin-niacin plus antioxidants; or placebos. The end points were arteriographic evidence of a change in coronary stenosis and the occurrence of a first cardiovascular event (death, myocardial infarction, stroke, or revascularization). The mean levels of LDL and HDL cholesterol were unaltered in the antioxidant group and the placebo group; these levels changed substantially (by -42 percent and +26 percent, respectively) in the simvastatin-niacin group. The protective increase in HDL2 with simvastatin plus niacin was attenuated by concurrent therapy with antioxidants. The average stenosis progressed by 3.9 percent with placebos, 1.8 percent with antioxidants (P=0.16 for the comparison with the placebo group), and 0.7 percent with simvastatin-niacin plus antioxidants (P=0.004) and regressed by 0.4 percent with simvastatin-niacin alone (P<0.001). The frequency of the clinical end point was 24 percent with placebos; 3 percent with simvastatin-niacin alone; 21 percent in the antioxidant-therapy group; and 14 percent in the simvastatin-niacin-plus-antioxidants group. Simvastatin plus niacin provides marked clinical and angiographically measurable benefits in patients with coronary disease and low HDL levels. The use of antioxidant vitamins in this setting must be questioned.


Causal Evidence for the Role of Neuronal Oscillations in Top-Down and Bottom-Up Attention.
Beta and gamma frequency neuronal oscillations have been implicated in top-down and bottom-up attention. In this study, we used rhythmic TMS to modulate ongoing beta and gamma frequency neuronal oscillations in frontal and parietal cortex while human participants performed a visual search task that manipulates bottom-up and top-down attention (single feature and conjunction search). Both task conditions will engage bottom-up attention processes, although the conjunction search condition will require more top-down attention. Gamma frequency TMS to superior precentral sulcus (sPCS) slowed saccadic RTs during both task conditions and induced a response bias to the contralateral visual field. In contrary, beta frequency TMS to sPCS and intraparietal sulcus decreased search accuracy only during the conjunction search condition that engaged more top-down attention. Furthermore, beta frequency TMS increased trial errors specifically when the target was in the ipsilateral visual field for the conjunction search condition. These results indicate that beta frequency TMS to sPCS and intraparietal sulcus disrupted top-down attention, whereas gamma frequency TMS to sPCS disrupted bottom-up, stimulus-driven attention processes. These findings provide causal evidence suggesting that beta and gamma oscillations have distinct functional roles for cognition.


Specific antibody responses in dogs experimentally infected with Echinococcus granulosus.
Six dogs reared helminth-free were divided into 2 groups. Four dogs were infected per os with 200,000 protoscoleces each of Echinococcus granulosus and 2 were kept as uninfected controls. All the dogs were kept together until 32 days after infection, when 1 infected dog was killed, its intestine removed and the contents examined to confirm that the infection with E. granulosus had been successful. The remaining 3 infected dogs were transferred to high security housing and their feces inspected daily to establish the time infections became patent. The infected and control dogs were bled every 5 days for 75 days from the time of infection and the sera were stored at -70 degrees C. Sera were tested by the enzyme-linked immunosorbent assay (ELISA) for antibodies to E. granulosus scolex excretory/secretory (ES) antigen, protoscolex antigen and oncosphere antigen. Antibodies to scolex ES antigen and protoscolex antigen were detected in the sera of infected dogs within 2 weeks of infection. Antibody titers rose rapidly and remained at a high level until the dogs were killed 75 days after infection. Antibodies in these sera did not cross react with antigens prepared from Taenia ovis, T. hydatigena, T. pisiformis, Ancylostoma caninum, Trichuris vulpis and Toxocara canis.


Dissociation of reward and effort sensitivity in methcathinone-induced Parkinsonism.
Methcathinone-induced Parkinsonism is a recently described extrapyramidal syndrome characterized by globus pallidus and substantia nigra lesions, which provides a unique model of basal ganglia dysfunction. We assessed motivated behaviour in this condition using a novel cost-benefit decision-making task, in which participants decided whether it was worth investing effort for reward. Patients showed a dissociation between reward and effort sensitivity, such that pallidonigral complex dysfunction caused them to become less sensitive to rewards, while normal sensitivity to effort costs was maintained.


N-3 polyunsaturated fatty acids impair lifespan but have no role for metabolism.
Although generally considered as beneficial components of dietary fats, polyunsaturated fatty acids (PUFA) have been suspected to compromise maximum lifespan (MLSP) in mammals. Specifically, high amounts of phospholipid PUFAs are thought to impair lifespan due to an increase in the susceptibility of membranes to lipid peroxidation and its damaging effect on cellular molecules. Also, there is evidence from in vitro studies suggesting that highly unsaturated PUFAs elevate basal metabolic rate (BMR). Previous comparative studies in this context were based on small sample sizes, however, and, except for one study, failed to address possible confounding influences of body weight and taxonomic relations between species. Therefore, we determined phospholipid membrane composition in skeletal muscle from 42 mammalian species to test for a relation with published data on MLSP, and with literature data on BMR (30 species). Using statistical models that adjust for the effects of body weight and phylogeny, we found that among mammals, MLSP indeed decreases as the ratio of n-3 to n-6 PUFAs increases. In contrast to previous studies, we found, however, no relation between MLSP and either membrane unsaturation (i.e. PUFA content or number of double bonds) or to the very long-chain, highly unsaturated docosahexaenoic acid (DHA). Similarly, our data set gave no evidence for any notable relation between muscle phospholipid fatty acid composition and BMR, or MLSP and BMR in mammals. These results contradict the 'membrane pacemaker theory of aging', that is, the concept of a direct link between high amounts of membrane PUFAs, elevated BMR, and thus, impaired longevity.


Functional protein network activation mapping reveals new potential molecular drug targets for poor prognosis pediatric BCP-ALL.
In spite of leukemia therapy improvements obtained over the last decades, therapy is not yet effective in all cases. Current approaches in Acute Lymphoblastic Leukemia (ALL) research focus on identifying new molecular targets to improve outcome for patients with a dismal prognosis. In this light phosphoproteomics seems to hold great promise for the identification of proteins suitable for targeted therapy. We employed Reverse Phase Protein Microarrays to identify aberrantly activated proteins in 118 pediatric B-cell precursor (BCP)-ALL patients. Signal transduction pathways were assayed for activation/expression status of 92 key signalling proteins. We observed an increased activation/expression of several pathways involved in cell proliferation in poor clinical prognosis patients. MLL-rearranged tumours revealed BCL-2 hyperphosphorylation through AMPK activation, which indicates that AMPK could provide a functional role in inhibiting apoptosis in MLL-rearranged patients, and could be considered as a new potential therapeutic target. Second, in patients with poor clinical response to prednisone we observed the up-modulation of LCK activity with respect to patients with good response. This tyrosine-kinase can be down-modulated with clinically used inhibitors, thus modulating LCK activity could be considered for further studies as a new additional therapy for prednisone-resistant patients. Further we also found an association between high levels of CYCLIN E and relapse incidence. Moreover, CYCLIN E is more expressed in early relapsed patients, who usually show an unfavourable prognosis. We conclude that functional protein pathway activation mapping revealed specific deranged signalling networks in BCP-ALL that could be potentially modulated to produce a better clinical outcome for patients resistant to standard-of-care therapies.


Assembly of 500,000 inter-specific catfish expressed sequence tags and large scale gene-associated marker development for whole genome association studies.
Through the Community Sequencing Program, a catfish EST sequencing project was carried out through a collaboration between the catfish research community and the Department of Energy's Joint Genome Institute. Prior to this project, only a limited EST resource from catfish was available for the purpose of SNP identification. A total of 438,321 quality ESTs were generated from 8 channel catfish (Ictalurus punctatus) and 4 blue catfish (Ictalurus furcatus) libraries, bringing the number of catfish ESTs to nearly 500,000. Assembly of all catfish ESTs resulted in 45,306 contigs and 66,272 singletons. Over 35% of the unique sequences had significant similarities to known genes, allowing the identification of 14,776 unique genes in catfish. Over 300,000 putative SNPs have been identified, of which approximately 48,000 are high-quality SNPs identified from contigs with at least four sequences and the minor allele presence of at least two sequences in the contig. The EST resource should be valuable for identification of microsatellites, genome annotation, large-scale expression analysis, and comparative genome analysis. This project generated a large EST resource for catfish that captured the majority of the catfish transcriptome. The parallel analysis of ESTs from two closely related Ictalurid catfishes should also provide powerful means for the evaluation of ancient and recent gene duplications, and for the development of high-density microarrays in catfish. The inter- and intra-specific SNPs identified from all catfish EST dataset assembly will greatly benefit the catfish introgression breeding program and whole genome association studies.


Form birefringence of muscle.
We investigate the sensitivity of measurements of muscle birefringence to cross-bridge dynamics in the resting, active, and rigor states. The theory of form birefringence is reviewed, and an optical model is constructed for the form birefringence of muscle. Values for the parameters in the model are selected or deduced from the literature. As an illustration of the use of the model, plausible distributions for the orientations of cross-bridges in the resting, active, and rigor states are constructed using a model for cross-bridge dynamics suggested by Huxley and Kress (1985). The general magnitude of the predictions of our model is comparable with that of published measurements of muscle birefringence. However, the precise values of the predicted birefringence for the resting, active, and rigor states are sensitive to the assumed orientations of cross-bridges. We also investigate the dependence of muscle birefringence on sarcomere length and on disorder in the orientation of the myofilament array. We conclude that measurements of muscle birefringence can play a useful role in distinguishing between proposed models of cross-bridge dynamics.


Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells.
The nature and site of tumor-antigen presentation to immune T cells by bone-marrow-derived cells within the tumor microenvironment remains unresolved. We generated a fluorescent mouse model of spontaneous immunoevasive breast cancer and identified a subset of myeloid cells with significant similarity to dendritic cells and macrophages that constitutively ingest tumor-derived proteins and present processed tumor antigens to reactive T cells. Using intravital live imaging, we determined that infiltrating tumor-specific T cells engage in long-lived interactions with these cells, proximal to the tumor. In vitro, these cells capture cytotoxic T cells in signaling-competent conjugates but do not support full activation or sustain cytolysis. The spatiotemporal dynamics revealed here implicate nonproductive interactions between T cells and antigen-presenting cells on the tumor margin.


Four distinct trajectories of tau deposition identified in Alzheimer's disease.
Alzheimer's disease (AD) is characterized by the spread of tau pathology throughout the cerebral cortex. This spreading pattern was thought to be fairly consistent across individuals, although recent work has demonstrated substantial variability in the population with AD. Using tau-positron emission tomography scans from 1,612 individuals, we identified 4 distinct spatiotemporal trajectories of tau pathology, ranging in prevalence from 18 to 33%. We replicated previously described limbic-predominant and medial temporal lobe-sparing patterns, while also discovering posterior and lateral temporal patterns resembling atypical clinical variants of AD. These 'subtypes' were stable during longitudinal follow-up and were replicated in a separate sample using a different radiotracer. The subtypes presented with distinct demographic and cognitive profiles and differing longitudinal outcomes. Additionally, network diffusion models implied that pathology originates and spreads through distinct corticolimbic networks in the different subtypes. Together, our results suggest that variation in tau pathology is common and systematic, perhaps warranting a re-examination of the notion of 'typical AD' and a revisiting of tau pathological staging.


Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M1 and M2.
A set of hybrid compounds composed of the fragment of allosteric modulators of the muscarinic receptor, i.e. W84 and naphmethonium, and the well-known AChE inhibitor tacrine on the one hand, and the skeletons of the orthosteric muscarinic agonists, iperoxo and isox, on the other hand, were synthesized. The two molecular moieties were connected via a polymethylene linker of varying length. These bipharmacophoric compounds were investigated for inhibition of AChE (from electric eel) and BChE (from equine serum) as well as human ChEs in vitro and compared to previously synthesized dimeric inhibitors. Among the studied hybrids, compound 10-C10, characterized by a 10 carbon alkylene linker connecting tacrine and iperoxo, proved to be the most potent inhibitor with the highest pIC50 values of 9.81 (AChE from electric eel) and 8.75 (BChE from equine serum). Docking experiments with compounds 10-C10, 7b-C10, and 7a-C10 helped to interpret the experimental inhibitory power against AChE, which is affected by the nature of the allosteric molecular moiety, with the tacrine-containing hybrid being much more active than the naphthalimido- and phthalimido-containing analogs. Furthermore, the most active AChE inhibitors were found to have affinity to M1 and M2 muscarinic receptors. Since 10-C10 showed almost no cytotoxicity, it emerged as a promising lead structure for the development of an anti-Alzheimer drug.


Tandem catalysis in multicomponent solvent-free biofluids.
Enzymes are widely employed to reduce the environmental impact of chemical industries as biocatalysts improve productivity and offer high selectively under mild reaction conditions in a diverse range of chemical transformations. The poor stability of biomacromolecules under reaction conditions is often a critical bottleneck to their application. Protein engineering or immobilization onto solid substrates may remedy this limitation but, unfortunately, this is often at the expense of catalytic potency or substrate specificity. In this work, we show that the combinatorial approach of chemical modification and supramolecular nanoencapsulation can endow mechanistically diverse enzymes with apparent extremophilic behavior. A protein-polymer surfactant core-shell architecture facilitates construction of increasingly complex biofluids from individual biosynthetic components, each of which retain biological activity at hydration levels almost two orders of magnitude below solvation. The herein constructed multifunctional biofluids operate in tandem up to 150 °C and in the total absence of solvent under apparent diffusional mass-transport limitation. The biosynthetic promotion of extremophilic traits for enzymes with diverse catalytic motions and chemical functions highlights the extraordinary capacity for a viscous surfactant milieu to replace both hydration and bulk waters.


Housing accessibility for senior citizens in Sweden: Estimation of the effects of targeted elimination of environmental barriers.
To estimate the effects of targeted elimination of environmental barriers (EB) in the ordinary housing stock in Sweden, and to explore the estimated effects on accessibility at a population level in relation to (a) residents with different functional profiles, (b) different housing types and (c) building periods. Data on dwellings from existing Swedish research databases were utilized. EB and accessibility were assessed by means of the Housing Enabler instrument. In simulations of EB removal, five items that correspond to the most common housing adaptations were selected. The simulations were applied to four functional profiles of different complexity. EB known to be commonly removed by housing adaptations exist in large proportions of the existing ordinary housing stock. Estimated targeted elimination of selected barriers would have the largest accessibility effects for the more complex functional profiles. The effects would be consistently larger for one-family houses, and for all types of dwellings built before 1960. The elimination of the EB most commonly addressed by housing adaptations could result in a reduction of the housing accessibility problems that community-living older people are facing. For society to solve the housing situation for the ageing population well-informed and efficient upgrading of ordinary housing is imperative.


Influence of genes from the major histocompatibility complex on the antibody repertoire against culture filtrate antigens in mice infected with live Mycobacterium bovis BCG.
C57BL/10 and C57BL/6 mice (H-2b); B10 congenic mice with f, k, p, q, r, and s H-2 haplotypes; B10 mice with recombinant g2, o2, a, h2, h4, i5, and bq1 H-2 haplotypes; and B6 mice with major histocompatibility complex (MHC) mutant bm1 and bm13 (class I) and bm12 (class II) haplotypes were infected intravenously with 4 x 10(6) CFU of live Mycobacterium bovis BCG and examined by Western immunoblot analysis for serum antibodies against BCG culture filtrate antigens, following a boost injection with live BCG or with BCG culture filtrate. Parental B10 and B6 mice reacted very intensely with three culture filtrate protein bands with estimated molecular masses of 37, 38, and 40 kDa. Response against the 40-kDa protein was stronger following a boost injection with live BCG than following a boost with culture filtrate. Sera from mice with f, p, i5, bm1, and bm13 haplotypes reacted strongly, with both the 37-38- and 40-kDa antigens, and sera from mice with q and bq1 haplotypes showed a somewhat weaker reaction. Sera from mice with r, s, and bm12 haplotypes reacted against the 37-38-kDa antigen but not against the 40-kDa antigen, and sera from mice with the h2 haplotype reacted only with the 40-kDa antigen but not with the 37-38-kDa antigen. Sera from mice with the k, g2, o2, a, and h4 haplotypes showed, at most, a very weak reaction with the 37-38- and 40-kDa antigens. These results demonstrate that MHC genes profoundly affect the antibody repertoire used against culture filtrate antigens in mice infected with live M. bovis BCG. In particular, as shown in mice with the recombinant H-2 haplotype and in class II mutant bm12 mice, the I-A heterodimer controls the recognition of the immunodominant 40-kDa antigen. By using crossed immunoelectrophoresis, this 40-kDa antigen was identified as antigen 88 according to the reference system of Closs et al. for BCG antigens.


Interaction of two complementary fragments of the bovine spinal cord myelin basic protein with phosphatidylglycerol bilayers, studied by 2H and 31P NMR spectroscopy.
The interaction of two complementary fragments of myelin basic protein from bovine spinal cord with bilayers of dimyristoylphosphatidylglycerol has been studied by broad line 2H and 31P NMR. The fragments, produced by cleavage at the single tryptophan, consist of an N-terminal portion of molecular mass 12.6 kDa and a C-terminal portion of molecular mass 5.8 kDa. The phosphatidylglycerol lipid was deuterated at all three segments of the glycerol headgroup. The approximately linear dependence of the 2H quadrupole splittings and 31P chemical shift anisotropy on protein/lipid ratio in the complexes indicates that the lipids interacting with the protein fragments were in fast exchange on the NMR time scale (approximately 10(-4)-10(-5) s). The relative gradients of the dependence on protein/lipid ratio of both these parameters decrease with the size of the protein fragment and correlate reasonably well with both the net charge on the protein and the lipid binding stoichiometries in the absence of salt. The results are therefore consistent with a model in which the perturbation of the quadrupole splittings either is determined by the net surface potential or is constant for the different protein fragments. Either possibility is consistent with the reduced activity of the fragments relative to the whole protein.


Global mapping of the protein structure space and application in structure-based inference of protein function.
We have constructed a map of the "protein structure space" by using the pairwise structural similarity scores calculated for all nonredundant protein structures determined experimentally. As expected, proteins with similar structures clustered together in the map and the overall distribution of structural classes of this map followed closely that of the map of the "protein fold space" we have reported previously. Consequently, proteins sharing similar molecular functions also were found to colocalize in the protein structure space map, pointing toward a previously undescribed scheme for structure-based functional inference for remote homologues based on the proximity in the map of the protein structure space. We found that this scheme consistently outperformed other predictions made by using either the raw scores or normalized Z-scores of pairwise DALI structure alignment.


The virtual reality transurethral prostatic resection trainer: evaluation of discriminate validity.
To understand how urologists acquire resection skills we analyzed factors correlating with favorable resection metrics in groups defined as experts, residents and novices. We then evaluated discriminate validity by determining factors correlating with proficiency among individuals in the expert, resident and novice groups. A total of 136 subjects completed the protocol, including 72 urologists, 45 residents and 19 novices. After a pre-task questionnaire and training video subjects performed a standardized 5-minute resection task. Primary metrics were gm resected, blood loss, irrigant volume used, foot pedal use and differential time spent with orientation, cutting or coagulation. Among experts larger resection correlated with more time spent cutting (p <0.001). In contrast, increased coagulation time correlated with gm resected in the novice group (p = 0.001). The number of transurethral prostate resections that residents reported having done in the real operating room correlated with gm resected (p = 0.043), use of more irrigating fluid (p = 0.024) and less time spent coagulating (p = 0.027) on the simulator. In residents and experts exclusively primary resection efficiency metrics, fluid use and blood loss correlated with cuts at tissue and correlated inversely with coagulation and orientation time (p <0.05). Different factors determine transurethral prostate resection performance metrics among experts, residents and novices. These correlations reinforce discriminate validity and provide insight into specific factors that likely determine success at different training levels. Such data could be used to isolate and train skill subsets in the curriculum and they may elucidate the safest and most efficient approach to train resection skills.


Castration resistance in human prostate cancer is conferred by a frequently occurring androgen receptor splice variant.
Progression of prostate cancer following castration is associated with increased androgen receptor (AR) expression and signaling despite AR blockade. Recent studies suggest that these activities are due to the generation of constitutively active AR splice variants, but the mechanisms by which these splice variants could mediate such effects are not fully understood. Here we have identified what we believe to be a novel human AR splice variant in which exons 5, 6, and 7 are deleted (ARv567es) and demonstrated that this variant can contribute to cancer progression in human prostate cancer xenograft models in mice following castration. We determined that, in human prostate cancer cell lines, ARv567es functioned as a constitutively active receptor, increased expression of full-length AR (ARfl), and enhanced the transcriptional activity of AR. In human xenografts, human prostate cancer cells transfected with ARv567es cDNA formed tumors that were resistant to castration. Furthermore, the ratio of ARv567es to ARfl expression within the xenografts positively correlated with resistance to castration. Importantly, we also detected ARv567es frequently in human prostate cancer metastases. In summary, these data indicate that constitutively active AR splice variants can contribute to the development of castration-resistant prostate cancers and may serve as biomarkers for patients who are likely to suffer from early recurrence and are candidates for therapies directly targeting the AR rather than ligand.