Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons.
The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR) are active in the central nervous system (CNS) and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb)-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis. To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (LeprEYFPΔGHR). The mice were generated by crossing the Leprcre on the cre-inducible ROSA26-EYFP mice to GHRL/L mice. Parameters of body composition and glucose homeostasis were evaluated. Our results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in LeprEYFPΔGHR mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in LeprEYFPΔGHR mice. These findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding.


Reverse saphenous conduit flap in small animals: Clinical applications and outcomes.
Due to the lack of skin elasticity defects of the distal hind limb can be a challenge to close. This article assesses a well-described, but completely under-used technique for closure of wounds on the distal tarsus. The technique was used with good success in six cases presenting to the Bryanston Veterinary Hospital with a wide range of underlying pathology ranging from trauma to neoplastic disease of the tarsus. All six cases were treated with a reverse saphenous conduit flap and two of them underwent radiation therapy with no adverse side effects. All cases showed excellent results with a very low degree of flap necrosis that never exceeded 15% of the total flap area. This skin flap provides an excellent treatment method that is reliable in closure of defects of the distal tarsus with few adverse effects. To the author's knowledge there has been only one previously published report on the clinical use of this type of skin flap, even though the flap is well described in most texts.


Effects of chronic waterborne nickel exposure on two successive generations of Daphnia magna.
In a 21-d chronic toxicity test in which an F0 generation of Daphnia magna were exposed to waterborne Ni, the no-observable-effect concentration (for survival, reproduction, and growth) was 42 microg Ni L(-1), or 58% of the measured 21-d median lethal concentration (LC50) of 71.9 microg Ni L(-1) (95% confidence interval, 56.5-95.0). Chronic exposure to 85 microg Ni L(-1) caused marked decreases in survival, reproduction, and growth in F0 animals. In the F1 generation (daphnids born of mothers from the chronically exposed F0 generation), animals chronically exposed to 42 microg Ni L(-1) for 11 d weighed significantly less (20%) than controls, indicating increased sensitivity of F1 animals. Additionally, in this successive generation, significant decreases in whole-body levels of metabolites occurred following exposure to both 42 microg Ni L(-1) (decreased glycogen and adenosine triphosphate [ATP]) and 21 microg Ni L(-1) (decreased ATP). No significant changes were observed in whole-body total lipid, total protein, and lactate levels at any concentration. Whereas F1 neonates with mothers that were exposed to 21 microg Ni L(-1) showed increased resistance to acute Ni challenge, as measured by a significant (83%) increase in the acute (48-h) LC50, F1 neonates with mothers that were exposed to 42 microg Ni L(-1) were no more tolerant of acute Ni challenge than control animals were. Nickel accumulations in F1 animals chronically exposed to 21 and 42 microg Ni L(-1) were 11- and 18-fold, respectively, above control counterparts. The data presented suggest that chronic Ni exposure to two successive generations of D. magna lowered the overall energy state in the second generation. Whereas the quantity of neonates produced was not affected, the quality was; thus, environmentally meaningful criteria for regulating waterborne Ni concentrations in freshwater require consideration of possible multigenerational effects.


Neurovascular and tendinous damage with placement of anteroposterior distal locking bolts in the tibia.
To determine the proximity of anteroposterior locking bolts inserted into the distal metaphyseal tibia to nearby neural, vascular, and tendinous structures. A cadaver study. University trauma center. Sixteen legs (8 matched pairs) were nailed in either neutral (Group 1) or 10 degrees of internal rotation (Group 2) and locked using one anteroposterior bolt. The anterior tibial and extensor hallucis longus tendons and neurovascular bundle were identified, and their respective locations in relation to the bolt head were measured. Average distances were calculated for each structure in each group and statistically compared. Damage to any structure was noted at final dissection. Average distances from the bolt head to the neurovascular bundle, extensor hallucis longus, and anterior tibial tendons were 0.6, 0.5, and 1.6 mm, respectively, for Group 1 and 1.0, 1.5, and 1.8 mm, respectively, for Group 2 legs. Statistical comparison of distances for each anatomic entity for the two groups revealed no detectable significant differences (P = 0.7, 0.4, 0.7, respectively). For all specimens, the rate of nerve, artery, extensor hallucis longus, and anterior tibial tendon injury was 25%, 19%, 0%, and 6%, respectively. However, the incidence of at least one structure damage in Group 1 legs was 63% versus 12% in Group 2 specimens (P = 0.2). Anteroposterior distal tibial locking bolts lie in close proximity to the neurovascular bundle. With standard percutaneous techniques, these structures can be damaged. Although 10 degrees of internal rotation does not statistically affect the measured distance of the locking bolt to the neurovascular bundle, it appears to decrease the incidence of neurovascular injury. This difference may best be explained by the necessary path the drill bit must take through the soft tissues to reach the underlying bone. Regardless of nail orientation, larger incisions with careful dissection and clear visualization of the anatomy are recommended to help prevent this complication.


Diversity and circulation of Jingmen tick virus in ticks and mammals.
Since its initial identification in ticks in 2010, Jingmen tick virus (JMTV) has been described in cattle, rodents, and primates. To better understand the diversity, evolution, and transmission of JMTV, we sampled 215 ticks, 104 cattle bloods, 216 bats, and 119 rodents in Wenzhou city, Zhejiang Province, China as well as 240 bats from Guizhou and Henan Provinces. JMTV was identified in 107 ticks (from two species), 54 bats (eleven species), 8 rodents (three species), and 10 cattle, with prevalence levels of 49.8, 11.8, 6.7, and 9.6 per cent, respectively, suggesting that bats may be a natural reservoir of JMTV. Phylogenetic analyses revealed that all the newly identified JMTVs were closely related to each other and to previously described viruses. Additionally, all tick and mammalian JMTV sampled in Wenzhou shared a consistent genomic structure, suggesting that the virus can cocirculate between ticks and mammals without observable variation in genome organization. All JMTVs sampled globally could be divided into two phylogenetic groups, Mantel tests suggested that geographic isolation, rather than host species, may be the main driver of JMTV diversity. However, the exact geographical origin of JMTV was difficult to determine, suggesting that this virus has a complex evolutionary history.


Chondrocyte Attachment, Proliferation, and Differentiation on Three-Dimensional Polycaprolactone Fumarate Scaffolds.
Current treatment options for cartilage injuries are limited. The goals of this study are to create a biodegradable polymer scaffold with the capabilities of sustaining chondrocyte growth and proliferation, enable cell-to-cell communication and tissue regeneration through large pores, and assess the biological augmentation of the scaffold capabilities using platelet lysate (PL). We synthesized biodegradable polycaprolactone fumarate (PCLF) scaffolds to allow cell-cell communication through large interconnected pores. Molds were printed using a three-dimensional printer and scaffolds synthesized through UV crosslinking. Culture medium included alpha modified Eagle's media with either 10% fetal bovine serum (FBS) or 5% PL, a mixture of platelet release products, after being seeded onto scaffolds through a dynamic bioreactor. Assays included cellular proliferation (MTS), toxicity and viability (live/dead immunostaining), differentiation (glycosaminoglycan [GAG], alkaline phosphatase [ALP], and total collagen), and immunostaining for chondrogenic markers collagen II and Sox 9 (with collagen I as a negative control). The large interconnected pores (500 and 750 μm) enable cell-to-cell communication and cellular infiltration into the scaffolds, as the cells remained viable and proliferated for 2 weeks. Chondrocytes cultured in PL showed increased rates of proliferation when compared with FBS. The chondrogenic markers GAG and total collagen contents increased over 2 weeks at each time point, whereas the osteogenic marker ALP did not significantly change. Immunostaining at 2 and 4 weeks for the expression of chondrogenic markers Collagen II and Sox 9 was increased when compared with control human fibroblasts. These results show that the PCLF polymer scaffold enables chondrocytes to attach, proliferate, and retain their chondrogenic phenotypes, demonstrating potential in chondrocyte engineering and cartilage regeneration.


Mathematical models of solute retention in gas chromatography as sources of thermodynamic data. Part III. Alkylbenzenes as the test analytes.
Direct determination of thermodynamic data has always been a complicated and troublesome experimental task. Gas chromatography is among long-established working tools well suited to performing this particular task indirectly. Our own results were first presented in the papers by Ciazynska-Halarewicz and Kowalska (1,2), and this article is Part III in the series. Present experiments are carried out on low- and medium-polarity stationary phases at five different temperatures ranging from 323K to 423K. They enable determination of two thermodynamic properties of the alkylbenzenes, molar enthalpy of vaporization (DeltaH(vap)), and the chemical potential of partitioning of the methylene group between the two phases of the chromatographic system (Delta micro (p(-CH2-))). These properties are obtained from eight nonempirical models and, as is apparent from their derivation (3-7), the terms of the models have clearly defined physical meaning, which enables calculation of thermodynamic properties.


Case Report: Therapeutic Threshold for Rifampicin-Resistant Tuberculosis in a Patient from Maputo, Mozambique.
We present a case of a patient in Mozambique, who initiated treatment for rifampicin-resistant tuberculosis (RR-TB) without proof of resistance. For this patient, we estimated the probability of RR-TB using likelihood ratios of clinical arguments. The probability of RR-TB in Mozambique, positive HIV status, and treatment failure after a first treatment and after retreatment were included as confirming arguments, and a rapid molecular test showing rifampicin susceptibility as excluding argument. The therapeutic threshold to start treatment for RR-TB is unknown, but probably lower than 47% and should be calculated to guide clinical decisions.


[Cervical-uterine-cancer associated factors in Nayarit state, Mexico].
To establish the association between high-grade intraepithelial lesions and cervical-uterine-cancer, and the infection by human papillomavirus, genetic antecedents, socioeconomics, sexual behavior and gynecology and obstetrics factors in women of the State of Nayarit, Mexico. With a case-control design were studied 66 cases of high-grade intraepithelial lesions and cervical-uterine-cancer, and 132 controls. The information upon the risk factors was obtained by the application of a structured questionnaire. Polymerase Chain Reaction executed the virus identification. In the statistical analysis the association was obtained by odds ratio. The statistical significance was evaluated by the chi-square-Fisher and Student t tests, and multivariate logistic regression was used to explain the factors' influence. In women with high-risk squamous intraepithelial lesions and cervical-uterine-cancer, the most frequently high-risk human papillomavirus found were: 18, 35, 58, 16, 31, 33 and 51. Familial data of cervical-uterine-cancer, socioeconomic level, number of sexual partners, data of sexual transmitted diseases, and infection due to human papillomavirus 18 and 35 are the factors related to high-risk squamous intraepithelial lesions and cervical-uterine-cancer.


Proximal femoral allograft-prosthesis composites in revision hip replacement: a 12-year follow-up study.
We report the use of an allograft prosthetic composite for reconstruction of the skeletal defect in complex revision total hip replacement for severe proximal femoral bone loss. Between 1986 and 1999, 72 patients (20 men, 52 women) with a mean age of 59.9 years (38 to 78) underwent reconstruction using this technique. At a mean follow-up of 12 years (8 to 20) 57 patients were alive, 14 had died and one was lost to follow-up. Further revision was performed in 19 hips at a mean of 44.5 months (11 to 153) post-operatively. Causes of failure were aseptic loosening in four, allograft resorption in three, allograft nonunion in two, allograft fracture in four, fracture of the stem in one, and deep infection in five. The survivorship of the allograft-prosthesis composite at ten years was 69.0% (95% confidence interval 67.7 to 70.3) with 26 patients remaining at risk. Survivorship was statistically significantly affected by the severity of the pre-operative bone loss (Paprosky type IV; p = 0.019), the number of previous hip revisions exceeding two (p = 0.047), and the length of the allograft used (p = 0.005).


Limited Service Availability, Readiness, and Use of Facility-Based Delivery Care in Haiti: A Study Linking Health Facility Data and Population Data.
Understanding the barriers that women in Haiti face to giving birth at a health facility is important for improving coverage of facility delivery and reducing persistently high maternal mortality. We linked health facility survey data and population survey data to assess the role of the obstetric service environment in affecting women's use of facility delivery care. Data came from the 2012 Haiti Demographic and Health Survey (DHS) and the 2013 Haiti Service Provision Assessment (SPA) survey. DHS clusters and SPA facilities were linked with their geographic coordinate information. The final analysis sample from the DHS comprised 4,921 women who had a live birth in the 5 years preceding the survey. Service availability was measured with the number of facilities providing delivery services within a specified distance from the cluster (within 5 kilometers for urban areas and 10 kilometers for rural areas). We measured facility readiness to provide obstetric care using 37 indicators defined by the World Health Organization. Random-intercept logistic regressions were used to model the variation in individual use of facility-based delivery care and cluster-level service availability and readiness, adjusting for other factors. Overall, 39% of women delivered their most recent birth at a health facility and 61% delivered at home, with disparities by residence (about 60% delivered at a health facility in urban areas vs. 24% in rural areas). About one-fifth (18%) of women in rural areas and one-tenth (12%) of women in nonmetropolitan urban areas lived in clusters where no facility offered delivery care within the specified distances, while nearly all women (99%) in the metropolitan area lived in clusters that had at least 2 such facilities. Urban clusters had better service readiness compared with rural clusters, with a wide range of variation in both areas. Regression models indicated that in both rural and nonmetropolitan urban areas availability of delivery services was significantly associated with women's greater likelihood of using facility-based delivery care after controlling for other covariates, while facilities' readiness to provide delivery services was also important in nonmetropolitan urban areas. Increasing physical access to delivery care should become a high priority in rural Haiti. In urban areas, where delivery services are more available than in rural areas, improving quality of care at facilities could potentially lead to increased coverage of facility delivery.


Resistance to ErbB2 tyrosine kinase inhibitors in breast cancer is mediated by calcium-dependent activation of RelA.
The widespread clinical use of therapies targeting the ErbB2 receptor tyrosine kinase oncogene represents a significant advance in breast cancer treatment. However, the development of therapeutic resistance represents a dilemma limiting their clinical efficacy, particularly small-molecule tyrosine kinase inhibitors that block ErbB2 autophosphorylation and activation. Here, we show that lapatinib (GW572016), a highly selective, small-molecule inhibitor of the ErbB2 and epidermal growth factor receptor tyrosine kinases, which was recently approved for the treatment of advanced-stage ErbB2(+) breast cancer, unexpectedly triggered a cytoprotective stress response in ErbB2(+) breast cancer cell lines, which was mediated by the calcium-dependent activation of RelA, the prosurvival subunit of NF-kappaB. Abrogation of lapatinib-induced RelA activation using either small interfering RNA constructs or an intracellular calcium chelator enhanced the apoptotic effects of lapatinib in parental ErbB2(+) breast cancer cells and overcame therapeutic resistance to lapatinib in ErbB2(+) breast cancer lines that had been rendered resistant to lapatinib through chronic exposure to the drug, mimicking the clinical setting. In addition, analysis of changes in phospho-RelA expression in sequential clinical biopsies from ErbB2(+) breast cancers treated with lapatinib monotherapy revealed marginally statistically significant differences between responders and nonresponders, which was consistent with our preclinical findings. Elucidating the regulation of RelA by lapatinib in ErbB2(+) breast cancers, and showing its role in the development of therapeutic resistance to lapatinib, identifies another therapeutic target to overcome or prevent the onset of resistance to lapatinib in some women with ErbB2(+) breast cancers.


Sodium ion interactions with aqueous glucose: insights from quantum mechanics, molecular dynamics, and experiment.
In the last several decades, significant efforts have been conducted to understand the fundamental reactivity of glucose derived from plant biomass in various chemical environments for conversion to renewable fuels and chemicals. For reactions of glucose in water, it is known that inorganic salts naturally present in biomass alter the product distribution in various deconstruction processes. However, the molecular-level interactions of alkali metal ions and glucose are unknown. These interactions are of physiological interest as well, for example, as they relate to cation-glucose cotransport. Here, we employ quantum mechanics (QM) to understand the interaction of a prevalent alkali metal, sodium, with glucose from a structural and thermodynamic perspective. The effect on β-glucose is subtle: a sodium ion perturbs bond lengths and atomic partial charges less than rotating a hydroxymethyl group. In contrast, the presence of a sodium ion significantly perturbs the partial charges of α-glucose anomeric and ring oxygens. Molecular dynamics (MD) simulations provide dynamic sampling in explicit water, and both the QM and the MD results show that sodium ions associate at many positions with respect to glucose with reasonably equivalent propensity. This promiscuous binding nature of Na(+) suggests that computational studies of glucose reactions in the presence of inorganic salts need to ensure thorough sampling of the cation positions, in addition to sampling glucose rotamers. The effect of NaCl on the relative populations of the anomers is experimentally quantified with light polarimetry. These results support the computational findings that Na(+) interacts similarly with α- and β-glucose.


Acute tryptophan depletion in depressed patients treated with a selective serotonin-noradrenalin reuptake inhibitor: augmentation of antidepressant response?
It has frequently been demonstrated that experimental lowering of serotonin (5-HT) neurotransmission by acute tryptophan depletion (ATD) induces a transient depressed mood in 50-60% of patients treated with a selective serotonin reuptake inhibitor (SSRI) who are in remission from depression. In unmedicated depressed patients, ATD has no immediate effect on symptoms. The effects in currently depressed medicated patients have not been investigated. Fourteen currently depressed patients (seven patients treated with a selective serotonin-noradrenalin reuptake inhibitor (SSNRI); seven other treatment, non-SSNRI) received ATD in a double-blind, crossover design. Different strengths of the ATD mixture (aimed at 50% and 90% reduction of tryptophan) were used on separate days. Psychiatric symptoms were assessed at both sessions prior to, at +6.5 h, and at +24 h after ATD. The ATD mixtures induced the expected reductions of plasma tryptophan levels. Full but not partial depletion improved mood and other psychiatric symptoms at +24 h in patients who received SSNRI treatment, as indicated by clinical ratings and self-report. Subjective sleep quality also improved. The effects of ATD on psychiatric symptoms in currently depressed patients are remarkably different from the results in recently remitted SSRI-treated patients. ATD in currently depressed patients treated with serotonergic antidepressants possibly provides important information about the mechanism of action of SSRIs.


Color stability of bulk-fill and universal composite restorations with dissimilar dentin replacement materials.
To determine color changes in bulk-fill composite and universal composite restorations with dissimilar dentin replacement materials in extracted teeth after staining in red wine. Cylindrical, 4 mm deep, class I cavities were prepared in 140 human molars. Bottom 2 mm was restored with Biodentine (Septodont), everX posterior (GC) or experimental HAP inserts. Each dentin replacement material was covered with a 2-mm layer of a universal composite Filtek Z250 or Z550 (3M ESPE) or Gradia Posterior (GC). Groups combining top composite layer and the underlying dentin replacement were designated as "composite_dentin replacement." Filtek Bulk Fill (3M ESPE) and Tetric EvoCeram Bulk Fill (Ivoclar Vivadent) were placed as a single 4-mm layer. Color measurements were performed using Vita Easyshade 4.0 (Vita Zahnfabrik) initially and after 48-hours storage in red wine at 37°C. Color differences (ΔEoo ) ranged between 2.1 ± 0.7 (Z250_HAP) and 7.8 ± 1.1 (Z550_everX). EverX resulted in higher ΔEoo of the overlying composite than HAP (P < .001) and Biodentine (P = .006). Generally, ΔEoo was affected more by decreasing lightness (ΔL') than changes in chroma (ΔC'). EverX resulted in higher ΔEoo of the restoration than Biodentine and experimental HAP after staining in red wine. No significant differences in ΔEoo may be expected in different composites with the same underlying dentin replacement material. The same was generally true for bulk-fill and universal composites. Similar extent of color changes may be expected in bulk-fill and universal composites. Highly translucent everX might exhibit greater color differences irrespective of the capping composite than non-translucent materials. Clinicians have a wider choice of composite materials to cover a particular dentin replacement material, for example, everX or Biodentine, as similar color differences may be expected in various overlying composite brands.


Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type 1-associated and sporadic gastrinomas and pancreatic endocrine tumors.
Endocrine tumors (ETs) of pancreas and duodenum occur sporadically and as a part of multiple endocrine neoplasia type 1 (MEN1). The MEN1 tumor suppressor gene has been localized to chromosome 11q13 by linkage analysis but has not yet isolated. Previous allelic deletion studies in enteropancreatic ETs suggested MEN1 gene involvement in tumorigenesis of familial pancreatic ETs (nongastrinomas) and sporadic gastrinomas. However, only a few MEN1-associated duodenal gastrinomas and sporadic pancreatic nongastrinomas have been investigated. We used tissue microdissection to analyze 95 archival pancreatic and duodenal ETs and metastases from 50 patients for loss of heterozygosity (LOH) on 11q13 with 10 polymorphic markers spanning the area of the putative MEN1 gene. Chromosome 11q13 LOH was detected in 23 of 27 (85%) MEN1-associated pancreatic ETs (nongastrinomas), 14 of 34 (41%) MEN1-associated gastrinomas, 3 of 16 (19%) sporadic insulinomas, and 8 of 18 (44%) sporadic gastrinomas. Analysis of LOH on 11q13 showed different deletion patterns in ETs from different MEN1 patients and in multiple tumors from individual MEN1 patients. The present results suggest that the MEN1 gene plays a role in all four tumor types. The lower rate of 11q13 LOH in MEN1-associated and sporadic gastrinomas and sporadic insulinomas as compared to MEN1 nongastrinomas may reflect alternative genetic pathways for the development of these tumors or mechanisms of the MEN1 gene inactivation that do not involve large deletions. The isolation of the MEN1 gene is necessary to further define its role in pathogenesis of pancreatic and duodenal ETs.


Management of Peri-Implant Hypertrophic Scarring for an Ear Prosthesis.
The clinical report describes a case of a 14-year-old patient with a traumatic amputation of the left auricle and severe hypertrophic scarring. The management of peri-implant soft tissue was challenging, but successful in the rehabilitation of a patient with auricular prosthesis retained by implants. The prosthesis restored the patient's facial aesthetics and contributed not only to function, but also to psychosocial well-being.


Protocol for gene transduction and expansion of human T lymphocytes for clinical immunogene therapy of cancer.
In preparation of a clinical phase I/II study in renal cell carcinoma (RCC) patients, we developed a clinically applicable protocol that meets good clinical practice (GCP) criteria regarding the gene transduction and expansion of primary human T lymphocytes. We previously designed a transgene that encodes a single chain (sc) FvG250 antibody chimeric receptor (ch-Rec), specific for a RCC tumor-associated antigen (TAA), and that genetically programs human T lymphocytes with RCC immune specificity. Here we describe the conditions for activation, gene transduction, and proliferation for primary human T lymphocytes to yield: (a) optimal functional expression of the transgene; (b) ch-Rec-mediated cytokine production, and (c) cytolysis of G250-TAA(POS) RCC by the T-lymphocyte transductants. Moreover, these parameters were tested at clinical scale, i.e., yielding up to 5-10 x 10(9) T-cell transductants, defined as the treatment dose according to our clinical protocol. The following parameters were, for the first time, tested in an interactive way: (1) media compositions for production of virus by the stable PG13 packaging cell; (2) T-lymphocyte activation conditions and reagents (anti-CD3 mAb; anti-CD3+anti-CD28 mAbs; and PHA); (3) kinetics of T-lymphocyte activation prior to gene transduction; (4) (i) T-lymphocyte density, and (ii) volume of virus-containing supernatant per surface unit during gene transduction; and (5) medium composition for T-lymphocyte maintenance (i) in-between gene transduction cycles, and (ii) during in vitro T-lymphocyte expansion. Critical to gene transduction of human T lymphocytes at clinical scale appeared to be the use of the fibronectin fragment CH-296 (Retronectin) as well as Lifecell) X-fold cell culture bags. In order to comply with GCP requirements, we used: (a) bovine serum-free human T-lymphocyte transduction system, i.e., media supplemented with autologous patients' plasma, and (b) a closed cell culture system for all lymphocyte processing. This clinical protocol routinely yields 30-65% scFvG250 ch-Rec(POS) T lymphocytes in both healthy donors and RCC patients.


Clinico-haematological profile of acute megakaryoblastic leukaemia: report of five cases.
Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia. Although known as a distinct entity for a very long time, because of lack of distinct clinical features and morphological criteria, it is difficult to diagnose this variant correctly. We herein present the clinical, morphological, cytochemical, and immunocytochemical features of five cases of AMKL. Certain morphological features such as presence of abnormal platelet count, giant platelets, and cytoplasmic blebbing in blasts were found to be important pointers towards the diagnosis. However, none of the features were found to be consistent and thus morphological diagnosis has to be confirmed by cytochemistry and immunocytochemistry.


Embryonal survival to 6 days in mice selected on different criteria for litter size.
Embryonal survival was compared in mice resulting from four criteria of selection: LS = selection on number born; IX = selection on an index of ovulation rate and ova success; UT = selection on number born to unilaterally ovariectomized females; and LC = unselected control. Selection occurred for 21 generations with three replicates of the four criteria; thereafter, relaxed selection was practiced. The evaluation was performed using mice of two replicates at Generation 35 and one replicate at Generation 36. Data on a total of 289 female mice were recorded. Females, at an average age of 9 wk, were mated to males of the same line. Six days after mating, each female was killed, ovaries were excised, corpora lutea were counted and equated to number of ova shed, and the numbers of implantation sites in each uterine horn were recorded. Least squares means were .84, .91, .85, and .82 for left embryonal survival (left implantations/left ova) and .91, .90, .86, and .87 for right embryonal survival for LS, IX, UT, and LC, respectively. The right side had greater ovulation rate (P < .001) and number of implantations (P < .001). For embryonal survival, the criterion x side interaction was possibly important (P < .09). Selection for litter size by different criteria increased ovulation rate (P < .003) and embryonal survival (P < .05) to 6 d. However, responses in embryonal survival were not greater after UT selection compared with LS or IX selection.


Conjunction in the Language of Emotions.
Oatley and Johnson-Laird (1987) have proposed a cognitive theory of emotion. According to this theory, there are five basic emotions. A major prediction of the theory is that it should permit satisfactory definitions for all the emotion words in a language, and this was essayed for the English language by Johnson-Laird and Oatley (1989). The theory proposes that only one emotional state can be operative at a time, and therefore words referring to mixed emotions were defined by Johnson-Laird and Oatley as disjunctions of basic emotions. Two experiments are reported which com pared these disjunctive definitions with conjunctive definitions (i.e. definitions inconsistent with the theory). For a number of words, conjunctive definitions tended to be preferred. This tendency was increased when the disjunctions and conjunctions were made more explicit. This finding sug gests that Oatley and Johnson-Laird's theory should be modified so as to embrace the conjunction of emotion. That is, it should allow that two or more emotions can be exnerienced in parallel.


Prognostic impact of Claudin 18.2 in gastric and esophageal adenocarcinomas.
The tight junction molecule Claudin 18.2 is selectively expressed in healthy and malignant gastric epithelial tissue and is a promising therapy target for high Claudin 18.2 expressing adenocarcinomas of the esophagogastric junction and stomach (AEG/S). This study analyzed the prevalence, characteristics and prognostic impact of Claudin 18.2 expression in primary tumor, lymph node and distant metastasis in a large Caucasian AGE/S cohort with 414 patients. Claudin 18.2 was highly expressed in 17.1% of primary tumors, 26.7% of lymph node metastasis and 16.7% of distant metastasis. High Claudin 18.2 expression in lymph node metastasis and primary tumors correlated significantly (p < 0.001). High expression of Claudin 18.2 was neither associated with histomorphogical subtype, or tumor state, nor with overall survival. In Caucasian AEG/S patients, 17.1% appeared to be eligible for an anti-Claudin 18.2 therapy. Claudin 18.2 expression itself has no impact on prognosis and is not related to any tumor subtype.


Fifty Years of Unraveling the Clinical Pharmacology of Corticosteroids.
This review will highlight portions of Dr. William Jusko's and colleagues' work that affected the clinical use and study of corticosteroids in acute and chronic disease management. Selected publications related to corticosteroid pharmacokinetics and pharmacodynamics from the 1970s through today were included in this review, with a focus on the foundational human-based studies conducted in the 1970s-1990s. Dr. Jusko contributed significantly to early corticosteroid pharmacology across several domains including: 1) foundational corticosteroid pharmacokinetic methods and parameter development, 2) disease state-variation in corticosteroid pharmacokinetics, 3) drug interaction effects on corticosteroid pharmacokinetics, and 4) early corticosteroid pharmacodynamic studies. In an era where little was known about the pharmacokinetics and pharmacodynamics of corticosteroids, Dr. Jusko's work opened the eyes of researchers and clinicians to the potential for disease and drug interactions that could reduce or enhance the effects of corticosteroids. This significant body of work paved the way for alternative routes of administration that would be useful in concentrating the activity at the site of action and markedly reduced systemic drug exposure, minimizing the risk of adverse effects through application of the dose-sparing pharmacokinetic and pharmacodynamic principles.


The continuous performance test: a window on the neural substrates for attention?
Attention is a complex process whose disturbance is considered a core deficit in a number of disorders [e.g., Attention Deficit Hyperactivity Disorder (ADHD), schizophrenia]. In 1956, Rosvold and colleagues [J. Consult. Psychol. 20 (1956) 343.] demonstrated that the continuous performance test (CPT) as a measure of sustained attention was highly sensitive to brain damage or dysfunction. These findings have been replicated with various populations and with various versions of the CPT. The CPT is now cited as the most frequently used measure of attention in both practice and research. Across studies, results are consistent with models of sustained attention that involve the interaction of cortical (frontal, temporal, parietal), subcortical (limbic, basal ganglia), and functional systems including the pathways between the basal ganglia, thalamus, and frontal lobes. Right hemisphere involvement (asymmetric response) is also evident across multiple studies. As such, the CPT demonstrates sensitivity to dysfunction of the attentional system whether this is due to diffuse or more focal damage/dysfunction or in conjunction with any specific disorder. CPT performance can be viewed as symptom specific (attentional disturbance), but it is not disorder specific (e.g., ADHD). Implications for neuropsychological interpretation of CPT results are presented.


Call for Cultural and Language-Concordant Diabetes Care, Nutrition Education, and Self-Management for South Asian Individuals Living in the US.
Ethnic South Asian Americans have the highest relative risk of type 2 diabetes mellitus in the US. Culturally tailored and language-concordant diabetes care and nutrition interventions can potentially promote South Asian diabetes management and disease progression. From our perspective, the extent of their use and evaluation in the US settings remains limited. This Perspective characterizes and evaluates the necessity and outcomes of culturally and linguistically adapted lifestyle interventions targeted toward type 2 diabetes mellitus indicators among South Asian individuals in the US. Suggestions for how this education could be modified include emphasizing the cultural and linguistic knowledge and self-awareness of diabetes educators and the sociological and historical factors that influence the cultural and linguistic orientation of diabetes care professionals and their clients. Such strategies could ensure better diabetes education and self-management among South Asian individuals.


Clinical Features of Oral Multiple Primary Carcinomas Compared with Oral Single Primary Carcinoma.
Owing to the increase in the older population and the increased life span, the number of patients with oral multiple primary carcinomas will increase. Predicting the second and third carcinoma clinically is difficult, and the presence of second or third carcinomas is a factor that determines the prognosis of oral carcinoma. In this study, we examined the clinical features of oral multiple primary carcinomas treated in our department. We retrospectively reviewed the medical records of patients with oral squamous cell carcinoma who underwent radical treatment at and were followed by the Department of Oral and Maxillofacial Surgery, Tottori University Hospital from January 2003 to October 2017. This study included 261 patients: 241 patients had oral single primary carcinoma and 20 patients had oral multiple primary carcinomas. Oral multiple primary carcinomas showed female predilection and occurred more frequently in the lower gingiva and significantly less frequently in the tongue (P < 0.01). Oral multiple primary carcinomas showed a significantly higher recurrence rate (P < 0.01). The 5-year overall survival of oral single primary carcinoma patients was 88.0% compared with 95% for oral multiple primary carcinomas, with no significant difference (log rank test, P = 0.54). However, the 15-year survival rate dropped to 28.1% in oral multiple primary carcinomas. The cumulative disease incidence rates of metachronous second primary carcinoma from first carcinoma at 5 years and 10 years were 3.45% and 5.36%, respectively. Oral multiple primary carcinomas rarely occur in the tongue. The 5-year survival rate showed no difference between single and multiple carcinoma patients, but over longer observation, the prognosis of multiple carcinoma was poor owing to a high recurrence rate. Because of the high recurrence rate and risk of further metachronous carcinoma in oral multiple primary carcinomas, longer-term follow-up is required.


The immunosuppressive activity of C1q degradation peptides.
We have previously reported the existence and activity of a collagen-like, low molecular weight, suppressive peptide complex in patients with greater than 40% BSA burns. Since C1q participates in the inflammatory response and contains a collagen-like sequence, we have tested, in vitro, the putative generation and immunologic activity of C1q peptide fragments under physical conditions present in burned patients. Nanogram quantities of heat- and enzyme-generated fragments of C1q were shown to be suppressive in vitro to neutrophil chemotaxis, and the mixed lymphocyte response (MLR). The addition of lymphocytes pretreated with C1q fragments suppressed ongoing MLR, indicating the activation of suppressor cells by the peptides. Rabbit anti-C1q globulin was found to reduce the suppressive activity of the collagen-like suppressor which was isolated from human burn sera. Our results therefore suggest that C1q may be an early source of degradation peptides which have strong nonspecific immunosuppressive activity following thermal injuries.


A mechanical model for intraplate earthquakes: application to the new madrid seismic zone
We present a time-dependent model for the generation of repeated intraplate earthquakes that incorporates a weak lower crustal zone within an elastic lithosphere. Relaxation of this weak zone after tectonic perturbations transfers stress to the overlying crust, generating a sequence of earthquakes that continues until the zone fully relaxes. Simulations predict large (5 to 10 meters) slip events with recurrence intervals of 250 to 4000 years and cumulative offsets of about 100 meters, depending on material parameters and far-field stress magnitude. Most are consistent with earthquake magnitude, coseismic slip, recurrence intervals, cumulative offset, and surface deformation rates in the New Madrid Seismic Zone. Computed interseismic strain rates may not be detectable with available geodetic data, implying that low observed rates of strain accumulation cannot be used to rule out future damaging earthquakes.


A giant myelolipoma discovered as an adrenal incidentaloma: radiological, endocrine and pathological evaluation.
A 51-year-old Filipino woman presenting with hypertension was unexpectedly found to have a large right adrenal mass by ultrasound. As she did not have symptoms of adrenal disease, this was labelled an adrenal incidentaloma. Ultrasound and CT imaging demonstrated a large adrenal mass on the right measuring 15 cm at its greatest diameter, with both benign and malignant features. Tests for endocrine hyperfunction (excess of cortisol, catecholamines and aldosterone) concluded that the mass was hormonally non-functioning. The patient eventually underwent open adrenalectomy. Histopathological examination revealed myelolipoma.


Inferring the diameter of a biopolymer from its stretching response.
We investigate the stretching response of a thick polymer model by means of extensive stochastic simulations. The computational results are synthesized in an analytic expression that characterizes how the force versus elongation curve depends on the polymer structural parameters: its thickness and granularity (spacing of the monomers). The expression is used to analyze experimental data for the stretching of various different types of biopolymers: polypeptides, polysaccharides, and nucleic acids. Besides recovering elastic parameters (such as the persistence length) that are consistent with those obtained from standard entropic models, the approach allows us to extract viable estimates for the polymers diameter and granularity. This shows that the basic structural polymer features have such a profound impact on the elastic behavior that they can be recovered with the sole input of stretching measurements.


Dietary hesperidin exerts hypoglycemic and hypolipidemic effects in streptozotocin-induced marginal type 1 diabetic rats.
Citrus bioflavonoids may offer some protection against the early stage of diabetes mellitus and the development of complications. We investigated the effect of hesperidin on blood glucose levels, hepatic glucose-regulating enzyme activities, serum insulin and adiponectin levels, serum and hepatic lipid levels, and parameters of bone loss in streptozotocin (STZ)-induced marginal type 1 diabetic rats. Weanling male rats were randomly assigned to experimental 3 groups: a control (C) group, a STZ induced marginal type 1 diabetes (S) group, and a diabetes and hesperidin group, and fed their respective diets for 4 weeks. STZ injection increased blood glucose in rats, but the increase was marginal. Serum and hepatic lipids, serum adiponectin and insulin levels were significantly changed by STZ injection. Dietary hesperidin (10 g/kg diet) decreased blood glucose by altering the activity of glucose-regulating enzymes, and normalized the lipids and adiponectin levels, but did not change bone parameters in the marginal type 1 diabetic rats. Hesperidin showed both hypoglycemic and hypolipidemic effects but did not affect bone tissue and bone metabolic makers in STZ-injected marginal diabetic weanling rats without any body weight loss due to STZ injection.


Deconstructing B cell tolerance to basement membranes.
Basement membrane antigens are frequent targets of autoantibody attack in systemic and organ-restricted autoimmunity. These specialized and highly organized matrices are composed of multiple components with restricted tissue distributions and limited epitope exposure. To dissect mechanisms controlling humoral autoimmunity to nephritogenic basement membrane antigens, we developed autoantibody transgenic models. In mice bearing the LamH Ig transgene encoding B cell receptors specific for laminin, autoreactive B cells are readily generated but actively regulated in vivo. In this model, anti-laminin B cells are immunologically censored by mechanisms that include central deletion, kappa light-chain editing, and anergy. Tolerance is maintained when the transgene is established in MRL and BXSB genetic backgrounds with inherited autoimmune susceptibility, and despite provocation with potent environmental stimulants. Collectively, these studies indicate that the pathogenic anti-laminin reactivity characteristic of systemic lupus is tightly regulated. A novel anti-collagen transgenic model is used to assess the tolerogenesis of a structurally distinct pathogenic basement membrane epitope and to determine if reactivity to putative cryptic epitopes targeted in organ-restricted disease is regulated. These studies should provide insight into the molecular mechanisms controlling basement membrane autoreactivity and ultimately facilitate the development of novel strategies to inactivate autoreactive cells and treat autoimmune disease.


Mining level of control in medical organizations.
In literature of strategic management, there are three layers of control defined in organizational structures. These layers are strategic, tactical and operational, in which resides senior, medium level and low level managers respectively. In strategic level, institutional strategies are determined according to senior managers' perceived state of organization. In tactical level, this strategy is processed into methods and activities of a business management plan. Operational level embodies actions and functions to sustain specified business management plan. An acknowledged lead organization in Turkish medical area is examined using case study and data mining method in the scope of this paper. The level of decisions regarded in managerial purposes evaluated through chosen organization's business intelligence event logs report. Hence specification of management level importance of medical organizations is made. Case study, data mining and descriptive statistical method of taken case's reports present that positions of "Chief Executive Officer", "Outpatient Center Manager", "General Manager", monitored and analyzed functions of operational level management more frequently than strategic and tactical level. Absence of strategic management decision level research in medical area distinguishes this paper and consequently substantiates its significant contribution.


Usefulness of artificial endocrine pancreas during resection of insulinoma.
A 71-year-old woman had an episode of syncope due to hypoglycemia of 27 mg/dl. She was diagnosed with insulinoma and scheduled for laparoscopic enucleation along with the use of an artificial endocrine pancreas (STG-22, Nikkiso Co., Ltd., Tokyo, Japan). Anesthesia was maintained with sevoflurane and remifentanil. Her blood glucose level was controlled using the artificial endocrine pancreas, which enabled continuous blood glucose monitoring and computer-operated glucose and insulin infusion to maintain the blood glucose level at a steady state. The target concentration of blood glucose was set at 80-120 mg/dl during surgery. Until removal of the tumor, the blood glucose level was kept at around 80-100 mg/dl. After removal of the tumor, the blood glucose level gradually increased, but it was kept in the normal range by the artificial endocrine pancreas. The artificial endocrine pancreas was useful to monitor and maintain blood glucose levels during and after the removal of insulinoma, without any hyper- or hypoglycemia.


On the epigenetic regulation of the human reelin promoter.
Reln mRNA and protein levels are reduced by approximately 50% in various cortical structures of post-mortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. To study mechanisms responsible for this down-regulation, we have analyzed the promoter of the human reelin gene. We show that the reelin promoter directs expression of a reporter construct in multiple human cell types: neuroblastoma cells (SHSY5Y), neuronal precursor cells (NT2), differentiated neurons (hNT) and hepatoma cells (HepG2). Deletion constructs confirmed the presence of multiple elements regulating Reln expression, although the promoter activity is promiscuous, i.e. activity did not correlate with expression of the endogenous gene as reflected in terms of reelin mRNA levels. Co-transfection of the -514 bp human reelin promoter with either Sp1 or Tbr1 demonstrated that these transcription factors activate reporter expression by 6- and 8.5-fold, respectively. Within 400 bp of the RNA start site there are 100 potential CpG targets for DNA methylation. Retinoic acid (RA)-induced differentiation of NT2 cells to hNT neurons was accompanied by increased reelin expression and by the appearance of three DNase I hypersensitive sites 5' to the RNA start site. RA-induced differentiation was also associated with demethylation of the reelin promoter. To test if methylation silenced reelin expression, we methylated the promoter in vitro prior to transfection. In addition, we treated NT2 cells with the methylation inhibitor aza-2'-deoxycytidine and observed a 60-fold increase in reelin mRNA levels. The histone deacetylase inhibitors trichostatin A (TSA) and valproic acid also induced expression of the endogenous reelin promoter, although TSA was considerably more potent. These findings indicate that one determinant responsible for regulating reelin expression is the methylation status of the promoter. Our data also raise the interesting possibility that the down-regulation of reelin expression documented in psychiatric patients might be the consequence of inappropriate promoter hypermethylation.


Major abdominal complications following cardiac transplantation. Utah Transplantation Affiliated Hospitals Cardiac Transplant Program.
Serious complications involving the alimentary tract are commonly reported following cardiac transplantation, and may be associated with significant morbidity and mortality. The aim of this report was to review the incidence, severity, and outcome of abdominal complications in our heart transplant population in whom we used corticosteroid-sparing protocols for immunosuppression. From March 1985 through September 1988, 178 patients underwent 185 cardiac transplants. Twenty-six cardiac transplant recipients (15%) sustained 33 major abdominal complications, including gastrointestinal bleeding (n = 8), pancreatitis (n = 8), bowel perforation (n = 6), cholecystitis (n = 4), and miscellaneous other problems (n = 7). Operative therapy was required in 61% of cases. No deaths were caused by the gastrointestinal complications of their operative management. Corticosteroid-sparing immunosuppression may be responsible for the low incidence of abdominal morbidity, and early, aggressive surgical intervention may reduce subsequent mortality.


Adherence to Healthy Lifestyle and the Risk of Function Limitations in Late Life: The Atherosclerosis Risk in Communities Study.
Background: Physiological function impairment is the main precursor of assisted living, movement disorder, and disability in the elderly. The relationship between a combination of healthy lifestyle factors and functional limitations is unclear. We investigated the association between healthy lifestyle scores and the risk of functional impairment in community residents. Methods: A total of 10,602 participants (aged 40-64 years) of the Atherosclerosis Risk in Communities (ARIC) study with no history of cardiovascular events and tumors and who came for their fourth visit (1997-1999) were included in the final analysis. Primary outcomes were recorded during the fourth visit; these included impaired lower extremity function, activities of daily living, and instrumental activities of daily living. A logistic regression model was used to test the associations between healthy lifestyle scores and functional impairment. The lifestyle score comprised six factors: healthy diet, moderate alcohol consumption, coffee consumption, physical activity, normal body weight, and no smoking. Results: Among the 10,602 participants with a median follow-up of 9 years, the prevalence rates of impaired lower extremity function, activities of daily living, and instrumental activities of daily living were 50.6%, 14.7%, and 21.6%, respectively. In the adjusted Cox regression model, participants with a healthy lifestyle score of 5 plus 6 had a significant lower risk of impaired lower extremity function (odds ratio = 0.252, 95% confidence interval: 0.184-0.344, P < 0.001), activities of daily living (odds ratio = 0.201, 95% confidence interval: 0.106-0.380, P < 0.001), and instrumental activities of daily living (odds ratio = 0.274, 95% confidence interval: 0.168-0.449, P < 0.001) than did participants with a score of 0. The association of healthy lifestyle scores with impaired activities of daily living and instrumental activities of daily living was stronger for individuals without diabetes than for those with it (P for interaction < 0.05). This can be partly explained by the fact that the lowest risk of functional impairment among the participants with diabetes was associated with being overweight. Conclusion: Adherence to an overall healthy lifestyle was associated with a lower risk of physiological function limitation. This study highlights the importance of behavioral interventions in the prevention of disabilities. Clinical Trial Registration: www.ClinicalTrials.gov; Unique identifier: NCT00005131.


Percutaneous nephrolithotomy in the oblique supine lithotomy position and prone position: a comparative study.
To compare the safety, efficacy, and complications of percutaneous nephrolithotomy (PCNL) in the oblique supine lithotomy position vs the prone position in a randomized comparative study. The study included 101 and 102 patients in the oblique supine lithotomy position and prone position, respectively. Inclusion criteria were renal and upper ureteral stones. Exclusion criteria were uncorrectable bleeding disorders, active urinary tract infection, and pregnancy. Both the groups were comparable regarding the male/female ratio, stone size, and site. No significant differences were found in terms of the stone-free rate, blood transfusion rate, and complication rates. Significant differences were reported in mean hemoglobin loss (-1.03 and -2.18 g/dL), mean operative time (86.16 and 111.7 minutes), and mean hospital stay (49.88 and 81.2 hours) in the supine and prone positions, respectively, and anesthesiological parameters (the mean blood pressure decreased by 2 and 14.06 mm Hg, the mean heart rate changed by -0.82 and +13.28 beat/minute, and the peak air way pressure changed by +1.08 cm H2O and +7.56 cm H2O in the supine and prone positions, respectively). PCNL in both positions was equally successful with no significant differences in complications. PCNL in the oblique supine lithotomy position was superior to PCNL in the prone position regarding operative time, hospital stay, and effects on respiratory and cardiovascular status, making it more comfortable for patients and anesthesiologists. Morbidly obese patients, patients with cardiologic disorders, and patients with pulmonary obstructive airway disease need further studies to show if they would benefit from these differences. Additionally, it is more comfortable for the surgeon with little challenges added in the initial puncture.


Assessing the prevalence of alcohol consumption in early pregnancy using blood biomarker analysis: a consistent pattern across north-east England?
We previously investigated the prevalence of alcohol consumption in early pregnancy in Northumbria Healthcare NHS Foundation Trust, a locality of north-east England. The prevalence was 1.4% based on blood sample biomarker analysis using carbohydrate deficient transferrin (CDT) and 3.5% for gamma-glutamyltransferase (GGT). To supplement this research by investigating the prevalence of alcohol use using identical methods in a different locality of the same region. Six-hundred random blood samples taken at the antenatal booking appointment were anonymously analysed for the presence of CDT, a validated marker of chronic alcohol exposure (normalizing 2-3 weeks from abstinence) and GGT, a liver enzyme elevated for up to 8 weeks after alcohol exposure. The North Tees and Hartlepool NHS Foundation Trust data revealed a CDT prevalence rate of 1.7% (95% CI: 0.7-2.9) and GGT prevalence rate of 4.2% (95% CI: 2.6-5.9). However, these measures are not sensitive to low levels of alcohol; and no overlapping cases were identified or a significant correlation demonstrated between CDT or GGT. These data support our earlier work. Prevalence rates according to CDT and GGT analysis were similar in both areas, suggesting similar patterns of sustained alcohol use in pregnancy across the region.


Phenotypic expression of the fibroblast growth factor receptor 3 (FGFR3) mutation P250R in a large craniosynostosis family.
The craniosynostosis syndromes are a heterogeneous group of sporadic, autosomal dominant disorders with significant clinical overlap. Recently, we described a large family with autosomal dominant craniosynostosis suggestive of Saethre-Chotzen syndrome, in which linkage to the Saethre-Chotzen syndrome loci on 7p had been excluded. We now report the presence of a mutation in the fibroblast growth factor receptor 3 (FGFR3) in this family. The mutation, P250R, had been previously reported in 10 patients with non-syndromic craniosynostosis. Variable expression of this mutation is evident especially in two additional members of this family, one of whom is severely affected with pancraniosynostosis. The family provides a further example of genetic heterogeneity and variable expression of the craniosynostosis syndromes and broadens the phenotypic spectrum associated with the FGFR3 mutation P250R. In addition, we found a polymorphism (F384L) in the transmembrane domain of FGFR3 which occurs with a frequency of 3% in the Turkish population but is uncommon among Germans.


Positron emission tomography scans in the evaluation of postchemotherapy residual masses in patients with seminoma.
To assess the ability of positron emission tomography (PET) scans in differentiating between necrosis and viable seminoma in postchemotherapy (PC) residual disease. We conducted a prospective study of 29 patients with seminoma at Indiana University. All patients had PC residual disease. Computed tomography and PET scans were performed for 19 patients after primary chemotherapy (group A) and for 10 patients after salvage chemotherapy (group B). In group A, the PC masses were >/= 3 cm in 14 patients, less than 3 cm in three patients, and not quantified in two patients. All of the patients in group A had negative PET scan results and have had stable or decreasing residual mass size (median follow-up duration, 11.5 months; range, 6 to 26 months). In group B, the PC masses were >/= 3 cm in four patients, less than 3 cm in five patients, and not quantified in one patient. One patient had a positive PET scan result for a posterior mediastinal mass. Pathologic diagnosis of the PET-positive mass showed only necrotic tissue. The same patient had a negative PET scan of the retroperitoneal mass but relapsed in that area. Overall, of patients in group B, five have stable or decreasing mass (median follow-up duration, 8 months; range, 7 to 22 months), and five had relapsed disease. PET scans have no apparent benefit in PC evaluation of residual masses in bulky seminoma.


'Phasing out pig tail docking in the EU - present state, challenges and possibilities'.
European legislation dictates that pig tail docking is not allowed to be performed routinely (European Union. Council Directive 2008/120/EC of 18 December 2008 laying down minimum standards for the protection of pigs. OJ L 47, 18.2.2009). Nevertheless, tail docking is still practiced routinely in many European countries, while four countries stopped routine tail docking completely. Tail docking is also practiced in many countries outside Europe.The Federation of Veterinarians of Europe (FVE), the European Association of Porcine Health Management (EAPHM) together with the European Commission carried out an online survey to investigate the situation regarding the practice of pig tail docking and the provision of enrichment material across 24 European countries. It also focuses on the role of the veterinary profession and gives an overview on published literature regarding the challenges and possibilities related to the raising of pigs with intact tails. Fifty-seven (57) usable survey responses from 24 countries were received. On average 77% (median = 95%) of pigs are routinely tail-docked. In Finland, Norway, Sweden, Switzerland, less than 5% of the pigs are tail-docked. According to the respondents, 67% of pigs (median = 76%) across the 24 EU countries surveyed are given suitable enrichment materials. Training of veterinary practitioners, their role in advising the producer and undertaking a risk assessment of tail biting were more positively valued in countries that stopped routine tail docking than in countries that had not stopped routine tail docking. Initiatives such as training from national authorities to encourage abandoning tail docking and routine recording of tail biting at the slaughterhouse were identified as two successful items to promote the raising of pigs with entire tails. In many European countries the majority of the pigs are still routinely tail-docked, which is a violation of the European legislation. To stop routine tail docking it is necessary to raise the awareness and education about risk factors to prevent tail biting. The growing knowledge about the reasons for failing voluntary national initiatives as well as about successful measures taken by some countries to make pig production with intact tails feasible should be distributed throughout the EU pig producing community. The veterinary profession has a significant role to play in raising awareness, facilitate knowledge transfer and to identify risk factors and solutions on farm level for the benefit of pig health and welfare.


The Relationship Between Scope of Practice Laws for Task Delegation and Nurse Turnover in Home Health.
Nurse turnover can compromise the quality and continuity of home health care. Scope of practice laws, which determine the tasks nurses are allowed to perform and delegate, are an important element of autonomy and vary across states. In this study, we used human resource records from a multistate home health organization to examine the relationship between nurse turnover and whether nurses can delegate tasks to unlicensed aides. A retrospective, cross-sectional analysis. The study sample included 1820 licensed practical nurses and 3309 registered nurses, who spanned 30 states. The study period was 2016 through 2018. We used weighted least squares to study the relationship between nurse turnover for registered and licensed practical nurses and task delegation across state-years. We measured task delegation continuously (0-16 tasks) and as a binary variable (14 or more tasks, which indicated the state was in the top half of the distribution). Across state-years, the turnover rate was 30.8% for licensed practical nurses and 36.8% for registered nurses. Although there was no significant relationship between task delegation and turnover among registered nurses, we found that states in which nurses could delegate the most tasks had lower turnover rates among licensed practical nurses. The ability to delegate tasks to unlicensed aides was correlated with lower turnover rates among licensed practical nurses, but not among registered nurses. This suggests that the ability to delegate tasks is more likely to affect the workload of licensed practical nurses. This also points to a potential and unexplored element of expanding the scope of practice for nurses: reduced turnover. Given the added work-related hazards associated with home health care, including working in isolation, a lack of social recognition, and inadequate reimbursement, states should consider whether changes in their policy environment could benefit nurses working in home health.


Rank information: a structure-independent measure of evolutionary trace quality that improves identification of protein functional sites.
Protein functional sites are key targets for drug design and protein engineering, but their large-scale experimental characterization remains difficult. The evolutionary trace (ET) is a computational approach to this problem that has been useful in a variety of case studies, but its proteomic scale application is partially hindered because automated retrieval of input sequences from databases often includes some with errors that degrade functional site identification. To recognize and purge these sequences, this study introduces a novel and structure-free measure of ET quality called rank information (RI). It is shown that RI decreases in response to errors in sequences, alignments, or functional classifications. Conversely, an automated procedure to increase RI by selectively removing sequences improves functional site identification so as to nearly match manually curated traces in kinases and in a test set of 79 diverse proteins. Thus we conclude that RI partially reflects the evolutionary consistency of sequence, structure, and function. In practice, as the size of the proteome continues to grow exponentially, it provides a novel and structure-free measure of ET quality that increases its accuracy for large-scale automated annotation of protein functional sites.


The interplay between acute bacterial skin and skin structure infections and depression: a vicious circle of major clinical importance.
Previous studies suggest an association between depression and increased risk of various type of infections, including acute bacterial skin and skin structure infections (ABSSSI). Here, we review the latest advancement in our understanding of immunity in patients with depression and its relevance to disease management and diagnosis, with a special focus on patients suffering from ABSSSI. Recent studies have highlighted the role of hypothalamic-pituitary-adrenal axis, neuro-endocrine stress signaling pathways and behavioral attitudes (substance abuse and homelessness) in the pathogenesis of infections in depressed patients. Furthermore, acute bacterial infections, in turn, have emerged as a possible risk for depression development because of different mechanisms including antibiotic-driven changes in the microbiota. Recent evidences have emphasized the threat that comanagement of depression and infection pose to infectious disease physician and psychiatrist. Depressed patients with ABSSSI must be closely monitored for drug side-effects, drug-drug interactions, toxicity, and adequate compliance. New management strategies including new long-acting antibiotics (e.g., dalbavancin) are welcome.


Tau Biology, Tauopathy, Traumatic Brain Injury, and Diagnostic Challenges.
There is considerable interest in the pathobiology of tau protein, given its potential role in neurodegenerative diseases and aging. Tau is an important microtubule associated protein, required for the assembly of tubulin into microtubules and maintaining structural integrity of axons. Tau has other diverse cellular functions involving signal transduction, cellular proliferation, developmental neurobiology, neuroplasticity, and synaptic activity. Alternative splicing results in tau isoforms with differing microtubule binding affinity, differing representation in pathological inclusions in certain disease states, and differing roles in developmental biology and homeostasis. Tau haplotypes confer differing susceptibility to neurodegeneration. Tau phosphorylation is a normal metabolic process, critical in controlling tau's binding to microtubules, and is ongoing within the brain at all times. Tau may be hyperphosphorylated, and may aggregate as detectable fibrillar deposits in tissues, in both aging and neurodegenerative disease. The hypothesis that p-tau is neurotoxic has prompted constructs related to isomers, low-n assembly intermediates or oligomers, and the "tau prion". Human postmortem studies have elucidated broad patterns of tauopathy, with tendencies for those patterns to differ as a function of disease phenotype. However, there is extensive overlap, not only between genuine neurodegenerative diseases, but also between aging and disease. Recent studies highlight uniqueness to pathological patterns, including a pattern attributed to repetitive head trauma, although clinical correlations have been elusive. The diagnostic process for tauopathies and neurodegenerative diseases in general is challenging in many respects, and may be particularly problematic for postmortem evaluation of former athletes and military service members.


In-depth structural characterization of oligosaccharides released by GH107 endofucanase MfFcnA reveals enzyme subsite specificity and sulfated fucan substructural features.
The extracellular matrix of brown algae represents an abundant source of fucose-containing sulfated polysaccharides (FCSPs). FCSPs include sulfated fucans, essentially composed of fucose, and highly heterogeneous fucoidans, comprising various monosaccharides. Despite a range of potentially valuable biological activities, the structures of FCSPs are only partially characterized and enzymatic tools leading to their deconstruction are rare. Previously, the enzyme MfFcnA was isolated from the marine bacterium Mariniflexile fucanivorans and biochemically characterized as an endo-α-1 → 4-l-fucanase, the first member of glycoside hydrolase family 107. Here, MfFcnA was used as an enzymatic tool to deconstruct the structure of the sulfated fucans from Pelvetia canaliculata (Fucales brown alga). Oligofucans released by MfFcnA at different time points were characterized using mass spectrometry coupled with liquid chromatography and tandem mass spectrometry through Charge Transfer Dissociation. This approach highlights a large diversity in the structures released. In particular, the analyses show the presence of species with less than three sulfates per two fucose residues. They also reveal species with monosaccharides other than fucose and the occurrence of laterally branched residues. Precisely, the lateral branching is either in the form of a hexose accompanied by a trisulfated fucose nearby, or of a side chain of fucoses with a pentose as the branching point on the polymer. Overall, the results indicate that the structure of sulfated fucans from P. canaliculata is more complex than expected. They also reveal the interesting capacity of MfFcnA to accommodate different substrates, leading to structurally diverse oligofucan products that potentially could be screened for bioactivities.


Long-term prediction of functional outcome after stroke using the Alberta Stroke Program Early Computed Tomography Score in the subacute stage.
Stroke patients who arrive at hospital more than 24 hours after symptom onset could benefit from a simple means of assessing long-term prognosis in this subacute stage. We evaluated whether clinical factors along with ischemic injury assessed subacutely using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) had predictive value for functional independence after stroke. Computed tomography (CT) scans obtained ≥ 2 days after first-ever ischemic stroke were scored independently and retrospectively by 3 stroke neurologists using the ASPECTS. Functional outcome was measured using the Functional Independence Measure, which assesses the amount of caregiver assistance required by patients during daily activities. Multiple linear regression was used to develop a predictive model for functional prognosis at 1 month, 3 months, and 1 year poststroke. For our 55 patients, CT scanning was done on average 4 days poststroke. The interrater agreement for subacute ASPECTS was excellent, with a κ-weighted value of 0.90. Lesions involving the frontal and superior parietal ASPECTS regions were significant predictors of lower Functional Independence Measure scores at all 3 time points studied. In combination with such factors as age, marital status, and the severity of initial neurologic deficit, a subacute ASPECTS score >5 had significant predictive value for greater functional independence at 3 months (R(2) = 0.701; P < .001) and 1 year (R(2) = 0.528; P < .001) poststroke. Our data indicate that in the subacute stage, ASPECTS is reliable and can help predict which patients may be likely to regain functional independence up to 1 year after sustaining ischemic stroke.


[Frequency of skeletal chest injuries associated with cardiopulmonary resuscitation: forensic autopsy].
Fractured ribs and sternum are frequent complications of thoracic compression during CPR (cardiopulmonary resuscitation) in adults. This study was conducted to determine the incidence of rib and sternal fractures after conventional closed-chest compression in the treatment of cardiac arrest. We reviewed the forensic autopsy findings of 231 deaths referred to the Pamukkale University Department of Forensic Medicine over a 12-month period, 2004-2005. CPR-related chest injuries comprising rib and sternum fractures, ecchymosis and subcostal hemorrhage were compared retrospectively in 104 patients. Ninety-one (87.5%) of the 104 patients were adults, and 13 patients (12.5%) were children. The mean (SD) age in the pediatric group (5F/8M) was 5.48 (+/-5.96) and in the adult group (18F/73M) was 44.88 (+/-18.31). Forty-four (42.3%) of the 104 patients died of traumatic cause and 60 (57.7%) of non-traumatic cause. Ecchymosis was present in 26 (28.8%) patients, subcostal hemorrhage in 16 (17.6%) patients and fractures (sternal and costal) in 12 (13.2%) patients in adults. There were no significant differences between groups according to age, sex and traumatic-nontraumatic cause in terms of skeletal chest injuries associated with CPR in adult patients (p>0.05). This study shows a low incidence of rib and sternal fracture after closed-chest compression in the treatment of cardiac arrest in forensic autopsy cases.


Inhibition of the Na,K pump by vanadate in high-Na solutions. Modification of the reaction mechanism by external Na acting at a high-affinity site.
We have examined vanadate inhibition of the Na,K pump in the presence of external Na (Nao). Nao protects against inhibition of the Na,K pump by vanadate, but not against inhibition by phosphate or arsenate. Protection by Nao is reversed by external K (Ko). Although the site at which Na exerts its protective effect has properties similar to the two transport sites for K at the outside of the pump, it is not one of the transport sites. The data can be qualitatively accounted for if it is postulated that there is a protective site, separate from the transport sites, at which Nao and Ko compete. When the site is empty or bound to K, vanadate combines with high affinity with pumps that have two K ions bound to the transport sites, but not with pumps that have Na bound to the protective site, even if K is bound to the transport sites. The protective site has a high affinity for both Na and K; the apparent K 1/2 for external Na is less than 2 mM, which is similar to that of a previously described site at which Nao inhibits a number of the partial reactions of the pump. Nao protects against vanadate inhibition of the K-K exchange in the absence of cell Na, and against vanadate inhibition of p-nitrophenylphosphatase activity of the pump in the absence of ATP. The protective site is a manifestation of an E2 conformation of the pump. The protective effect of Nao is not changed by altering the intracellular Mg2+ concentration.


Anatomy of a Woebot® (WB001): agent guided CBT for women with postpartum depression.
Postpartum depression (PPD) is common, persistent, and stigmatized. There are insufficient trained professionals to deliver appropriate screening, diagnosis, and treatment. WB001 is a Software as a Medical Device (SaMD) based Agent-Guided Cognitive-Behavioral Therapy (AGCBT) program for the treatment of PPD, for which Breakthrough Device Designation was recently granted by the US Food and Drug Administration. WB001 combines therapeutic alliance, human-centered design, machine learning techniques, and established principles from CBT and interpersonal therapy (IPT). We introduce AGCBT as a new model of service delivery, whilst describing Woebot, the agent technology that enables guidance through the replication of some elements of human relationships. The profile describes the device's design principles, enabling technology, risk handling, and efficacy data in PPD. WB001 is a dynamic and personalized tool with which patients may establish a therapeutic bond. Woebot is designed to augment (rather than replace) human healthcare providers, unlocking the therapeutic potency associated with guidance, whilst retaining the scalability and agency that characterizes self-help approaches. WB001 has the potential to improve both the quality and the scalability of care through providing support to patients on waiting lists, in between clinical encounters, and enabling automation of measurement-based-care.


Purification and characterization of two isoenzymes of lipoxygenase from soybeans.
A chromatographic procedure for the purification of two lipoxygenase isoenzymes (linoleate: O2 oxidoreductase, EC 188.8.131.52.) from soybean is described. The procedure for the purification of isoenzyme L-1 includes optimalized extraction, ammonium sulfate fractionation, heat treatment and gradient elution from a CM-Sephadex C-50 column. The purification of L-2 includes ammonium sulfate fractionation, gelfiltration on Sephadex G-150 and gradient elution from a DEAE-cellulose column. Both isoenzymes L-1 and L-2 appear homogeneous after Disc-PAGE. The isoelectric points are 5.6 for L-1 and 5.8 for L-2. Molecular weights are estimated as 100,000 for L-1 as well as L-2 applying three different methods. Both isoenzymes contain 0.9 mol iron per mol protien. The estimated turn over numbers are 8,200 mol linoleate per mol enzyme and min for L-1 and 3,100 for L-2. Amino acid compositions determined after acid hydrolysis show marked differences between L-1 and L-2, particularly with respect to the amino acids Lys, Phe, Ser, Gly and Leu. L-1 posesses a total of 9 cysteine molecules, 6 of which are present as disulfide bonds. L-2 posesses a total of 8 cysteine molecules with only one disulfide bond.


Type 1 IFN inhibits the growth factor deprived apoptosis of cultured human aortic endothelial cells and protects the cells from chemically induced oxidative cytotoxicity.
It has been shown that the genesis of atherosclerotic lesions is resulted from the injury of vascular endothelial cells and the cell damage is triggered by oxygen radicals generated from various tissues. Human vascular endothelial cells can survive and proliferate depending on growth factors such as VEGF or basic FGF and are induced apoptosis by the deprivation of growth factor or serum. It was found that type 1 IFN inhibits the growth factor deprived cell death of human aortic endothelial cells (HAEC) and protects the cells from chemically induced oxidative cytotoxicity. The anti-apoptotic effects of type 1 IFN were certified by flow cytometry using annexin-V-FITC/PI double staining and cell cycle analysis, fluorescence microscopy using Hoechst33342 and PI, colorimetric assay for caspase-3 activity, p53 and bax mRNA expressions, and cell counts. It was considered that IFN-β inhibits the executive late stage apoptosis from the results of annexin-V-FITC/PI double staining and the inhibition of caspase-3 activity, and that the anti-apoptotic effect might be owing to the direct inhibition of the apoptotic pathway mediated by p53 from the transient down-regulation of bax mRNA expression. Whereas, type 1 IFN protected the cells from the oxidative cytotoxicity induced by tertiary butylhydroperoxide (TBH) under the presence of Ca(2+). The effects of IFN-β is more potent inhibitor of cell death than IFN-α. These results indicate that type 1 IFN, especially IFN-β may be useful for the diseases with vascular endothelium damage such as atherosclerosis or restenosis after angioplasty as a medical treatment or a prophylactic.


Regional brain activation during proximal stomach distention in humans: A positron emission tomography study.
Hypersensitivity to proximal gastric distention due to abnormal central nervous system processing of visceral stimuli has been suggested as a possible underlying pathophysiologic mechanism in functional dyspepsia. However, the cortical regions activated by distention of the proximal stomach have not been identified. The aim of this study was to investigate regional brain activation during painful and nonpainful proximal gastric distention in humans. Positron emission tomography of the brain was performed in 11 healthy volunteers during 4 conditions: (1) no distention and isobaric distention to the individual thresholds for (2) first, (3) marked, and (4) unpleasant sensation. Data were analyzed using statistical parametric mapping. During maximal distention relative to baseline, significant (P corrected <.05) regional brain activation occurred in the left and right gyrus postcentralis (Brodmann area [BA] 43), the left gyrus temporalis superior (BA 38), the right gyrus frontalis inferior (BA 47, orbitofrontal cortex), the right midanterior cingulate gyrus (BA 24), the right anterior insula, and the left cerebellar hemisphere. These areas showed a progressive increase in activation with increasing intensity of the distending stimulus. We found evidence for a neuronal network processing distention stimuli of the proximal stomach that is overall consistent with the "visceral stimulation network" described in the literature. In addition, we found activation of the orbitofrontal cortex, confirming its role as a convergence zone for processing of food-related stimuli and regulation of hunger, appetite, satiety, and food intake. We found no evidence for a functional neuroanatomic divergence in the processing of noxious and innocuous gastric stimuli.


Visual short-term memory compared in rhesus monkeys and humans.
Change detection is a popular task to study visual short-term memory (STM) in humans [1-4]. Much of this work suggests that STM has a fixed capacity of 4 ± 1 items [1-6]. Here we report the first comparison of change-detection memory between humans and a species closely related to humans, the rhesus monkey. Monkeys and humans were tested in nearly identical procedures with overlapping display sizes. Although the monkeys' STM was well fit by a one-item fixed-capacity memory model, other monkey memory tests with four-item lists have shown performance impossible to obtain with a one-item capacity [7]. We suggest that this contradiction can be resolved using a continuous-resource approach more closely tied to the neural basis of memory [8, 9]. In this view, items have a noisy memory representation whose noise level depends on display size as a result of the distributed allocation of a continuous resource. In accord with this theory, we show that performance depends on the perceptual distance between items before and after the change, and d' depends on display size in an approximately power-law fashion. Our results open the door to combining the power of psychophysics, computation, and physiology to better understand the neural basis of STM.


Three-dimensional curvature contrast--geometric or brightness illusion?
Simultaneous contrast effects have been found across a wide range of visual dimensions. We describe a simultaneous contrast effect--three-dimensional curvature contrast--in which the apparent curvature of a surface defined by shading and texture information is influenced by the curvature of a surrounding surface. The effect is strong and easily measurable. We asked whether the effect depends upon the presence of contrast at the level of the internal representation of surface curvature or whether it could be better explained in terms of local changes in the apparent brightness of regions within the test patches induced by luminance transitions at the borders. The experimental results suggest that, while these luminance-contrast-induced effects do contribute to the observed changes in perceived curvature, there are additional influences. In particular changes in perceived curvature induced by a pattern of curved patches were eliminated or considerably weakened when the inducing pattern was transformed into a photographic negative, a procedure which disrupts the apparent three-dimensional structure of the surface patches without changing their brightness contrast. This suggests a component of the illusion involves comparisons at the level of representation of surface curvature. The observation that three-dimensional curvature contrast persists when the inducing surfaces are spatially separate from the test surface suggests that shape perception involves global, as well as local, operations.


Effects of Polyphenols on Oxidative Stress, Inflammation, and Interconnected Pathways during Spinal Cord Injury.
Despite the progression in targeting the complex pathophysiological mechanisms of neurodegenerative diseases (NDDs) and spinal cord injury (SCI), there is a lack of effective treatments. Moreover, conventional therapies suffer from associated side effects and low efficacy, raising the need for finding potential alternative therapies. In this regard, a comprehensive review was done regarding revealing the main neurological dysregulated pathways and providing alternative therapeutic agents following SCI. From the mechanistic point, oxidative stress and inflammatory pathways are major upstream orchestras of cross-linked dysregulated pathways (e.g., apoptosis, autophagy, and extrinsic mechanisms) following SCI. It urges the need for developing multitarget therapies against SCI complications. Polyphenols, as plant-derived secondary metabolites, have the potential of being introduced as alternative therapeutic agents to pave the way for treating SCI. Such secondary metabolites presented modulatory effects on neuronal oxidative stress, neuroinflammatory, and extrinsic axonal dysregulated pathways in the onset and progression of SCI. In the present review, the potential role of phenolic compounds as critical phytochemicals has also been revealed in regulating upstream dysregulated oxidative stress/inflammatory signaling mediators and extrinsic mechanisms of axonal regeneration after SCI in preclinical and clinical studies. Additionally, the coadministration of polyphenols and stem cells has shown a promising strategy for improving post-SCI complications.


The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis.
The beta-adrenergic receptors (betaARs) are members of the large family of G protein-coupled receptors. There are three betaAR subtypes (beta1AR, beta2AR beta3AR), each of which is coupled to Galphas and the stimulation of intracellular cAMP levels. While beta1AR and beta2AR are broadly expressed throughout tissues of the body, beta3AR is found predominantly in adipocytes. Stimulation of the betaARs leads to lipolysis in white adipocytes and nonshivering thermogenesis in brown fat. However, in essentially all animal models of obesity, the betaAR system is dysfunctional and the ability to stimulate lipolysis and thermogenesis is impaired. Nevertheless, we and others have shown that selective beta3AR agonists are able to prevent or reverse obesity and the loss of betaAR expression and to stimulate thermogenesis. This chapter will review the current understanding of the role of the sympathetic nervous system and the adipocyte betaARs in models of obesity; the physiologic impact of changes in betaAR expression on body composition and thermogenesis; and the regulation and unique properties of betaAR subtypes in brown and white adipocytes. The latter includes our recent discovery of novel signal transduction mechanisms utilized by beta3AR to activate simultaneously the protein kinase A and MAP kinase pathways. The impact of understanding these pathways and their potential role in modulating adaptive thermogenesis is discussed.


The Control Preferences Scale.
The Control Preferences Scale (CPS) was developed to measure a construct that emerged from a grounded theory of how treatment decisions are made among people with life-threatening illnesses. The control preferences construct is defined as "the degree of control an individual wants to assume when decisions are being made about medical treatment." The CPS consists of five cards that each portrays a different role in treatment decision-making using a statement and a cartoon. These roles range from the individual making the treatment decisions, through the individual making the decisions jointly with the physician, to the physician making the decisions. The CPS involves subjects in making a series of paired comparisons to provide their total preference order over the five cards. These preference orders are analyzed using unfolding theory to determine the distribution of preferences in different populations and the effect of covariates on consumer preferences. The scale has been tested in a variety of populations, ranging from the general public to highly stressed groups. The CPS has proven to be a clinically relevant, easily administered, valid, and reliable measure of preferred roles in health-care decision-making.


Validation of Polygenic Scores for QT Interval in Clinical Populations.
Polygenic risk scores (PGS) enable rapid estimation of genome-wide susceptibility for traits, which may be useful in clinical settings, such as prediction of QT interval. In this study, we sought to validate PGS for QT interval in 2 real-world cohorts of European ancestry (EA) and African ancestry (AA). Two thousand nine hundred and fifteen participants of EA and 366 of AA in the MGH CAMP study (Cardiology and Metabolic Patient) were genotyped on a genome-wide array and imputed to the 1000 Genomes reference panel. An additional 820 EA and 57 AA participants in the Partners Biobank were genotyped and used for validation. PGS were created for each individual using effect estimates from association tests with QT interval obtained from prior genome-wide association studies, with variants selected based from multiple significance thresholds in the original study. In regression models, clinical variables explained ≈9% to 10% of total variation in resting QTc in EA individuals and ≈12% to 18% in AA individuals. The PGS significantly increased variation explained at most significance thresholds (P<0.001), with a trend toward increased variation explained at more stringent P value cut points in the CAMP EA cohort (P<0.05). In AA individuals, PGS provided no improvement in variation explained at any significance threshold. For individuals of European descent, PGS provided a significant increase in variation in QT interval explained compared with a model with only nongenetic factors at nearly every significance level. There was no apparent benefit gained by relaxing the significance threshold from conventional genome-wide significance (P<5×10-8).


Effect of Cu intercalation on humidity sensing properties of Bi2Se3 topological insulator single crystals.
Here we report the self-flux method-based synthesis of CuxBi2Se3 (x = 0, 0.13 and 0.25) topological insulator (TI) single crystals with high phase purity for humidity sensing for the first time. The samples were thoroughly characterized using XRD, FESEM, Raman, etc. The chemi-resistive humidity sensing performance of the obtained Cu0.25Bi2Se3 single crystal exhibits high sensitivity (∼849%) with decent response time (24 s) and recovery (25 s) time, negligible hysteresis (<1%) and excellent stability within an 8-97% relative humidity (RH) range at room temperature. The Freundlich isotherm model shows improved adsorption parameters (k and α) for CuxBi2Se3 (x = 0.25) over the entire RH region demonstrating the improved sensing performance of Bi2Se3 TIs with Cu intercalation. The effect of Cu intercalation in Bi2Se3 was investigated using the Langmuir adsorption isotherm (LA) model signifying the role of faster conduction of water vapour over the surface with a single active site for the adsorption-desorption process. The current experimental results suggest that CuxBi2Se3 TIs hold immense potential for important applications related to sensing.


[Disorders of physiological parameters of the body (lipid peroxidation and microcirculation) after naso-orbital injuries and the methods of their correction].
A naso-orbital injury is often associated with a craniocerebral injury due to the close anatomical localization of the facial and cerebral compartments of the skull. Patients with such injuries showed enhancement of free-radical lipid oxidation and microcirculation disorders. They were controlled by traditional therapeutic methods in combination with antioxidants of direct and indirect action (ascorbic acid, flacumin, alpha-tocopherol acetate, pentoxifylline ) that were given in standard doses. Improvement of microcirculation and decrease of free-radical oxidation of lipids were followed by faster normalization of bioelectric activity and hemodynamics of the brain and earlier clinical recovery. Microcirculation parameters recorded during biomicroscopy of vessels of the bulbar conjunctiva can be used for evaluating cerebral circulation because vessel responses of the eyeball and the brain are similar.


An examination of the prepatent period and the absence of a crowding effect in Angiostrongylus cantonensis in laboratory rats.
The effects of the size of the infective inoculum on the prepatent period and the effect of crowding on body volume were examined in populations of Angiostrongylus cantonensis (Metastrongyloidea: Angiostrongylidae) in the laboratory rat. Groups of five rats were infected with 5, 10, 20 and 40 L3 of A. cantonensis, respectively. The prepatent period was determined by examination of faeces using a modified Baermann technique. The prepatent period ranged from 37 to 45 days and was best described by a negative logarithmic curve (y = 51.21 + x-3.838). Based on developmental data in the literature, it is suggested that 37 days represents the minimum prepatent period for A. cantonensis in this host. Worm population showed a significant, positive increase with inoculum size, yet there was no relationship between worm volume and population size in females and a slight, but significant, increase in worm volume and population size in males from rats necropsied 76-84 days post-infection. It is concluded that crowding is likely to have little effect on worm size in rats naturally infected with A. cantonensis.


Biphasic Effect of Profilin Impacts the Formin mDia1 Force-Sensing Mechanism in Actin Polymerization.
Formins are force-sensing proteins that regulate actin polymerization dynamics. Here, we applied stretching tension to individual actin filaments under the regulation of formin mDia1 to investigate the mechanical responses in actin polymerization dynamics. We found that the elongation of an actin filament was accelerated to a greater degree by stretching tension for ADP-G-actin than that for ATP-G-actin. An apparent decrease in the critical concentration of G-actin was observed, especially in ADP-G-actin. These results on two types of G-actin were reproduced by a simple kinetic model, assuming the rapid equilibrium between pre- and posttranslocated states of the formin homology domain two dimer. In addition, profilin concentration dramatically altered the force-dependent acceleration of actin filament elongation, which ranged from twofold to an all-or-none response. Even under conditions in which actin depolymerization occurred, applications of a several-piconewton stretching tension triggered rapid actin filament elongation. This extremely high force-sensing mechanism of mDia1 and profilin could be explained by the force-dependent coordination of the biphasic effect of profilin; i.e., an acceleration effect masked by a depolymerization effect became dominant under stretching tension, negating the latter to rapidly enhance the elongation rate. Our findings demonstrate that the biphasic effect of profilin is controlled by mechanical force, thus expanding the function of mDia1 as a mechanosensitive regulator of actin polymerization.