Defective imitation of gestures in patients with damage in the left or right hemispheres.
Defective imitation of meaningless gestures has repeatedly been demonstrated in patients with apraxia and has been interpreted as being due to a deficit of motor execution. There is, however, controversy as to whether some impairment of imitation also occurs in patients with right brain damage. The aim was to compare defective imitation in patients with left and right brain damage and to explore whether there are qualitative differences between them. Imitation was examined in 80 patients with left brain damage (LBD) and aphasia, 40 patients with right brain damage (RBD), and 60 controls for three types of gestures:hand positions, finger configurations, and combined gestures which required a defined hand position as well as a defined configuration of the fingers. Regardless of whether imitation of hand positions and finger configurations were tested each on their own or together, they showed differential susceptibility to RBD and LBD. Whereas imitation of finger configurations was about equally impaired in RBD and LBD, defective imitation of hand positions occurred almost exclusively in patients with LBD, and whereas controls as well as patients with RBD committed less errors with hand positions than with finger configurations, the reverse was the case in patients with LBD. The pattern of results goes against a deficit of motor execution as being the cause of defective imitation in patients with LBD, as it is difficult to see why such a deficit should affect proximal movements necessary for reaching hand positions more than differential finger movements. An alternative explanation would be that in patients with LBD errors are due to defective mediation by knowledge about the human body whereas in patients with RBD they stem from faulty visuospatial analysis of the demonstrated gesture.


Histone Acetyltransferase KAT6A Upregulates PI3K/AKT Signaling through TRIM24 Binding.
Lysine acetyltransferase KAT6A is a chromatin regulator that contributes to histone modification and cancer, but the basis of its actions are not well understood. Here, we identify a KAT6A signaling pathway that facilitates glioblastoma (GBM), where it is upregulated. KAT6A expression was associated with GBM patient survival. KAT6A silencing suppressed cell proliferation, cell migration, colony formation, and tumor development in an orthotopic mouse xenograft model system. Mechanistic investigations demonstrated that KAT6A acetylates lysine 23 of histone H3 (H3K23), which recruits the nuclear receptor binding protein TRIM24 to activate PIK3CA transcription, thereby enhancing PI3K/AKT signaling and tumorigenesis. Overexpressing activated AKT or PIK3CA rescued the growth inhibition due to KAT6A silencing. Conversely, the pan-PI3K inhibitor LY294002 abrogated the growth-promoting effect of KAT6A. Overexpression of KAT6A or TRIM24, but not KAT6A acetyltransferase activity-deficient mutants or TRIM24 mutants lacking H3K23ac-binding sites, promoted PIK3CA expression, AKT phosphorylation, and cell proliferation. Taken together, our results define an essential role of KAT6A in glioma formation, rationalizing its candidacy as a therapeutic target for GBM treatment. Cancer Res; 77(22); 6190-201. ©2017 AACR.


Primary care physician workforce and Medicare beneficiaries' health outcomes.
Despite a widespread interest in increasing the numbers of primary care physicians to improve care and to moderate costs, the relationship of the primary care physician workforce to patient-level outcomes remains poorly understood. To measure the association between the adult primary care physician workforce and individual patient outcomes. A cross-sectional analysis of the outcomes of a 2007 20% sample of fee-for-service Medicare beneficiaries aged 65 years or older (N = 5,132,936), which used 2 measures of adult primary care physicians (general internists and family physicians) across Primary Care Service Areas (N = 6542): (1) American Medical Association (AMA) Masterfile nonfederal, office-based physicians per total population and (2) office-based primary care clinical full-time equivalents (FTEs) per Medicare beneficiary derived from Medicare claims. Annual individual-level outcomes (mortality, ambulatory care sensitive condition [ACSC] hospitalizations, and Medicare program spending), adjusted for individual patient characteristics and geographic area variables. Marked variation was observed in the primary care physician workforce across areas, but low correlation was observed between the 2 primary care workforce measures (Spearman r = 0.056; P < .001). Compared with areas with the lowest quintile of primary care physician measure using AMA Masterfile counts, beneficiaries in the highest quintile had fewer ACSC hospitalizations (74.90 vs 79.61 per 1000 beneficiaries; relative rate [RR], 0.94; 95% confidence interval [CI], 0.93-0.95), lower mortality (5.38 vs 5.47 per 100 beneficiaries; RR, 0.98; 95% CI, 0.97-0.997), and no significant difference in total Medicare spending ($8722 vs $8765 per beneficiary; RR, 1.00; 95% CI, 0.99-1.00). Beneficiaries residing in areas with the highest quintile of primary care clinician FTEs compared with those in the lowest quintile had lower mortality (5.19 vs 5.49 per 100 beneficiaries; RR, 0.95; 95% CI, 0.93-0.96), fewer ACSC hospitalizations (72.53 vs 79.48 per 1000 beneficiaries; RR, 0.91; 95% CI, 0.90-0.92), and higher overall Medicare spending ($8857 vs $8769 per beneficiary; RR, 1.01; 95% CI, 1.004-1.02). A higher level of primary care physician workforce, particularly with an FTE measure that may more accurately reflect ambulatory primary care, was generally associated with favorable patient outcomes.


The spread of carbapenemase-producing bacteria in Africa: a systematic review.
Carbapenems are the last line of defence against ever more prevalent MDR Gram-negative bacteria, but their efficacy is threatened worldwide by bacteria that produce carbapenemase enzymes. The epidemiology of bacteria producing carbapenemases has been described in considerable detail in Europe, North America and Asia; however, little is known about their spread and clinical relevance in Africa. We systematically searched in PubMed, EBSCOhost, Web of Science, Scopus, Elsevier Masson Consulte and African Journals Online, international conference proceedings, published theses and dissertations for studies reporting on carbapenemase-producing bacteria in Africa. We included articles published in English or French up to 28 February 2014. We calculated the prevalence of carbapenemase producers only including studies where the total number of isolates tested was at least 30. Eighty-three studies were included and analysed. Most studies were conducted in North Africa (74%, 61/83), followed by Southern Africa (12%, 10/83), especially South Africa (90%, 9/10), West Africa (8%, 7/83) and East Africa (6%, 6/83). Carbapenemase-producing bacteria were isolated from humans, the hospital environment and community environmental water samples, but not from animals. The prevalence of carbapenemase-producing isolates in hospital settings ranged from 2.3% to 67.7% in North Africa and from 9% to 60% in sub-Saharan Africa. Carbapenemase-producing bacteria have been described in many African countries; however, their prevalence is poorly defined and has not been systematically studied. Antibiotic stewardship and surveillance systems, including molecular detection and genotyping of resistant isolates, should be implemented to monitor and reduce the spread of carbapenemase-producing bacteria.


Case report of a parathyroid adenoma demonstrated by dual tracer (T1-201 and Tc-99m) subtraction scan.
It is generally agreed that the Technetium-Thallium Subtraction Scan is a reliable method for locating abnormal parathyroid glands in patients with clinical and biochemical evidence of parathyroid hyperactivity. This report illustrates the value of scintigraphy in diagnosis and in the subsequent surgical management of a patient with primary hyperparathyroidism.


Effect of Amino Acid Supplementation on Iron Regulation after Endurance Exercise.
The purpose of this study was to determine the effects of pre-exercise amino acid (AA) supplementation on post-exercise iron regulation. Ten healthy males participated under two different sets of conditions in a randomized, double-blind, crossover design with a washout period of at least 21 days. Participants received either an AA supplement or placebo (PLA) for five consecutive days (4 g/dose, 3 doses/day). On the sixth day, participants ran on a treadmill for 60 min at 70% of maximal oxygen consumption (V˙O2max). Venous blood samples were collected before (baseline), immediately after, and 1 and 3 h after exercise. The serum hepcidin levels increased significantly 3 h post-exercise in both trials when compared to the baseline (p < 0.001), but the levels were not different between trials. The plasma interleukin-6 (IL-6) level significantly increased immediately after exercise compared to the baseline (p < 0.001) and was significantly higher in the AA trial than in the PLA trial (p = 0.014). Moreover, the exercise-induced increase in serum glycerol level was significantly higher in the AA trial (21.20 ± 3.98 mg/L) than in the PLA trial (17.28 ± 4.47 mg/L, p = 0.017). No significant differences were observed between the AA and PLA trials for serum iron, ferritin, and total ketone body levels (p > 0.05). In conclusion, five days of AA supplementation augmented exercise-induced increases in IL-6 and glycerol in healthy males. However, it did not affect post-exercise iron status or regulation.


Down-regulation of MHC class II expression through inhibition of CIITA transcription by lytic transactivator Zta during Epstein-Barr virus reactivation.
The presentation of peptides to T cells by MHC class II molecules is of critical importance in specific recognition to a pathogen by the immune system. The level of MHC class II directly influences T lymphocyte activation. The aim of this study was to identify the possible mechanisms of the down-regulation of MHC class II expression by Zta during EBV lytic cycle. The data in the present study demonstrated that ectopic expression of Zta can strongly inhibit the constitutive expression of MHC class II and CIITA in Raji cells. The negative effect of Zta on the CIITA promoter activity was also observed. Scrutiny of the DNA sequence of CIITA promoter III revealed the presence of two Zta-response element (ZRE) motifs that have complete homology to ZREs in the DR and left-hand side duplicated sequence promoters of EBV. By chromatin immunoprecipitation assays, the binding of Zta to the ZRE(221) in the CIITA promoter was verified. Site-directed mutagenesis of three conserved nucleotides of the ZRE(221) substantially disrupted Zta-mediated inhibition of the CIITA promoter activity. Oligonucleotide pull-down assay showed that mutation of the ZRE(221) dramatically abolished Zta binding. Analysis of the Zta mutant lacking DNA binding domain revealed that the DNA-binding activity of Zta is required for the trans repression of CIITA. The expression of HLA-DRalpha and CIITA was restored by Zta gene silencing. The data indicate that Zta may act as an inhibitor of the MHC class II pathway, suppressing CIITA transcription and thus interfering with the expression of MHC class II molecules.


Self-Propelling Hydrogel/Emulsion-Hydrogel Soft Motors for Water Purification.
We fabricate a kind of catalytic self-propelling hydrogel soft motor (H-motor) via a facile injection loading method with low energy consumption. The factors influencing the practicability of H-motors, including locomotive ability and reusability, are investigated. The succession of rapid bubble evolution and propulsion endows the millimeter-sized columnar H-motors with length/diameter of 1 a remarkable speed of 3.84 mm s(-1) in 10% (w/w) hydrogen peroxide (H2O2) solution. Moreover, the H-motors maintain undiminished propulsion capability and functionality even after repeated loading for 6 times. Additionally, we also fabricate emulsion-hydrogel soft motors (E-H-motors) templated from the oil/water (O/W) emulsion for the first time, which exhibit a faster speed of 4.33 mm s(-1) under the same conditions. It can be ascribed to the additional liberation of low-boiling oil phase stored in the emulsion-hydrogels caused by catalytic reaction heat, which is appropriate for larger propulsive situations. The stabilized, efficient, and reusable H-motors are selected for industrial effluents purification to fit the imperious demands about the disposal of organic pollutants in water. The synergy effect between catalytic degradation and enhanced intermixing of the fluid flow around the miniaturized soft motors gives rise to an effective and exhaustive removal of organic contaminants.


GLIDA: GPCR--ligand database for chemical genomics drug discovery--database and tools update.
G-protein coupled receptors (GPCRs) represent one of the most important families of drug targets in pharmaceutical development. GLIDA is a public GPCR-related Chemical Genomics database that is primarily focused on the integration of information between GPCRs and their ligands. It provides interaction data between GPCRs and their ligands, along with chemical information on the ligands, as well as biological information regarding GPCRs. These data are connected with each other in a relational database, allowing users in the field of Chemical Genomics research to easily retrieve such information from either biological or chemical starting points. GLIDA includes a variety of similarity search functions for the GPCRs and for their ligands. Thus, GLIDA can provide correlation maps linking the searched homologous GPCRs (or ligands) with their ligands (or GPCRs). By analyzing the correlation patterns between GPCRs and ligands, we can gain more detailed knowledge about their conserved molecular recognition patterns and improve drug design efforts by focusing on inferred candidates for GPCR-specific drugs. This article provides a summary of the GLIDA database and user facilities, and describes recent improvements to database design, data contents, ligand classification programs, similarity search options and graphical interfaces. GLIDA is publicly available at http://pharminfo.pharm.kyoto-u.ac.jp/services/glida/. We hope that it will prove very useful for Chemical Genomics research and GPCR-related drug discovery.


Small molecule inhibitors that selectively block dengue virus methyltransferase.
Crystal structure analysis of Flavivirus methyltransferases uncovered a flavivirus-conserved cavity located next to the binding site for its cofactor, S-adenosyl-methionine (SAM). Chemical derivatization of S-adenosyl-homocysteine (SAH), the product inhibitor of the methylation reaction, with substituents that extend into the identified cavity, generated inhibitors that showed improved and selective activity against dengue virus methyltransferase (MTase), but not related human enzymes. Crystal structure of dengue virus MTase with a bound SAH derivative revealed that its N6-substituent bound in this cavity and induced conformation changes in residues lining the pocket. These findings demonstrate that one of the major hurdles for the development of methyltransferase-based therapeutics, namely selectivity for disease-related methyltransferases, can be overcome.


Genome-scale analysis of escherichia coli FNR reveals complex features of transcription factor binding.
FNR is a well-studied global regulator of anaerobiosis, which is widely conserved across bacteria. Despite the importance of FNR and anaerobiosis in microbial lifestyles, the factors that influence its function on a genome-wide scale are poorly understood. Here, we report a functional genomic analysis of FNR action. We find that FNR occupancy at many target sites is strongly influenced by nucleoid-associated proteins (NAPs) that restrict access to many FNR binding sites. At a genome-wide level, only a subset of predicted FNR binding sites were bound under anaerobic fermentative conditions and many appeared to be masked by the NAPs H-NS, IHF and Fis. Similar assays in cells lacking H-NS and its paralog StpA showed increased FNR occupancy at sites bound by H-NS in WT strains, indicating that large regions of the genome are not readily accessible for FNR binding. Genome accessibility may also explain our finding that genome-wide FNR occupancy did not correlate with the match to consensus at binding sites, suggesting that significant variation in ChIP signal was attributable to cross-linking or immunoprecipitation efficiency rather than differences in binding affinities for FNR sites. Correlation of FNR ChIP-seq peaks with transcriptomic data showed that less than half of the FNR-regulated operons could be attributed to direct FNR binding. Conversely, FNR bound some promoters without regulating expression presumably requiring changes in activity of condition-specific transcription factors. Such combinatorial regulation may allow Escherichia coli to respond rapidly to environmental changes and confer an ecological advantage in the anaerobic but nutrient-fluctuating environment of the mammalian gut.


Muscarinic M1 receptors stimulate a nonadrenergic noncholinergic inhibitory pathway in the isolated rat duodenum.
We examined the effect of the muscarinic agonist McN-A-343 (4-m-chlorophenylcarbamoyloxy-2-butynyl trimethyl ammonium) on in vitro preparations of rat small intestine. McN-A-343 (0.1-10 microM) induced a concentration-dependent relaxation of duodenum, jejunum and ileum. This effect was due to activation of muscarinic receptors of the M1 subtype, inasmuch as it was antagonized by atropine (pA2, 8.93) and by the selective M1 antagonists pirenzepine and dicyclomine with high affinity (pA2, 8.09 and 8.14, respectively). Tetrodotoxin, but not hexamethonium, abolished McN-A-343 relaxation indicating involvement of neural pathways and absence of nicotinic transmission. Moreover, in the presence of apamin (0.1 microM) McN-A-343 induced a contractile response. Unlike McN-A-343, acetylcholine contracted the rat duodenum; its concentration-response curve was significantly potentiated by tetrodotoxin, suggesting stimulation of the McN-A-343 sensitive receptor by acetylcholine (P less than .01). Prior treatment of animals with reserpine reduced the potency of McN-A-343 only by 2.5-fold. The gamma-aminobutyric acid (GABA) antagonist bicuculline inhibited McN-A-343 with an affinity comparable to that found for GABA(A) receptors (pA2, 5.52), indicating involvement of GABAergic fibers. ATP is also likely to play a role, as desensitization experiments showed that alpha-beta-methylene ATP induced a comparable decrease of both McN-A-343 and its own response. In contrast, desensitization induced by GABA occurred to a minor extent. Thus, in the rat duodenum, activation of an M1 muscarinic receptor induces relaxation by releasing GABA, and possibly ATP, from myenteric neurons.


Pancreatic abscess following acute pancreatitis.
Pancreatic abscess is probably the most serious complication of acute pancreatitis. During the ten-year period from 1966 to 1975, twenty-eight patients with pancreatic abscess following acute pancreatitis were treated by surgical drainage. A review of these cases revealed that there was a lull in the clinical course of the antecedent pancreatitis prior to the time of surgical drainage in 70% of the cases. Despite an aggressive surgical approach, there were major postoperative problems in 26 patients. Sepsis persisted in 14 patients. Major gastrointestinal hemorrhage occurred in seven, intra-abdominal bleeding in nine, and fistulization in 13. Fourteen patients died (a mortality of 50%). The operative treatment of pancreatic abscess must be aggressive and persistent. In addition to extensive drainage with soft sump drains, vigilance must be exercised to avoid pressure against bowel or major vessels. Reoperation should be considered if postoperative improvement is not sustained.


What type of learner are your students? Preferred learning styles of undergraduate gross anatomy students according to the index of learning styles questionnaire.
Students learn and process information in many different ways. Learning styles are useful as they allow instructors to learn more about students, as well as aid in the development and application of useful teaching approaches and techniques. At the undergraduate level there is a noticeable lack of research on learning style preferences of students enrolled in gross anatomy courses. The Index of Learning Styles (ILS) questionnaire was administered to students enrolled in a large enrollment undergraduate gross anatomy course with laboratory to determine their preferred learning styles. The predominant preferred learning styles of the students (n = 505) enrolled in the gross anatomy course were active (54.9%), sensing (85.1%), visual (81.2%), and sequential (74.4%). Preferred learning styles profiles of particular majors enrolled in the course were also constructed; analyses showed minor variation in the active/reflective dimension. An understanding of students' preferred learning styles can guide course design but it should not be implemented in isolation. It can be strengthened (or weakened) by concurrent use of other tools (e.g., flipped classroom course design). Based on the preferred learning styles of the majority of undergraduate students in this particular gross anatomy course, course activities can be hands on (i.e., active), grounded in concrete information (i.e., sensing), utilize visual representation such as images, figures, models, etc. (i.e., visual), and move in small incremental steps that build on each topic (i.e., sequential). Anat Sci Educ 11: 358-365. © 2017 American Association of Anatomists.


Histologic evaluation of stapled right atrial appendages with fabric buttressing.
The aim of this study was to histologically evaluate the importance of using buttressing materials in stapling the atrial appendages. We stapled the right atrial appendage with a commercial apparatus in 11 mongrel dogs. To evaluate the efficiency of using a buttressing material as an adjunct to stapling, we conducted 30-day studies without (group A: n = 2) or with buttressing material (group B: n = 3) and 90-day studies without (group C: n = 3) or with buttressing material (group D: n = 3) and thereafter made assessments using Doppler echocardiography and performed histologic analyses on all stapled appendages. During surgery, blood oozing from the stapling sites was observed in four of five cases of groups A and C; with buttressing, there was no oozing in groups B and D. In groups A and B, we observed the myocardium of the appendage being focally replaced with fibrous tissue. Myocardium in group C was infiltrated diffusely with loose fibrous tissue and in group D had been almost completely replaced with fibrous tissue. The buttressing material was useful not only in preventing oozing but also likely promoting the growth of fibrous tissue in the right atrial appendage.


Ascorbic acid-induced modulation of venous tone in humans.
Ascorbic acid appears to have vasodilatory properties, but the underlying mechanisms are not well understood. The aims of this study were to define the acute effects of locally infused ascorbic acid in human veins and to explore underlying mechanisms by using pharmacological tools in vivo. Ascorbic acid was infused in dorsal hand veins submaximally preconstricted with the alpha(1)-adrenoceptor agonist phenylephrine or with prostaglandin F(2alpha) in 23 healthy male nonsmokers, and the venodilator response was measured. Ascorbic acid produced dose-dependent dilation with maximum reversal of constriction of 38+/-4% in phenylephrine-preconstricted veins and of 51+/-13% in prostaglandin F(2alpha)-preconstricted veins. Oral pretreatment with the cyclooxygenase inhibitor acetylsalicylic acid or local coinfusion of ascorbic acid and the nitric oxide synthase inhibitor N:(G)-monomethyl-L-arginine had no effect, but coinfusion of ascorbic acid and methylene blue (to inhibit cGMP generation) abolished venodilation. Coinfusion of ascorbic acid and the nonselective potassium channel blocker quinidine abolished venodilation, whereas the inhibitor of ATP-dependent potassium channels glibenclamide had no effect. In cultured bovine endothelial cells, ascorbic acid did not affect intracellular calcium concentration but blunted the response to ATP or digitonin exposure. Ascorbic acid, in millimolar concentrations, dilates human hand veins, presumably by activation of vascular smooth muscle potassium channels through cGMP. This activation is independent of eNOS-mediated nitric oxide synthesis and cyclooxygenase products and does not involve ATP-dependent potassium channels.


Patch recordings from the electrocytes of electrophorus. Na channel gating currents.
Gating currents were recorded at 11 degrees C in cell-attached and inside-out patches from the innervated membrane of Electrophorus main organ electrocytes. With pipette tip diameters of 3-8 microns, maximal charge measured in patches ranged from 0.74 to 7.19 fC. The general features of the gating currents are similar to those from the squid giant axon. The steady-state voltage dependence of the ON gating charge was characterized by an effective valence of 1.3 +/- 0.4 and a midpoint voltage of -56 +/- 7 mV. The charge vs. voltage relation lies approximately 30 mV negative to the channel open probability curve. The ratio of the time constants of the OFF gating current and the Na current was 2.3 at -120 mV and equal at -80 mV. Charge immobilization and Na current inactivation develop with comparable time courses and have very similar voltage dependences. Between 60 and 80% of the charge is temporarily immobilized by inactivation.


Limited maximal vasodilator capacity of forearm resistance vessels in normotensive young men with a familial predisposition to hypertension.
The study was performed to determine whether there is a structural vascular abnormality in normotensive subjects with hypertensive relatives. We examined maximal vasodilator capacity of forearm resistance vessels in 23 normotensive young men (mean blood pressure 94 +/- 0.4 mm Hg, mean +/- SE) with hypertensive relatives (age 24 +/- 0.1 years) and in 17 normotensive subjects (mean blood pressure 85 +/- 0.4 mm Hg) with no family history of hypertension (age 24 +/- 0.1 years). Maximal vasodilator capacity was examined by measuring minimal vascular resistance during peak reactive hyperemia after release from 10 minutes of arterial occlusion. Minimal forearm vascular resistance after release from 10 minutes of arterial occlusion was 25% higher (P less than 0.02) in subjects with hypertensive relatives (2.0 +/- 0.02 units) than that in subjects with no family history (1.5 +/- 0.01) units. We confirmed the previous findings that increasing metabolic vasodilator stimulus by performing intermittent handgrip exercise during 10 minutes of arterial occlusion did not augment peak dilation. This suggests that 10 minutes of arterial occlusion produced maximal vasodilation. Forearm vascular responses to ice on the forehead was greater in subjects with hypertensive relatives than those in subjects with no family history. These results suggest that there may be a structural abnormality in the forearm resistance vessels in normotensive subjects with family history of hypertension.


Surface functional groups of carbon-based adsorbents and their roles in the removal of heavy metals from aqueous solutions: A critical review.
Carbon-based adsorbents such as graphene and its derivatives, carbon nanotubes, activated carbon, and biochar are often used to remove heavy metals from aqueous solutions. One of the important aspects of effective carbon adsorbents for heavy metals is their tunable surface functional groups. To promote the applications of functionalized carbon adsorbents in heavy metal removal, a systematic documentation of their syntheses and interactions with metals in aqueous solution is crucial. This work provides a comprehensive review of recent research on various carbon adsorbents in terms of their surface functional groups and the associated removal behaviors and performances to heavy metals in aqueous solutions. The governing removal mechanisms of carbon adsorbents to aqueous heavy metals are first outlined with a special focus on the roles of surface functional groups. It then summarizes and categorizes various synthesis methods that are commonly used to introduce heteroatoms, primarily oxygen, nitrogen, and sulfur, onto carbon surfaces for enhanced surface functionalities and sorptive properties to heavy metals in aqueous solutions. After that, the effects of various functional groups on adsorption behaviors of heavy metals onto the functionalized carbon adsorbents are elucidated. A perspective of future work on functional carbon adsorbents for heavy metal removal as well as other potential applications is also presented at the end.


Antiproliferative effects of allium derivatives from garlic.
There is increasing evidence that allium derivatives from garlic have significant antiproliferative actions on human cancers. Both hormone-responsive and hormone-unresponsive cells lines respond to these derivatives. The effects shown by allium derivatives include induction of apoptosis, regulation of cell cycle progression and modification of pathways of signal transduction. Allium derivatives appear to regulate nuclear factors involved in immune function and inflammation, as well as in cellular proliferation. Our own studies indicate that allium derivatives inhibit proliferation of the human prostate cancer cell line (LNCaP) and the human breast cancer cell line (MCF-7). Further research is required to clarify the mechanisms of inhibition of cellular proliferation by allium derivatives and to explore their potential application to cancer prevention and control.


PKN1 Exerts Neurodegenerative Effects in an In Vitro Model of Cerebellar Hypoxic-Ischemic Encephalopathy via Inhibition of AKT/GSK3β Signaling.
We recently identified protein kinase N1 (PKN1) as a negative gatekeeper of neuronal AKT protein kinase activity during postnatal cerebellar development. The developing cerebellum is specifically vulnerable to hypoxia-ischemia (HI), as it occurs during hypoxic-ischemic encephalopathy, a condition typically caused by oxygen deprivation during or shortly after birth. In that context, activation of the AKT cell survival pathway has emerged as a promising new target for neuroprotective interventions. Here, we investigated the role of PKN1 in an in vitro model of HI, using postnatal cerebellar granule cells (Cgc) derived from Pkn1 wildtype and Pkn1-/- mice. Pkn1-/- Cgc showed significantly higher AKT phosphorylation, resulting in reduced caspase-3 activation and improved survival after HI. Pkn1-/- Cgc also showed enhanced axonal outgrowth on growth-inhibitory glial scar substrates, further pointing towards a protective phenotype of Pkn1 knockout after HI. The specific PKN1 phosphorylation site S374 was functionally relevant for the enhanced axonal outgrowth and AKT interaction. Additionally, PKN1pS374 shows a steep decrease during cerebellar development. In summary, we demonstrate the pathological relevance of the PKN1-AKT interaction in an in vitro HI model and establish the relevant PKN1 phosphorylation sites, contributing important information towards the development of specific PKN1 inhibitors.


Ophthalmic manifestations of atypical IgD multiple myeloma.
A previously healthy 32-year-old Caucasian female presented with sudden-onset horizontal diplopia following a paroxysm of coughing. She had recently sustained a pubic ramus fracture during an innocuous fall and had also noted a firm lump developing at the right side of her forehead. On examination, she had a right fronto-temporal mass. Visual acuities were 6/6 bilaterally. There was reduced abduction of the right eye, bilateral white, granular corneal opacities and evidence of bilateral optic disc swelling. Haematological investigations revealed normocytic anaemia, hypercalcaemia and raised erythrocyte sedimentation rate (ESR). CT showed lytic foci throughout the skull, ribs, scapulae, spine, pelvis and upper femora. Serum protein electrophoresis revealed immunoglobulin D (IgD)-kappa paraproteinaemia; urine electrophoresis showed free light chain kappa and bone marrow biopsy demonstrated 87% plasma cells. A diagnosis of IgD multiple myeloma was made, with subsequent chemotherapeutic treatment and eventual autologous stem cell transplant resulting in resolution of neuro-ophthalmic manifestations and prolonged disease remission.


Conditional glycosylation in eukaryotic cells using a biocompatible chemical inducer of dimerization.
Chemical inducers of dimerization (CIDs) are cell-permeable small molecules capable of dimerizing two protein targets. The most widely used CID, the natural product rapamycin and its relatives, is immunosuppressive due to interactions with endogenous targets and thus has limited utility in vivo. Here we report a new biocompatible CID, Tmp-SLF, which dimerizes E. coli DHFR and FKBP and has no endogenous mammalian targets that would lead to unwanted in vivo side effects. We employed Tmp-SLF to modulate gene expression in a yeast three-hybrid assay. Finally, we engineered the Golgi-resident glycosyltransferase FucT7 for tunable control by Tmp-SLF in mammalian cells.


Parallel computing applied to breeding value estimation in dairy cattle.
Continuous genetic evaluation of dairy cattle with test-day models is desired in Finland. However, the computing time for the genetic evaluation is 4 d and exceeds the minimum of a weekend. Three parallel implementations of the preconditioned conjugate gradient iterative solver were programmed and compared to identify the best strategy for solving mixed model equations using parallel computing. The programs were used to solve two random regression test-day models with approximately 7.28 and 49.9 million unknowns. The latter model will be used in the Finnish dairy cattle evaluation. Computing times for the smaller model with the four processors available were 52, 32, and 27% of the single processor program when the complexity of the parallel program was increased. In practice, the best program required the most programming because the other parallel programs could not solve the larger model because of excess memory requirements. Parallel computing with four processors reduced the time to obtain solutions of Finnish dairy cattle evaluations to under 2 d. Benefit from parallel computing will be increased if amount of computing memory is increased.


Follicular helper T cells: implications in neoplastic hematopathology.
A distinct subset of T helper cells, named follicular T helper cells (T(FH), has been recently described. T(FH) cells are characterized by their homing capacities in the germinal centers of B-cell follicles where they interact with B cells, supporting B-cell survival and antibody responses. T(FH) cells can be identified by the expression of several markers including the chemokine CXCL13, the costimulatory molecules PD1 and inducible costimulator, and the transcription factor BCL6. They appear to be relevant markers for the diagnosis of angioimmunoblastic T-cell lymphoma (AITL) and have helped to recognize subsets of peripheral T-cell lymphoma, not otherwise specified, with nodal or cutaneous presentation expressing T(FH) antigens that might be related to AITL. In B-cell neoplasms, T(FH) cells are present within the microenvironment of nodular lymphocyte-predominant Hodgkin lymphoma and follicular lymphoma, where they likely support the growth of neoplastic germinal center-derived B cells. Interestingly, the amount of PD1+ cells in the neoplastic follicles might have a favorable impact on the outcome of follicular lymphoma patients. Altogether, the availability of antibodies directed to T(FH)-associated molecules has important diagnostic and prognostic implications in hematopathology. In addition, T(FH) cells could represent interesting targets in T(FH)-derived lymphomas such as AITL, or in some B-cell neoplasms where they act as part of the tumor microenvironment.


[Evaluation of different liquid media for the culture of Gardnerella vaginalis and characterization of the protein profile with PAGE-SDS electrophoresis].
3 liquid culture media: triptose soya broth supplemented with equine serum (TSB-es)/without supplement (TSB) and Casman broth (CB) were evaluated under different incubation conditions at 10% of CO2 and under aerobic conditions. There were no significant differences in the values of optic density for the TSB-es and CB media. However, on establishing the protein profile by PAGE-SDS for the evaluated conditions, the presence of protein of 14 kDa and the values of optic density allowed the selection of the CB medium for the culture of Gardnerella vaginalis. The sensitivity to different pH in this medium was studied. pH 7.2 proved to be optimum and it was established its growth cynetics. The analysis by PAGE-SDS of the complete cells corresponding to different clinical isolates of G. vaginalis with biochemical variations made possible to characterize the protein profile in this medium and showed similarity between the isolates.


Plant folklore: a tool for predicting sources of antitumor activity?
The National Cancer Institute's record of "active plants" (extracts which showed a significant inhibitory effect in experimental tumor systems) was compared with plants reported in folklore to have medicinal or poisonous properties. The occurrence of active plants was found to be higher in plants reported in folk literature than in plants collected at random, suggesting a correlation between plants used in folklore and those with anticancer activity.


DNA polymorphism, haplotype structure and balancing selection in the Leavenworthia PgiC locus.
A study of DNA polymorphism and divergence was conducted for the cytosolic phosphoglucose isomerase (PGI:E.C.18.104.22.168) gene of five species of the mustard genus Leavenworthia: Leavenworthia stylosa, L. alabamica, L. crassa, L. uniflora, and L. torulosa. Sequences of an internal 2.3-kb PgiC gene region spanning exons 6-16 were obtained from 14 L. stylosa plants from two natural populations and from one to several plants for each of the other species. The level of nucleotide polymorphism in L. stylosa PgiC gene was quite high (pi = 0.051, theta = 0.052). Although recombination is estimated to be high in this locus, extensive haplotype structure was observed for the entire 2.3-kb region. The L. stylosa sequences fall into at least two groups, distinguished by the presence of several indels and nucleotide substitutions, and one of the three charge change nucleotide replacements within the region sequenced correlates with the haplotypes. The differences between the haplotypes are older than between the species, and the haplotypes are still segregating in at least two of five species studied. There is no evidence of recent or ancient population subdivision that could maintain distinct haplotypes. The age of the haplotypes and the results of Kelly's Z(nS) and Wall's B and Q tests with recombination suggest that the haplotypes are maintained due to balancing selection at or near this locus.


Manipulating Electron Redistribution in Ni2 P for Enhanced Alkaline Seawater Electrolysis.
Developing bifunctional electrocatalyst for seawater splitting remains a persistent challenge. Herein, an approach is proposed through density functional theory (DFT) preanalysis to manipulate electron redistribution in Ni2 P addressed by cation doping and vacancy engineering. The needle-like Fe-doped Ni2 P with P vacancy (Fe-Ni2 Pv) is successfully synthesized on nickel foam, exhibiting a superior bifunctional hydrogen evolution reaction (HER) and oxygen evolution reaction (OER) catalytic activity for seawater electrolysis in alkaline condition. As a result, bifunctional Fe-Ni2 Pv achieves the industrially required current densities of 1.0 and 3.0 A cm-2 at low voltages of 1.68 and 1.73 V, respectively, for seawater splitting at 60 °C in 6.0 m KOH circumstances. The theoretical calculation and the experimental results collectively reveal the reasons for the enhancement of catalyst activity. Specifically, Fe doping and P vacancies can accelerate the reconstruction of OER active species and optimize the hydrogen adsorption free energy (ΔGH* ) for HER. In addition, the active sites of Fe-Ni2 Pv are identified, where P vacancies greatly improve the electrical conductivity and Ni sites are the dominant OER active centers, meanwhile Fe atoms as active centers for the HER. The study provides a deep insight into the exploration for the enhancement of activity of nickel-based phosphide catalysts and the identification of their real active centers.


Methods used during gross necropsy to determine watercraft-related mortality in the Florida manatee (Trichechus manatus latirostris).
Between 1993 and 2003, 713 (24%) of 2,940 dead Florida manatees (Trichechus manatus latirostris) recovered from Florida waters and examined were killed by watercraft-induced trauma. It was determined that this mortality was the result of watercraft trauma because the external wound patterns and the internal lesions seen during gross necropsy are recognizable and diagnostic. This study documents the methods used in determining watercraft-related mortality during gross necropsy and explains why these findings are diagnostic. Watercraft can inflict sharp- and blunt-force trauma to manatees, and both types of trauma can lead to mortality. This mortality may be a direct result of the sharp and blunt forces or from the chronic effects resulting from either force. In cases in which death is caused by a chronic wound-related complication, the original incident is usually considered to be the cause of death. Once a cause of death is determined, it is recorded in an extensive database and is used by Federal and state managers in developing strategies for the conservation of the manatee. Common sequelae to watercraft-induced trauma include skin lesions, torn muscles, fractured and luxated bones, lacerated internal organs, hemothorax, pneumothorax, pyothorax, hydrothorax, abdominal hemorrhage and ascites, and pyoperitoneum.


Comparison of results of total disc replacement in postdiscectomy patients versus patients with no previous lumbar surgery.
Data for this study were collected as part of a prospective Food and Drug Administration regulated IDE trial for the ProDisc total disc replacement. The purpose of the study was to compare the results of total disc replacement (TDR) in patients with previous discectomy to patients who had no such previous surgery. Discectomy is a well accepted surgical procedure for appropriately selected patients. However, removal of a portion of the disc may lead to further disc degeneration and collapse of the disc space. In the past, treatment options for such patients included a variety of fusion procedures, particularly ones incorporating an interbody graft to restore disc space height. Currently, TDR is being used to treat symptomatic disc degeneration. The results of this procedure have not been specifically investigated in patients with previous discectomy. Data were drawn from 1 center participating in the IDE trial for ProDisc. Only patients reaching the 24-month follow-up period were included. Patients were divided into 2 subgroups: those who had previously undergone lumbar discectomy (N = 20) and those who had not (N = 67). Data for this study were collected prospectively before surgery, and at 6 weeks, 3, 6, 12, 18, and 24 months after surgery. The primary outcome measures used were visual analog scales (VAS) assessing pain, Oswestry questionnaire, postoperative patient satisfaction measured on a 0 to 10 VAS, and asking patients if they would have the same procedure again. The outcome measures were compared between the 2 subgroups. The results of this study found no differences between the 2 groups based on any of the 4 outcome measures used at any of the follow-up periods (all P > 0.10). Both groups improved significantly from the preoperative baseline on the VAS assessing pain and the Oswestry questionnaire. The mean satisfaction scores were greater than 7.5 at all follow-up periods and more than 80% of patients in both groups indicated that they would have the same surgery again. The results of this study indicate that the outcome of TDR is not compromised among patients witha history of previous discectomy. This finding supports TDR as a viable treatment for patients with symptomatic disc degeneration arising from a previously operated lumbar disc.


A Journey to Understand Glucose Homeostasis: Starting from Rat Glucose Transporter Type 2 Promoter Cloning to Hyperglycemia.
My professional journey to understand the glucose homeostasis began in the 1990s, starting from cloning of the promoter region of glucose transporter type 2 (GLUT2) gene that led us to establish research foundation of my group. When I was a graduate student, I simply thought that hyperglycemia, a typical clinical manifestation of type 2 diabetes mellitus (T2DM), could be caused by a defect in the glucose transport system in the body. Thus, if a molecular mechanism controlling glucose transport system could be understood, treatment of T2DM could be possible. In the early 70s, hyperglycemia was thought to develop primarily due to a defect in the muscle and adipose tissue; thus, muscle/adipose tissue type glucose transporter (GLUT4) became a major research interest in the diabetology. However, glucose utilization occurs not only in muscle/adipose tissue but also in liver and brain. Thus, I was interested in the hepatic glucose transport system, where glucose storage and release are the most actively occurring.


Flt3 signaling involves tyrosyl-phosphorylation of SHP-2 and SHIP and their association with Grb2 and Shc in Baf3/Flt3 cells.
Flt3 ligand (FL) is an early-acting potent co-stimulatory cytokine that regulates proliferation and differentiation of a number of blood cell lineages. Its receptor Flt3/Flk2 belongs to class III receptor tyrosine kinases that also include the receptors for colony-stimulating factor 1, Steel factor, and platelet-derived growth factor. Using CSF-1 receptor/Flt3 chimeras, two groups have characterized some of the post-receptor signaling events and substrate specificity of murine Flt3 receptor. However, there are few studies on the signaling pathway through human Flt3. We examined human Flt3 signaling pathways in a murine IL-3-dependent hematopoietic cell line Baf3, which stably expresses full-length human Flt3 receptor. This subline proliferates in response to human FL. Like the chimeric murine Flt3, human Flt3 undergoes autophosphorylation, associates with Grb2, and leads to tyrosine phosphorylation of Shc on ligand binding. We found that SHP-2, but not SHP-1, is tyrosine-phosphorylated by FL stimulation. SHP-2 does not associate with Flt3, but binds directly to Grb2. SHIP is also tyrosine-phosphorylated and associates with Shc after FL simulation. We further examined the downstream signaling pathway. FL transiently activates MAP kinase. This activation could be blocked by PD98059, a specific MEK inhibitor. PD98059 also blocked cell proliferation in response to FL. These results demonstrate that SHP-2 and SHIP are important components in the human Flt3 signaling pathway and suggest that SHP-2 and SHIP, by forming complexes with adapter proteins Grb2 and Shc, may modulate MAP kinase activation, which may be necessary for the mitogenic signaling of Flt3.


Pre-existent vertebral rotation in the human spine is influenced by body position.
Human bipedalism appears to be a prerequisite for the development of idiopathic scoliosis. The objective of this study was to examine the effect of different positions of the human spine on vertebral rotation in vivo. Thirty asymptomatic volunteers underwent MRI scanning of the spine in three different body positions; upright, quadrupedal-like and supine. Vertebral rotation in the local transverse plane was measured and compared at different spinal levels between the three body positions. It was shown that in all three positions the mid and lower thoracic vertebrae were predominantly rotated to the right. However, rotation was significantly less in certain areas of the spine in the quadrupedal-like position than in both the standing upright and supine positions. We hypothesize that the erect position of the human spine, but also the supine position, increases dorsally directed shear loads that may increase the tendency of certain spinal segments to rotate.


When the baby falls!: the cultural construction of miscarriage among Hmong women in Australia.
In this paper, traditional Hmong explanations about miscarriage and the ethnomedical knowledge and practices which pertain to it are explored. They are derived from in-depth interviews and participant observation with the Hmong who are now living in Melbourne, Australia. The loss of pregnancy creates considerable anxiety in Hmong society. This is not only because it calls for a socially justifiable explanation for a family's failure to extend their lineage, but also reduces the venue for a soul to be re-born into the family. This is a threat for Hmong society since it means the extinction of the family, clan and lineage and hence Hmong society. The cultural construction of the causes of miscarriage among the Hmong surrounds two main categories: the natural world which is related to the woman's body and her behaviour; and the supernatural world. These explanations point to the influence that individuals, both living and dead, have on pregnancies. In traditional Hmong society, health is perceived as a harmony between the social, and religious or supernatural realm. A woman being unable to bring forth an offspring because of miscarriage indicates disharmony with the living and/or between the living and the dead.


[Sequestrating senile scleral plaque simulating "necrotizing scleritis". Surgical management].
Presentation and surgical treatment of a sequestrating senile scleral plaque, a rare clinical disorder. A 76 year-old-female patient presented with foreign body sensation and epiphora. Half a year before, she had first noticed a "black spot" in her eye which had now progressed to a painless yellow-greyish plaque. The patient had previously undergone a steroid-treatment elsewhere with a diagnosis "necrotizing scleritis" without any improvement. We found a yellow-greyish degenerative plaque sequestrating from the surrounding scleral tissue. In order to prevent superinfection and to secure the tissue defect we surgically removed the plaque and covered the remaining thin inner scleral tissue layers with autologous sclera and conjunctiva. The clinical diagnosis of a calcified senile scleral plaque was histologically confirmed. The patient has been free from any symptoms since the operation. To our knowledge this is the first description of surgical removal of a deeply sequestrating senile sceral plaque. Calcified sequesters represent a very rare complication of the otherwise frequent senile scleral plaques. Surgical intervention may be required to prevent superinfection and to cover the deep sceral defect. The clinical picture can be distinguished from necrotizing scleritis or scleromalacia perforans. Sequestrating senile scleraplaques do not tend to perforate. They are, however, a risk for infection and chronic inflammation.


[Method of isolating spontaneous variants of actinomycete cultures, producers of antibiotics].
The necessity of taking into account the specific characteristics of the colony differentiation for isolation of spontaneous variants of the initial culture with the method of monospore plating was shown on the examples of the geliomycin-producing culture Actinomyces chromogenes var. trienicus 141-18. It was found that the population density of the colonies had a significant effect on the differentiation rate during the subsequent stages and completeness of the culture development. The less was the population density, the longer was the period of the colony complete development. Definite levels of the colony organization (fractionation of morphogenesis) corresponded to different dilutions of the monospore suspension providing definite population densities of the colonies on the plates. On the basis of the data on the colony differentiation compared with the data on the population density effect upon differentiation it was possible to determine without mistake stable variants on the plates at any dilution of the monospore culture, i.e. with any population density of the colony.


Continuous positive airway pressure titration in infants with severe upper airway obstruction or bronchopulmonary dysplasia.
Noninvasive continuous positive airway pressure (CPAP) is recognized as an effective treatment for severe airway obstruction in young children. The aim of the present study was to compare a clinical setting with a physiological setting of noninvasive CPAP in infants with nocturnal alveolar hypoventilation due to severe upper airway obstruction (UAO) or bronchopulmonary dysplasia (BPD). The breathing pattern and respiratory muscle output of all consecutive infants due to start CPAP in our noninvasive ventilation unit were retrospectively analysed. CPAP set on clinical noninvasive parameters (clinical CPAP) was compared to CPAP set on the normalization or the maximal reduction of the oesophageal pressure (Poes) and transdiaphragmatic pressure (Pdi) swings (physiological CPAP). Expiratory gastric pressure (Pgas) swing was measured. The data of 12 infants (mean age 10 ± 8 mo) with UAO (n = 7) or BPD (n = 5) were gathered. The mean clinical CPAP (8 ± 2 cmH₂O) was associated with a significant decrease in Poes and Pdi swings. Indeed, Poes swing decreased from 31 ± 15 cmH₂O during spontaneous breathing to 21 ± 10 cmH₂O during CPAP (P < 0.05). The mean physiological CPAP level was 2 ± 2 cmH2₂O higher than the mean clinical CPAP level and was associated with a significantly greater improvement in all indices of respiratory effort (Poes swing 11 ± 5 cm H₂O; P < 0.05 compared to clinical CPAP). Expiratory abdominal activity was present during the clinical CPAP and decreased during physiological CPAP. A physiological setting of noninvasive CPAP, based on the recording of Poes and Pgas, is superior to a clinical setting, based on clinical noninvasive parameters. Expiratory abdominal activity was present during spontaneous breathing and decreased in the physiological CPAP setting.


Immediate and sustained hemodynamic and clinical improvement in chronic heart failure by an oral angiotensin-converting enzyme inhibitor.
The hemodynamic effects of an oral angiotensin-converting enzyme inhibitor, captopril, were evaluated in 10 symptomatic patients with chronic congestive heart failure. In all patients there was a significant increase in cardiac output (average 28%), stroke volume (49%), and stroke work index (26%), along with a decrease in pulmonary capillary wedge pressure (48%), indicating improved left ventricular function. Modest decreases in heart rate and arterial pressure were also observed. In seven patients maintained on captopril therapy, repeat hemodynamic studies at 2 months revealed sustained effects. These beneficial hemodynamic effects were accompanied by clinical improvement and improved exercise tolerance during maintenance therapy. These findings suggest that captopril may be a useful therapeutic adjunct for the long-term management of patients with chronic congestive heart failure.


Membrane proteome analysis of cerulein-stimulated pancreatic acinar cells: implication for early event of acute pancreatitis.
Cerulein pancreatitis is similar to human edematous pancreatitis with dysregulation of the production and secretion of digestive enzymes, edema formation, cytoplasmic vacuolization and the death of acinar cells. We hypothesized that membrane proteins may be altered as the early event during the induction of acute pancreatitis. Present study aims to determine the differentially expressed proteins in the membranes of cerulein-treated pancreatic acinar cells. Pancreatic acinar AR42J cells were treated with 10(-8) M cerulein for 1 hour. Membrane proteins were isolated from the cells and separated by two-dimensional electrophoresis using pH gradients of 5-8. Membrane proteins were identified by matrix-assisted laser desorption/ionization-time of flight mass spectrometry (MALDI-TOF MS) analysis of the peptide digests. The differentially expressed proteins, whose expression levels were more or less than three-fold in cerulein-treated cells, were analyzed. Two differentially expressed proteins (mannan-binding lectin-associated serine protease-2, heat shock protein 60) were up-regulated while four proteins (protein disulfide isomerase, gamma-actin, isocitrate dehydrogenase 3, seven in absentia homolog 1A) were down-regulated by cerulein treatment in pancreatic acinar cells. These proteins are related to cell signaling, oxidative stress, and cytoskeleton arrangement. Oxidative stress may induce cerulein-induced cell injury and disturbances in defense mechanism in pancreatic acinar cells.


Urocortin and corticotropin-releasing factor receptor expression in normal cycling human ovaries.
Urocortin is a member of the CRF neuropeptide family and has a 43% homology to CRF in amino acid sequence. Urocortin has been found to bind with high affinity to CRF receptors. CRF has been detected in the human ovary and has been demonstrated to suppress ovarian steroidogenesis in vitro. In this study we examined urocortin and CRF receptor expression in normal cycling human ovaries, using immunohistochemistry and RT-PCR. Normal cycling human ovaries were obtained at oophorectomy and hysterectomy from patients who underwent surgery for cervical cancer or myoma uteri. Intense urocortin immunoreactivity was detected in luteinized thecal cells of regressing corpora lutea, in which only luteinized thecal cells have the capacity for steroidogenesis. Immunoreactive urocortin was also detected in luteinized granulosa and thecal cells of functioning corpora lutea, in which both cell components are capable of producing steroids. RT-PCR analyses revealed that messenger ribonucleic acid levels for urocortin, CRF, and CRF receptor type 1 and type 2alpha were significantly higher in the regressing corpus luteum than in the functioning corpus luteum. The spatial and temporal immunolocalization patterns of CRF receptor were similar to those of urocortin. These results suggest that urocortin is locally synthesized in steroidogenic luteal cells and acts on them as an autocrine and/or paracrine regulator of ovarian steroidogenesis, especially during luteal regression.


Changes in radioiodine turnover in patients with autonomous thyroid adenoma treated with percutaneous ethanol injection.
In 24 patients with autonomous thyroid adenoma, we studied the hormonal pattern (free thyroxine, free triiodothyronine and thyroid stimulating hormone) and markers of radioiodine turnover before and after nodule ablation with percutaneous ethanol injection. The hormonal pattern was studied before treatment and at various intervals after nodule ablation. Changes in radioiodine turnover were studied measuring 131I protein-bound iodine and the biologic half-life of radioiodine in the thyroid (calculated from thyroid uptake at 24 and 48 hr) before and after ethanol treatment. The hormonal pattern was normalized by treatment in all patients and remained normal for the follow-up period. Before treatment, protein-bound 131I was elevated in all patients but 4; after treatment, it normalized in 15 patients with the disappearance of the adenoma on scintigraphy. In the remaining 9 patients with only partial nodule destruction on scintigraphy, protein-bound 131I remained elevated although markedly reduced. Biologic half-life was shortened in 18 of 24 patients before treatment; after treatment, it was normal in 18 of 24 patients (13 of 15 with complete nodule ablation and 5 of 9 with partial ablation). Ethanol treatment normalized the hormonal pattern in all patients. Measures of radioiodine turnover were better markers of residual disease in that they normalized in almost all patients with complete nodule ablation, whereas they remained abnormal in a high proportion of patients with incomplete ablation. Thyroid hormones remained normal over a follow-up period of 3-7 yr in all patients.


Triplexed CEA-NSE-PSA Immunoassay Using Time-Gated Terbium-to-Quantum Dot FRET.
Time-gated Förster resonance energy transfer (TG-FRET) between Tb complexes and luminescent semiconductor quantum dots (QDs) provides highly advantageous photophysical properties for multiplexed biosensing. Multiplexed Tb-to-QD FRET immunoassays possess a large potential for in vitro diagnostics, but their performance is often insufficient for their application under clinical conditions. Here, we developed a homogeneous TG-FRET immunoassay for the quantification of carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), and prostate-specific antigen (PSA) from a single serum sample by multiplexed Tb-to-QD FRET. Tb-IgG antibody donor conjugates were combined with compact QD-F(ab')2 antibody acceptor conjugates with three different QDs emitting at 605, 650, and 705 nm. Upon antibody-antigen-antibody sandwich complex formation, the QD acceptors were sensitized via FRET from Tb, and the FRET ratios of QD and Tb TG luminescence intensities increased specifically with increasing antigen concentrations. Although limits of detection (LoDs: 3.6 ng/mL CEA, 3.5 ng/mL NSE, and 0.3 ng/mL PSA) for the triplexed assay were slightly higher compared to the single-antigen assays, they were still in a clinically relevant concentration range and could be quantified in 50 µL serum samples on a B·R·A·H·M·S KRYPTOR Compact PLUS clinical immunoassay plate reader. The simultaneous quantification of CEA, NSE, and PSA at different concentrations from the same serum sample demonstrated actual multiplexing Tb-to-QD FRET immunoassays and the potential of this technology for translation into clinical diagnostics.


Broken rotational symmetry in the pseudogap phase of a high-T(c) superconductor.
The nature of the pseudogap phase is a central problem in the effort to understand the high-transition-temperature (high-T(c)) copper oxide superconductors. A fundamental question is what symmetries are broken when the pseudogap phase sets in, which occurs when the temperature decreases below a value T*. There is evidence from measurements of both polarized neutron diffraction and the polar Kerr effect that time-reversal symmetry is broken, but at temperatures that differ significantly from one another. Broken rotational symmetry was detected from both resistivity measurements and inelastic neutron scattering at low doping, and from scanning tunnelling spectroscopy at low temperature, but showed no clear relation to T*. Here we report the observation of a large in-plane anisotropy of the Nernst effect in YBa(2)Cu(3)O(y) that sets in precisely at T* throughout the doping phase diagram. We show that the CuO chains of the orthorhombic lattice are not responsible for this anisotropy, which is therefore an intrinsic property of the CuO(2) planes. We conclude that the pseudogap phase is an electronic state that strongly breaks four-fold rotational symmetry. This narrows the range of possible states considerably, pointing to stripe or nematic order.


Failure mode and effects analysis to reduce risk of heparin use.
Failure mode and effects analysis (FMEA) was used to identify safety risks of unfractionated heparin (UFH) use and to develop and implement countermeasures to improve safety. FMEA was used to analyze the transportation, preparation, dispensation, administration, therapeutic monitoring, and disposal of UFH in a tertiary care, freestanding pediatric hospital. The FMEA was conducted in a stepwise fashion. First, frontline staff mapped the different steps within the UFH use process. Next, key stakeholders identified potential failures of each process step. Finally, using calibrated scales, the stakeholders ranked the likelihood of occurrence, severity, and detectability for each potential failure's cause. The rankings were used to prioritize high-risk areas on which to focus efforts for improvement countermeasures. The analysis revealed 233 potential failures and 737 unique potential causes. After ranking of all identified potential causes, 45 were deemed high scoring. Those 45 causes were further refined into 13 underlying contributing causes. To address the contributing causes, selected team members developed 22 countermeasures. The FMEA showed that implementation of the countermeasures reduced the level of mathematical risk. FMEA was helpful in identifying, ranking, and prioritizing medication risks in the UFH use process. Twenty-two countermeasures were developed to reduce potential for error in the riskiest steps of the process.


A Cross-Sectional Comparison of the Effects of Phonotactic Probability and Neighborhood Density on Word Learning by Preschool Children.
Two experiments examined the effects of phonotactic probability and neighborhood density on word learning by 3-, 4-, and 5-year-old children. Nonwords orthogonally varying in probability and density were taught with learning and retention measured via picture naming. Experiment 1 used a within-story probability/across-story density exposure context. Experiment 2 used an across-story probability/within-story density exposure context. Results showed that probability and density interacted to create optimal learning conditions. Specifically, rare/sparse sound sequences appeared to facilitate triggering of word learning. In contrast, the optimal convergence for lexical configuration and engagement was dependent on exposure context. In particular, common sound sequences and dense neighborhoods were optimal when density was manipulated across stories, whereas rare sound sequences and sparse neighborhoods were optimal when density was manipulated within a story. Taken together, children's phonological and lexical representations were hypothesized to be interdependent on one another resulting in a convergence of form characteristics for optimal word learning.


In vitro effects of simvastatin on tubulointerstitial cells in a human model of cyclosporin nephrotoxicity.
To investigate the possibility that 3-hydroxy-3-methylglutaryl CoA (HMGCoA) reductase inhibitors ameliorate renal disease via direct effects on the tubulointerstitium, primary cultures of human proximal tubule cells (PTC) and renal cortical fibroblasts (CF) were exposed for 24 h to simvastatin (0.1-10 micromol/l) under basal conditions and in the presence of 1,000 ng/ml of cyclosporin (CsA), which we have previously shown to promote in vitro interstitial matrix accumulation at least partially via activation of local cytokine networks. Simvastatin, in micromolar concentrations, engendered cholesterol-independent inhibition of CF and PTC thymidine incorporation and cholesterol-dependent suppression of PTC apical Na+/H+ exchange (NHE) (ethylisopropylamiloride-sensitive apical 22Na+ uptake). Similarly, CF secretion of insulin-like growth factor-I (IGF-I) and IGF binding protein-3 were depressed, whereas CF collagen synthesis ([3H]proline incorporation) and PTC secretion of the fibrogenic cytokines, transforming growth factor-beta1, and platelet-derived growth factor were unaffected. A lower concentration (0.1 micromol/l) of simvastatin did not affect any of the above parameters under basal conditions but completely prevented CsA-stimulated CF collagen synthesis (control, 6.6 +/- 0.6; CsA, 8.3 +/- 0.6; CsA+simvastatin, 6.2 +/- 0.5%; P < 0.05) and IGF-I secretion (89.5 +/- 16.6, 204.7 +/- 57.0, and 94.6 +/- 22.3 ng. mg protein-1. day-1, respectively; P < 0.05). The results suggest that simvastatin exerts direct cholesterol-dependent and -independent effects on the human kidney tubulointerstitium. HMGCoA reductase inhibitors may ameliorate interstitial fibrosis complicating CsA therapy via direct actions on human renal cortical fibroblasts.


Thermal reaction products and formation pathways of two monoterpenes under in situ thermal desorption conditions that mimic vaping coil temperatures.
Vaping has become more popular and different brands and types of vaping devices have rapidly emerged. However, little is known about the potential health risks of human inhalation exposures to the volatile chemicals in the vapour, which includes both directly vaporised components of vaping liquid and their reaction products formed during vaping processes. This study investigated reaction products of two monoterpenes (α-pinene and terpinolene) that are used as flavouring agents in vaping liquids with a focus on the identification of reaction products and their formation pathways. The thermal desorption was conducted under an in situ condition that is in the range of heating coil temperature in vaping by thermally desorbing the chemicals at a temperature range of 100-300 °C. Additional clean air was introduced during the thermal desorption. 36 and 29 reaction products were identified from α-pinene and terpinolene, respectively, at a relative concentration of 0.01% and greater in the desorbed mixture. 3-Carene was the dominant reaction product of α-pinene, while reaction products of terpinolene was dominated by p-isopropenyltoluene. Several reaction pathways including ring opening, allylic oxidation, cyclo-etherification, Wagner-Meerwein rearrangement, epoxidation, cleavage and removal of partial structure, and dehydration were involved in the formation of various reaction products. These pathways and resulting relative concentrations of residual parent compound and reaction products were influenced by both temperature and amount of air present during thermal desorption. The study results demonstrate possible existence of reaction products from thermally labile chemicals like monoterpenes in vaping aerosols and can help inform policies regulating vaping devices and products to protect public health.


Evaluation and management of pulmonary arterial hypertension.
Pulmonary arterial hypertension is a devastating progressive disease mediated by different pathophysiologic pathways that result in progressive increase in pulmonary vascular resistance along with right ventricular failure and eventually premature death. Despite significant advances in the understanding of the underlying mechanisms and development of a number of targeted therapies, pulmonary arterial hypertension remains a challenging condition with high morbidity and mortality. New therapies are being actively sought, and early recognition remains of paramount importance. In an effort to improve the detection and management of pulmonary hypertension, the 6th World Symposium on Pulmonary Hypertension came up with most recent statements in 2018. The goal of this review is to summarize some key updates from the proceedings of the Symposium pertaining to different aspects of evaluation and management of patients with pulmonary arterial hypertension.


[Cancer, environment, radiation and nuclear medicine].
Today, although science and technology have greatly developed, cancer is still under the shadow of prejudice and considered as a death sentence. As for who is to blame for this situation, we should not forget the actual influence of natural, technical and social environment in which we all live and offer or receive various forms of energy. Various kinds of radiation including radiation from the sun are found in our natural environment and radiation from the sun contributes especially to the development of melanoma. In our social environment we tend to develop harmful habits such as smoking and alcohol drinking, to have insufficient physical exercise and increased body weight. All these habits are concidered potentially carcinogenic. A new branch of medicine, which also tries to diagnose and treat cancer has been created lately. This is the speciality of Nuclear Medicine which has developed since 1945. This new specialty, aided by modern equipment has many useful diagnostic and therapeutic applications against cancer as mentioned in this lecture.


Genetic identification of endangered North African ungulates using noninvasive sampling.
North African ungulates include several threatened and emblematic species, yet are poorly studied mainly due to their remoteness and elusiveness. Noninvasive sampling provides a useful approach to obtain ecological and genetic information essential to guide conservation actions. The very first and most important step in conservation planning is to accurately identify species, and molecular genetics has been proved to be a useful tool. Several molecular genetics protocols are available for species identification, even for samples with poor quality DNA, such as faeces, hairs or bones. Most of these protocols use mitochondrial DNA for barcoding despite this marker being especially prone to problems, including mtDNA introgression, nuclear insert copies, high intraspecific diversity or heteroplasmy. In this work, we developed a molecular method based on polymorphisms in small fragments of the mitochondrial cytochrome b (cytb, mtDNA) and the nuclear kappa casein genes (KCAS, nDNA) for identifying endangered North African ungulates. These fragments revealed polymorphisms, including species-specific variation, which allowed species identification of nine ungulate species that co-occur in North Africa. The method was validated across more than 400 samples, including different types of noninvasive samples collected in the field. The simplicity, high reliability and relative low cost of the described method make it a promising tool to improve ecological studies of the North African ungulates and consequently, the implementation of more efficient management and conservation plans for these endangered ungulates.


Apligraf in the treatment of neuropathic diabetic foot ulcers.
This study compared the efficacy and safety of Apligraf (Organogenesis, Inc., Canton, MA) in combination with standard therapy versus standard therapy alone in the treatment of neuropathic diabetic foot ulcers. Efficacy was assessed by time to complete wound healing (by 12 weeks) and incidence of complete wound closure (at 12 weeks). This was an international multi-center, randomized, controlled study. Patients were eligible for entry into the study if the following criteria were met: type 1 or type 2 diabetes mellitus, age 18 to 80 years, adequate glycemic control, and the presence of a full-thickness neuropathic ulcer for at least 2 weeks prior to the initial screening visit. Following the 2-week screening period, the 2 treatment groups received standard ulcer care consistent with international treatment guidelines that comprised sharp debridement, saline-moistened dressings, and a non-weight bearing regimen. There were 106 subjects screened for enrollment, 82 randomized to the treatment groups, and 72 treated (33 Apligraf subjects and 39 standard therapy subjects) before the study was terminated. Kaplan-Meier curves indicated a trend for shorter time to complete wound healing in the Apligraf group compared with the standard therapy group (p = .059; log-rank test). The median time to healing was 84 days in the Apligraf group, whereas no median time to healing could be determined for the standard therapy group because <50% of the standard therapy subjects healed. By 12 weeks, 51.5% (17/33) Apligraf subjects had achieved complete wound closure compared with 26.3% (10/38) of standard therapy subjects (p = .049; Fisher's exact test). Even though the study was halted prematurely, this study suggested that the use of Apligraf resulted in a higher incidence of wound closure by 12 weeks.


Adaptive control of a millimeter-scale flapping-wing robot.
Challenges for the controlled flight of a robotic insect are due to the inherent instability of the system, complex fluid-structure interactions, and the general lack of a complete system model. In this paper, we propose theoretical models of the system based on the limited information available from previous work and a comprehensive flight controller. The modular flight controller is derived from Lyapunov function candidates with proven stability over a large region of attraction. Moreover, it comprises adaptive components that are capable of coping with uncertainties in the system that arise from manufacturing imperfections. We have demonstrated that the proposed methods enable the robot to achieve sustained hovering flights with relatively small errors compared to a non-adaptive approach. Simple lateral maneuvers and vertical takeoff and landing flights are also shown to illustrate the fidelity of the flight controller. The analysis suggests that the adaptive scheme is crucial in order to achieve millimeter-scale precision in flight control as observed in natural insect flight.


Effect of autonomic blockade on power spectrum of heart rate variability during exercise.
To validate power spectral analysis of heart rate variability (HRV) as an autonomic indicator during exercise, ten males performed four identical progressive cycling tests during infusions of saline, esmolol (beta 1-blocker), glycopyrrolate (muscarinic blocker), or both drugs. Power spectra were constructed from the recorded electrocardiogram by Fourier algorithm and integrated for low-frequency power (LF) and high-frequency power (HF). Four different LF bands (0.004-0.1, 0.004-0.15, 0.05-0.1, and 0.05-0.15 Hz) and two different HF bands (0.1-1.0 and 0.15-1.0 Hz) were evaluated. The parasympathetic index, HF, decreased exponentially with workload and was attenuated by glycopyrrolate and combined treatments with both HF frequency bands measured. Whereas some sympathetic indexes (LF/total power and LF/HF) did reflect expected increases in sympathetic nerve activity associated with progressive increases in work intensity, none of the measured increases responded appropriately to autonomic blockade. It is concluded that HRV is a valid technique for noninvasive measurement of parasympathetic tone during exercise, but its validity as a measure of sympathetic tone during exercise is equivocal.


Ultra-structure, genetic characterization and Immunological approach of fish borne zoonotic trematodes (Family: Heterophyidae) of a redbelly tilapia.
Fish-borne zoonotic trematodes (FBZT) are highly significant zoonotic trematodes that can infect humans by eating raw or undercooked fish harboring active metacercaria. In this investigation, FBZT was found in samples of widely cultivated redbelly tilapia (Tilapia zillii) obtained from the Fayum governorate. Encysted metacercaria (EMC) infection was identified in fish belonging to the heterophyid family morphologically. The prevalence of heterophyid EMC was 30.5%. EMC was identified and implemented in a subsequent study on domestic pigeons (Columba livia domestica) carried out to allow adult flukes of Pygidiopsis (P.) genata; P. summa; and Ascocotyle (A.) pindoramensis species in their small intestine. This study presents the first report that combines ultra-structure, molecular approach of three species of heterophyid flukes, ultra-structure using transmission electron microscope in P. genata, and the study of host immunological responses and associated cytokines during Pygidiopsis species infection of pigeons in Egypt. Using Quantitative Real-time PCR (qRT- PCR), the gene expression levels of six cytokines (IL-1, IL-2, IL-6, IL-10, IFN-γ and TGF-β3) were assessed. The molecular confirmation of P. genata, P. summa, and A. pindoramensis have a registration in the GenBank under accession number MT672308.1, OR083433.1, and OR083431.1, respectively. Throughout the infection, the gut produced cytokines in considerably variable amounts. As a result of the Pygidiopsis species infection in pigeons, our data showed distinctive cytokine alterations, which could aid in figuring out the immunological pathogenesis and host defense mechanism against this infection. This study focused on different types of fish-borne trematodes, particularly the zoonotically important ones.


Hydrophobic and antioxidant effects in In, Sn, and Sb based two dimensional materials.
Hydrophobic and antioxidant effects of two dimensional materials Sn, SnSb, InSb, and InSn are investigated with the implementation of first principles calculations. The stable atomic configurations of two dimensional SnSb, InSb, and InSn are determined where the structures are buckled. Adsorption of water and oxygen molecules over such surfaces reveals that SnSb (with Sb as the top surface) particularly has an outstanding hydrophobic effect while InSb (with Sb as the top surface) has a high antioxidant effect. The physical origin rests on the charge transfer where electrons are transferred from O to H in H2O, resulting in an increase of polar states between H and O, thereby leading to weak H2O adsorption on SnSb. On the other hand, there is no charge transfer between O2 and InSb (with Sb as the top surface) while O2 adsorption is involved with large electron transfer from the surface to oxygen in other surfaces. Thus, two dimensional SnSb and InSb offer hydrophobic and antioxidant properties, respectively, where such properties would be appreciated for designing surface coatings and electric circuits.


Anatomic and radiographic correlates in the middle ear.
An experiment was designed to determine the frequency with which the stapes could be visualized radiographically. Ten human temporal bones were radiographically sectioned before and after stapedectomy using three routine views, and with lead-coated stapes replaced in the oval window. Five human temporal bones were radiographically sectioned before and after stapedectomy using the Guillen view, that is, with the tympanic cavity viewed through the orbit, and with the head tilted 15 degrees to the side under investigation. The Guillen view proved to be superior for evaluating the foot-plate and superstructure of the stapes because it placed these structures in a favorable position for contact with the x-ray beam.


Comparative effects of amiodarone and dronedarone treatments on cardiac function in a rabbit model.
The objective of the study was to compare the effects of amiodarone (AM) and dronedarone (DR) on heart rate variability (HRV) and cardiac contractility in a rabbit model. A total of 16 male New Zealand white rabbits were divided into two groups, treated either with AM or DR at incremental dosages of 50 mg/kg/day (AM50 and DR50) and 100 mg/kg/day (AM100 and DR100), orally administrated for 7 days. At the end of each period, electrocardiograms were recorded during consciousness and analyzed using the short-term time and frequency domains of HRV. Standard echocardiography and speckle-tracking echocardiography were studied during immobilization with xylazine and ketamine. The results showed that AM100 and DR100 significantly decreased heart rate, total power, low-frequency component, and low-to-high frequency ratio compared with baselines. Most echocardiogram parameters revealed no significant difference from baselines, except for the global circumferential plane strain rate and time to peak standard deviation of strain, which had statistical significances after treating with AM. Both AM and DR possess negative chronotropy and reduce HRV, which may be explained by their sympathetic suppression and calcium channel blocking activities. Theoretically, both antiarrhythmic drugs may also possess negative inotropy, but only AM is shown to have a negative inotropic effect and reduces cardiac dyssynchrony in this model.


Flower traits associated with the visitation patterns of bees.
Plant-pollinator interactions are partially driven by the expression of plant traits that signal and attract bees to the nutritional resources within flowers. Although multiple physical and chemical floral traits are known to influence the visitation patterns of bees, how distinct bee groups vary in their responses to floral traits has yet to be elucidated. In this study, we used a common garden experiment to test for morphological floral traits associated with pollen quantity at the plant species level, and examined how the visitation patterns of taxonomically and functionally distinct bee groups are related to flower trait characteristics of 39 wildflower species. We also determined how floral traits influence the structure of wild bee communities visiting plants and whether this varies among geographic localities. Our results suggest that floral area is the primary morphological floral trait related to bee visitation of several distinct bee groups, but that wild bee families and functionally distinct bee groups have unique responses to floral trait expression. The composition of the wild bee communities visiting different plants was most strongly associated with variability in floral area, flower height, and the quantity of pollen retained in flowers. Our results inform wildflower habitat management for bees by demonstrating that the visitation patterns of distinct bee taxa can be predicted by floral traits, and highlight that variability in these traits should be considered when selecting plants to support pollinators.


Allelic imbalance on the long arm of chromosome 5 in oral squamous cell carcinoma.
To obtain a more detailed estimate of chromosome 5 loci involvement in oral squamous cell carcinoma (SCC), thirty-two oral SCCs were examined for loss of heterozygosity (LOH) on the long arm of chromosome 5 (5q) by PCR-LOH assay using thirteen microsatellite markers. LOH was observed in 16 (51.6%) of 31 informative cases. The incidence or the number of regions showing LOH was significantly higher in moderately and poorly differentiated tumors than in the well differentiated ones. Among the loci tested, D5S178 exhibited LOH in 11 (39.3%) of 28 cases, suggesting this to be the site, at 5q, of a novel candidate tumor suppressor gene. These data indicate that the incidence of LOH at chromosome 5q is high and is associated with oral tumor differentiation.


Risk assessment of nutrients: There must be a threshold for their effects.
Nutrients serve physiological functions in a dose-dependent manner and that needs to be recognized in risk assessment. An example of the consequences of not properly considering this can be seen in a recent assessment by the European Food Safety Authority (EFSA). EFSA concluded in 2022 that the intake of added and free sugars should be "as low as possible in the context of a nutritionally adequate diet". That conclusion of EFSA is based on the effects on two surrogate endpoints for an adverse effect found in randomized controlled trials with high sugars intake levels: fasting glucose and fasting triglycerides. The lowest intake levels in these trials were around 10 energy% and at this intake level there were no adverse effects on the two outcomes. This indicates that the adverse effects of sugars have an observable threshold value for these two endpoints. The most appropriate interpretation from the vast amount of data is that currently no definitive conclusion can be drawn on the tolerable upper intake level for dietary sugars. Therefore, EFSA's own guidance would lead to the conclusion that the available data do not allow the setting of an upper limit for added sugars and hence, that more robust data are required to identify the threshold value for intake of sugars.


Expression of Interferon-γ Receptor Genes in Peripheral Blood Mononuclear Cells Is Associated With Rheumatoid Arthritis and Its Radiographic Severity in African Americans.
The factors responsible for radiographic severity in African American patients with rheumatoid arthritis (RA) are poorly understood. We sought to identify genes whose expression in peripheral blood mononuclear cells is associated with radiographic severity in RA. In the first phase of the study, we performed real-time quantitative polymerase chain reaction to analyze the expression of 182 candidate genes in 40 African American RA patients with extremes of radiographic damage (low versus high radiographic scores) and disease duration (≤2 years versus >2 years) and 20 healthy African American control subjects; the genes were selected based on plausible immune pathways. In the second phase, we analyzed the expression of the genes that were shown to be significantly associated with radiographic scores in 576 African American patients with RA and 51 African American control subjects who had not been studied previously, accounting for autoantibody status and disease duration. We observed significant differences in IFNGR1 expression between patients with RA and control subjects (adjusted P [P(adj)] = 6 × 10(-14)) and in IFNGR2 expression between RA patients with erosions and those with no erosions (P(adj) = 0.01 by Wilcoxon's rank sum test). We also observed significant correlations between IFNGR2 expression and radiographic scores (P(adj) = 0.03 for erosions, P(adj) = 0.04 for joint space narrowing, and P(adj) = 0.03 for total radiographic score [zero-inflated negative binomial regression model]) and annualized progression rate (P(adj) = 0.0024 by Spearman's correlation analysis). These findings have important implications with respect to the role of interferon-γ (IFNγ) in the pathogenesis of RA and may lead to identification of a biomarker for radiographic damage. Additional studies are needed to define the cell subsets responsible for the association of IFNγ receptor gene expression with radiographic findings, which downstream mechanisms are involved, and generalizability to other RA populations.


Patient healthcare passports in community specialist palliative care: a mixed methods study.
Patient held records need to be evaluated in palliative care settings. To evaluate how patients, families and professionals in a specialist palliative setting use a patient held record created through close consultation with patients and carers. A mixed methods prospective longitudinal cohort study in the UK-adult patients under community specialist palliative care nurse review or attending day hospice were given questionnaires at record introduction and after 4-6 weeks. Hospice staff completed a questionnaire and focus group after 8 months. From Sept 2016 to June 2017, 550 patients were screened, 347 (63.1%) were offered records and 259 accepted (74.6%). 238 accepted a research pack, 105 returned questionnaire 1 (44.1% response rate) and 26 returned questionnaire 2 (24.8% of initial respondents). Questionnaire 1 (patients): 40% found it burdensome repeating information, and almost 70% were interested in a record to reduce this. Questionnaire 2 (patients): 74% found the record easy to use, but few (4, 15.4%) used it regularly. Over 60% stated the record was useful and would recommend it to others, despite not using it themselves. Professionals indicated that it was mainly patients and relatives who used the record, not non-palliative professionals. While initial uptake of the record was high, use appeared low. While people saw real value in the record for others, they did not generally use it themselves. This evaluation demonstrates that patient held records are unlikely to be used by palliative care patients even though they see value in the concept.


Learning to use minimal access surgical instruments and 2-dimensional remote visual feedback: how difficult is the task for novices?
Performing minimal access surgery requires the use of 2-dimensional information to produce 3-dimensional movements, as well as precise motor control for manipulating laparoscopic tools. The added visuomotor demands of this task make it more demanding and complex than traditional open surgery. The purpose of this study was to determine the relative task difficulty of performing laparoscopic tool movements with normal vision or 'laparoscopic vision' provided by a remote 2-D monitor. A second purpose of this study was to evaluate whether movement performance changes are induced by practice with normal vision (NV) and laparoscopic vision (LV). The study was also designed to determine whether order of visual condition (NV or LV) practice impacts the rate of performance acquisition when transferred to the opposing visual condition. Eleven individuals participated in this study. All subjects performed a bean grasping and a suturing task in two visual conditions: normal vision and laparoscopic vision. Results revealed that laparoscopic tools themselves do not appear to be problematic in performing minimal access surgery. Furthermore, performance ability in normal vision does not positively transfer to performance when switched to a laparoscopic vision condition. The 2-dimensional video does appear to be problematic for skill acquisition, as performance levels decreased as complexity of the task increased.


Typing of halophilic Archaea and characterization of their cell surface carbohydrates by use of lectins.
Lectins are important tools for cell typing and for the study of cell surface components. They have been widely used for the analysis of carbohydrates on the surface of many eukaryotic and prokaryotic cells, but they have not yet been exploited in the study of the halophilic Archaea (family Halobacteriaceae), because of the high salinity required for the structural integrity of these microorganisms. We have defined the salt concentration threshold high enough for survival of the Archaea, but sufficiently low for lectins to bind to them. Under these conditions we studied the interactions of a series of lectins, exhibiting different sugar specificities, with diverse halophilic Archaea. Concanavalin A was the most reactive by virtue of its glucose (and mannose) binding. The other lectins varied in their interactions. The results indicate that lectins might be useful probes for both archaeal typing and analysis of their cell surface carbohydrates.


Sugar-cane bagasse derived cellulose enhances performance of polylactide and polydioxanone electrospun scaffold for tissue engineering.
Bagasse is a waste product of sugar extraction from sugar-cane with approximately 30% cellulose content. Cellulose was successfully extracted from sugar-cane bagasse using a modified mercerization-bleaching approach with a 40% yield. Extracted cellulose was converted to cellulose acetate for enhanced electrospinnability and blended with poly-l-Lactide or polydioxanone before solution electrospinning. Physico-chemical evaluation of the electrospun mats showed variable miscibility of blends. In vitro cell studies with L929 mouse fibroblast cells was quite conclusive as regards the biocompatibility of the blended mats with proliferative behavior of cells, extracellular matrix deposition and characteristic features of healthy cellular response. MTT assay indicated that the cellulose blended mats induced higher cell densities than the controls. Cellulose content influenced parameters such as fiber diameter, porosity and cell-matrix interaction of mats impacting on cell growth and behavior. Preliminary assessment of biomineralization potential of the mats by SEM showed nano-hydroxyapatite deposits on the electrospun fibers.


An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia.
Small-molecule inhibitors of kinases involved in B-cell receptor signaling are an important advance in managing lymphoid malignancies. Entospletinib (GS-9973) is an oral, selective inhibitor of spleen tyrosine kinase. This multicenter, phase 2 study enrolled subjects with relapsed or refractory chronic lymphocytic leukemia (CLL; n = 41) or non-Hodgkin lymphoma (n = 145). Participants received 800 mg entospletinib twice daily. We report efficacy outcomes in the CLL cohort (n = 41) and safety outcomes in all cohorts (N = 186). The primary end point was a progression-free survival (PFS) rate at 24 weeks in subjects with CLL. The PFS rate at 24 weeks was 70.1% (95% confidence interval [CI], 51.3%-82.7%); median PFS was 13.8 months (95% CI, 7.7 months to not reached). The objective response rate was 61.0% (95% CI, 44.5%-75.8%), including 3 subjects (7.3%) who achieved nodal response with persistent lymphocytosis. Fifty-four subjects (29.0%) had serious adverse events (SAEs). The most common treatment-emergent SAEs included dyspnea, pneumonia, febrile neutropenia, dehydration, and pyrexia. Common grade 3/4 laboratory abnormalities included neutropenia (14.5%) and reversible alanine aminotransferase/aspartate aminotransferase elevations (13.4%). Entospletinib demonstrates clinical activity in subjects with relapsed or refractory CLL with acceptable toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01799889.


The effects of short-term passive smoke exposure on endothelium-dependent and independent vasodilation.
There is limited information on the mechanisms mediating the deleterious effects of passive smoke exposure. Cross-sectional studies indicate that nonsmokers exposed chronically to passive smoke have impaired endothelium mediated vasodilation. We tested the hypothesis that acute exposure to sidestream (passive) smoke impairs endothelium-dependent vasodilation in healthy nonsmokers. We studied 12 healthy nonsmokers (aged 27 +/- 5 years, nine men and three women). We obtained measurements of blood pressure, heart rate, and bilateral forearm blood flow (FBF). Each individual was studied twice, following a randomized, placebo-controlled design. The effects of passive smoke were studied on one day and the effects of vehicle (room air) on a separate day. Acetylcholine (ACh) and sodium nitroprusside (SNP) were infused into the left brachial artery before and after 15 min of exposure to either passive smoke (carbon monoxide concentration between 20 and 40 p.p.m.) or vehicle (room air). The order of ACh and SNP, and smoke or vehicle, was randomized between individuals. Smoke exposure increased carboxyhemoglobin from 0.5 +/- 0.1 % to 0.8 +/- 0.1% (P= 0.002). Neither passive smoke nor vehicle changed baseline measurements of heart rate, blood pressure and forearm vascular resistance (FVR). The vasodilatory responses to ACh and SNP were very similar, both before and after exposure to passive smoke and before and after vehicle. Our data demonstrate that acute exposure to passive smoke does not alter either endothelium-dependent or independent vasodilatory responses in healthy nonsmoking individuals. Hence, impaired endothelial vasodilatory responses in nonsmokers chronically exposed to passive smoke most likely reflect chronic functional and/or structural changes in responses to cigarette smoke, rather than the acute effects of cigarette smoke toxicity on endothelial function.