Response to therapy is independently associated with survival prolongation in chronic myelogenous leukemia in the blastic phase.
Achievement of minimal tumor burden, such as complete response, has been accepted as a surrogate marker for improved survival in many solid and hematologic carcinomas. Several new agents have been approved recently for orphan disease indications or unmet medical needs, based on response analyses. This has not been the case for chronic myelogenous leukemia in the blastic phase (CML-BP), despite its poor prognosis, because response has not been proven to be a valuable endpoint for survival prolongation. The purpose of this study was to analyze the effect of response in CML-BP on survival prolongation. STUDY GROUP AND METHODS In total, 328 patients with CML-BP referred from 1989 to 1999 were studied; 311 patients received therapy for CML-BP, and 275 were evaluable for response. Blastic phase CML was defined by the presence of 30% or more blasts in the blood or bone marrow, or extramedullary disease. Treatment responses were reviewed and categorized as proposed in previous large studies. Four categoric response groups were defined further based on significant differences in outcome: cytogenetic response, hematologic response, bone marrow improvement, and failure. The association of treatment response with survival was evaluated by multivariate and landmark analyses. The association of response with survival was analyzed among the 275 patients who had evaluable responses, and follow-up information was documented. Univariate analysis of pretreatment characteristics found performance status, hemoglobin levels, platelet counts, peripheral blasts, additional chromosomal abnormalities, and blastic phase morphology as showing significant associations with survival (P < 0.1). A multivariate analysis found platelet counts and blastic morphology as independent significant factors associated with survival (P < 0.05). A landmark analysis conducted at 8 weeks from start of therapy showed the beneficial effect of achieving response on survival prolongation (P < 0.001). A repeat multivariate at the 8-week landmark time in the 240 patients alive at that time, which included pretreatment characteristics and treatment response, confirmed the independent significant association of morphology (P = 0.003), platelet counts (P = 0.04), and response (P < 0.001) with survival. Response to therapy is a significant independent factor associated with survival prolongation and maybe an acceptable therapeutic endpoint for approving new treatments in CML-BP.


Do psychosocial work factors and social relations exert independent effects on sickness absence? A six year prospective study of the GAZEL cohort.
The objective of this prospective cohort study was to determine whether psychosocial work characteristics and social relations exert independent effects on the incidence of sickness absence in a population of middle aged French employees over six years of follow up. This study included 9631 men and 3595 women participating in the French GAZEL cohort. Social relations (social networks, personal social support, and social relations satisfaction) were measured in 1994 by self report. Psychosocial work characteristics (decision latitude, psychological demands, and social support at work) were ascertained in 1995. Sickness absence data were collected independently. The authors studied the incidence of short (>7 days), intermediate (7-21 days), and long (>21 days) spells of absence from 1995 to 31 December 2001. Rate ratios associated with psychosocial exposures, adjusted on sociodemographic characteristics, and health behaviours, were calculated by means of log-linear Poisson regression. A cohort of 20000 employees of France's national gas and electricity company (the GAZEL study). Among men and women, levels of decision latitude and personal social support below the median predicted 17% to 24% increases in absence rates. Low satisfaction with social relations and low social support at work lead to a 10% to 26% excess in sick leaves among men. No interactive effects were found between the variables under study. The quality of the work environment and of social relations affect sickness absence over an extended period of follow up. This study supports the hypothesis of independent, not interactive effects.


Effect of anti-tumor necrosis factor-alpha gene therapy on wear debris-induced osteolysis.
Particle phagocytosis by macrophages induces the secretion of tumor necrosis factor-alpha, which is involved in the development of an osteolytic response. Therefore, we aimed to determine whether gene delivery of a soluble inhibitor of tumor necrosis factor-alpha (sTNFR:Fc) could prevent wear debris-induced osteolysis in a mouse model. sTNFR:Fc is a fusion protein containing the extracellular domain of the human type-I tumor necrosis factor receptor fused to the Fc region of mouse immunoglobulin. It acts by binding to tumor necrosis factor-alpha and preventing signaling through the membrane-bound tumor necrosis factor receptors. An adenoviral vector encoding the LacZ gene (Ad.CMV-NlacZ) was propagated and was tested for its ability to transduce calvarial tissue. Ad.CMV-TNFR:Fc (encoding sTNFR:Fc) or Ad.CMV-NlacZ was administered to CBAxB6 mice in the presence or absence of titanium particles implanted onto the calvaria. Serum levels of sTNFR:Fc were measured with enzyme-linked immunosorbent assay, and the mice were killed on the tenth postoperative day for histological analysis. The experiments were repeated in athymic nude mice to avoid complications associated with the adenovirus-specific immune response. Administration of the control virus (Ad.CMV-NlacZ) transduced 10% of the cells in the periosteum. Ad.CMV-NlacZ treatment of sham-treated or titanium-treated animals induced significant bone resorption and osteoclastogenesis above control levels (that is, those in animals not treated with a virus). Treatment with the sTNFR:Fc virus did not reduce bone resorption or osteoclast numbers below control levels in CBAxB6 mice. In the athymic mice, no increase in the midline sagittal suture area or osteoclastogenesis was observed after treatment with the control vector and sTNFR:Fc gene therapy reduced the suture area to background levels. An immunologic response to Ad.CMV-NlacZ was most likely responsible for the increase in bone resorption and osteoclastogenesis in the animals treated with the control vector alone. In the athymic mice, in the absence of this immune response, sTNFR:Fc gene therapy reduced bone resorption in the midline sagittal suture area but had no effect on osteoclastogenesis.


Influence of Exercise on Exhausted and Senescent T Cells: A Systematic Review.
The impaired effector function of exhausted and senescent T cells is implicated in cancer progression and inadequate vaccine responses. Exercise has been shown to improve cancer therapy and vaccine efficacy, most likely by improving immune function. However, given inconsistent terminology and definitions, the interactions between exercise and exhausted and senescent T cells remain unclear. We therefore performed a systematic review to investigate the effect of exercise on senescent and exhausted CD8+ T cell populations clearly defined by protein surface markers. Thirty articles were included, with the majority (n = 24) reporting senescent T cell populations defined according to a variety of surface markers. Repeated exercise was shown to be beneficial through limiting the accumulation of senescent and exhausted CD8+ T cells. This outcome is likely related to exercise-induced preferential mobilization of senescent T cells promoting apoptosis in the peripheral blood compartment. Future studies need to determine the clinical relevance of this effect in cancer prevention and vaccine efficacy. Data regarding exercise and exhausted T cells are limited due to a lack of available high-quality studies. Future studies require the control of confounding variables such as sex and cytomegalovirus (CMV) status, and consistent definitions of exhausted and senescent T cell populations to improve comparisons between studies and interventions.


[Punishment--"the work of God"--forensic accounts of crime and punishment].
This paper deals with coincidental deaths of persons previously engaged in violent behaviour. In victimology, violent deaths rest on legal authorities and public prosecutor. In some cases the clearance of circumstances is "sui generis", as a consequence of "vis maior". However, in some cases, depending of circumstances, perpetrators are uncovered without further investigations. This paper presents some of the most interesting cases from our Forensic practice: infanticides, "jealousy" killing, other murders. All crimes were recovered and sanctioned. History is full of cases like these described. Man is the only primate who kills and tortures other men. Nothing can fill the soul as hatred. Hatred is stronger than love. Love can easily lead to hate. Man is afraid of being killed, but often acts like a victim. The man proves himself worthy through his life, not death.


Products and mechanism of the reaction of OH radicals with 2,2,4-trimethylpentane in the presence of NO.
Alkanes are important constituents of gasoline fuel and vehicle exhaust, with branched alkanes comprising a significant fraction of the total alkanes observed in urban areas. Products of the gas-phase reactions of OH radicals with 2,2,4-trimethylpentane and 2,2,4-trimethylpentane-d18 in the presence of NO at 298+/-2 K and atmospheric pressure of air have been investigated using gas chromatography with flame ionization detection (GC-FID), combined gas chromatography-mass spectrometry (GC-MS), and in situ atmospheric pressure ionization tandem mass spectrometry (API-MS). Acetone, 2-methylpropanal, and 4-hydroxy-4-methyl-2-pentanone were identified and quantified by GC-FID from 2,2,4-trimethylpentane with molar formation yields of 54+/-7%, 26+/-3%, and 5.1+/-0.6%, respectively; upper limits to the formation yields of acetaldehyde, 2,2-dimethylpropanal, and 4,4-dimethyl-2-pentanone were obtained. Additional products observed from 2,2,4-trimethylpentane by API-MS and API-MS/MS analyses using positive and negative ion modes were hydroxy products of molecular weight 130 and 144, a product of molecular weight 128 (attributed to a C8-carbonyl), and hydroxynitrates of molecular weight 135, 177, and 191 (attributed to HOC4H8ONO2, HOC7H14ONO2, and HOC8H16-ONO2, respectively). Formation of HOC8H16ONO2 and HOC7H14-ONO2 is consistent with the observation of products of molecular weight 207 (HOC8D16ONO2) and 191 (HOC7D14-ONO2), respectively, in the API-MS analyses of the 2,2,4-trimethylpentane-d18 reaction (-OD groups rapidly exchange to -OH groups under our experimental conditions). These product data allow the reaction pathways to be delineated to a reasonable extent, and the reaction mechanism is discussed.


Involvement of ERK phosphorylation in the prevention of ischemia-induced ovarian follicular depletion by stem cells.
Ovarian failure is commonly caused by aging, autoimmune disease, menopause and cancer therapy. We used an ischemic model in the ovary to test the hypothesis that stem cells are helpful for ovarian regeneration after injury. Three treatment regimes were employed: sham-operated control, ligation plus PBS, and ligation plus immortalized human bone marrow stromal cells (stem cells) groups. After ligation-induced ischemia, stem cells or PBS were injected into rat ovaries. Then, pregnant mare serum gonadotropin was given intra-peritoneally to initiate folliculogenesis. The animals were then sacrificed. The ovary gland was weighed, and ovarian folliculogenesis, stem cell differentiation and vascular neogenesis were evaluated. In order to study improvement of folliculogenesis after ovarian ischemia, steroidogenic acute regulatory protein (StAR), p44/p42 MAPK (T-ERK1/2), and phospho-p44/ p42 MAPK (P-ERK1/2) expression were specifically evaluated. Results indicated that ovarian size was smaller and that the rate of folliculogenesis was lower in ovarian ischemic-reperfusion animals, but both recovered after stem cell treatment. The stem cells migrated into the ovary and differentiated into theca cells, granulosa cells, corona radiata cells and vascular endothelial cells. In addition, von Willebrand factor (vWF) expression was increased; 17beta-estradiol (E2), progesterone (P4), P-ERK1/2 and StAR protein expression was recovered by stem cells treatment in the ischemic ovaries. The serum LH was significantly increased in ovaries of ischemia-reperfusion animals, but the stem cell treatment restored the effects. These results suggest that stem cells might be helpful for ovarian regeneration after injuries by promoting vascular neogenesis and steroidogenesis through the MAPK pathway.


Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation.
The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast (OCL) formation and bone lesions is still unknown. Osteocytes regulate bone remodelling at least partially, as a result of their cell death triggering OCL recruitment. In this study, we found that the number of viable osteocytes was significantly smaller in MM patients than in healthy controls, and negatively correlated with the number of OCLs. Moreover, the MM patients with bone lesions had a significantly smaller number of viable osteocytes than those without, partly because of increased apoptosis. These findings were further confirmed by ultrastructural in vitro analyses of human preosteocyte cells cocultured with MM cells, which showed that MM cells increased preosteocyte death and apoptosis. A micro-array analysis showed that MM cells affect the transcriptional profiles of preosteocytes by upregulating the production of osteoclastogenic cytokines such as interleukin (IL)-11, and increasing their pro-osteoclastogenic properties. Finally, the osteocyte expression of IL-11 was higher in the MM patients with than in those without bone lesions. Our data suggest that MM patients are characterized by a reduced number of viable osteocytes related to the presence of bone lesions, and that this is involved in MM-induced OCL formation.


[Functional and morphological changes of the cochlea in guinea pigs during anoxia].
The influence to endocochlear potential (EP), cochlear microphonics (CM) and summating potential (SP), the ultrastructural changes of the cochlea and the survival time of hair cells in guinea pigs during anoxia and suffocation were investigated. We found that: 1) The stria vascularis was much more sensitive to anoxia than hair cells. 2) 85% CM was highly sensitive to anoxia, and 15% kept stable until the destruction of outer hair cells. 3) -SP turned into +SP after anoxia. 4) EP was related to the destruction of outer hair cells and the disappearance of CM.


A bio-anodic filter facilitated entrapment, decomposition and in situ oxidation of algal biomass in wastewater effluent.
This study examined for the first time the use of bioelectrochemical systems (BES) to entrap, decompose and oxidise fresh algal biomass from an algae-laden effluent. The experimental process consisted of a photobioreactor for a continuous production of the algal-laden effluent, and a two-chamber BES equipped with anodic graphite granules and carbon-felt to physically remove and oxidise algal biomass from the influent. Results showed that the BES filter could retain ca. 90% of the suspended solids (SS) loaded. A coulombic efficiency (CE) of 36.6% (based on particulate chemical oxygen demand (PCOD) removed) was achieved, which was consistent with the highest CEs of BES studies (operated in microbial fuel cell mode (MFC)) that included additional pre-treatment steps for algae hydrolysis. Overall, this study suggests that a filter type BES anode can effectively entrap, decompose and in situ oxidise algae without the need for a separate pre-treatment step.


Rapeseed or linseed in grass-based diets: effects on conjugated linoleic and conjugated linolenic acid isomers in milk fat from Holstein cows over 2 consecutive lactations.
Changes in the distribution of conjugated linoleic (CLA) and conjugated linolenic (CLnA) acid isomers in milk from Holstein cows in response to 4 different oilseed supplements rich in either cis-9 18:1 or 18:3n-3 were determined over 2 consecutive lactations in 58 and 35 cows during the first and second years, respectively. For the first 5 wk of the first lactation, all cows were fed the same diet. Thereafter, cows received 1 of 5 treatments for 2 consecutive lactations, including the prepartum period. Treatments comprised the basal diet with no additional lipid, or supplements of extruded linseeds (EL), extruded rapeseeds (ER), cold-pressed fat-rich rapeseed meal, or whole unprocessed rapeseeds to provide 2.5 to 3.0% of additional oil in diet dry matter. During indoor periods, cows were housed and received a mixture (3:1, wt/wt) of grass silage and hay, whereas cows were at pasture during outdoor periods. Over the entire study, EL resulted in the enrichment of ∆11,13 CLA, ∆12,14 CLA, trans-9,trans-11 CLA, trans-13,trans-15 CLA, ∆9,11,15 CLnA, and cis-9,trans-11,trans-13 CLnA (identified for the first time in bovine milk fat) in milk fat, whereas ER and cold-pressed fat-rich rapeseed meal in particular, increased milk fat trans-7,cis-9 CLA concentration. With the exception of the first indoor period, whole unprocessed rapeseeds decreased cis-9,trans-11 CLA, trans-9,cis-11 CLA, and trans-10,trans-12 CLA abundance. During the second indoor period, EL increased milk trans-9,cis-11 CLA and trans-10,cis-12 CLA concentrations, but the increases in cis-9,trans-11 CLA, cis-12,trans-14 CLA, trans-11,cis-13 CLA, and cis-9,trans-11,cis-15 CLnA concentrations to EL and ER were lower for the second than first indoor period. In contrast to the indoor periods, EL and ER decreased milk cis-9,trans-11 CLA, trans-9,cis-11 CLA, and trans-10,cis-12 CLA concentrations at pasture. The extent of changes in the relative distribution and abundance of CLA and CLnA isomers in milk fat were related to the nature (rapeseed or linseed) and form of oilseed (extruded, cold-pressed fat-rich meal or whole unprocessed) supplement and their interactions with the composition of the basal diet (conserved grass or pasture and dietary starch content). Furthermore, milk fat CLA and CLnA responses to treatments were repeatable between both outdoor periods. Variations in milk fat content and yield measured during the entire study were significantly and inversely associated with milk trans-10 18:1, trans-10,cis-12 CLA, and in particular, trans-9,cis-11 CLA concentrations.


Pregnenolone-16alpha-carbonitrile inhibits rodent liver fibrogenesis via PXR (pregnane X receptor)-dependent and PXR-independent mechanisms.
The effect of liver growth stimulation [using the rodent PXR (pregnane X receptor) activator PCN (pregnenolone-16alpha-carbonitrile)] in rats chronically treated with carbon tetrachloride to cause repeated hepatocyte necrosis and liver fibrogenesis was examined. PCN did not inhibit the hepatotoxicity of carbon tetrachloride. However, transdifferentiation of hepatic stellate cells and the extent of fibrosis caused by carbon tetrachloride treatment was significantly inhibited by PCN in vivo. In vitro, PCN directly inhibited hepatic stellate cell transdifferentiation to a profibrogenic phenotype, although the cells did not express the PXR (in contrast with hepatocytes), suggesting that PCN acts independently of the PXR. Mice with a functionally disrupted PXR gene (PXR-/-) did not respond to the antifibrogenic effects of PCN, in contrast with wild-type (PXR+/+) mice, demonstrating an antifibrogenic role for the PXR in vivo. However, PCN inhibited the transdifferentiation of PXR-/--derived mouse hepatic stellate cells in vitro, confirming that there is also a PXR-independent antifibrogenic effect of PCN through a direct interaction with hepatic stellate cells. These data suggest that the PXR is antifibrogenic in rodents in vivo and that a PXR-independent target for PXR activators exists in hepatic stellate cells that also functions to inhibit fibrosis.


Reduced description of exact coherent states in parallel shear flows.
A reduced description of exact coherent structures in the transition regime of plane parallel shear flows is developed, based on the Reynolds number scaling of streamwise-averaged (mean) and streamwise-varying (fluctuation) velocities observed in numerical simulations. The resulting system is characterized by an effective unit Reynolds number mean equation coupled to linear equations for the fluctuations, regularized by formally higher-order diffusion. Stationary coherent states are computed by solving the resulting equations simultaneously using a robust numerical algorithm developed for this purpose. The algorithm determines self-consistently the amplitude of the fluctuations for which the associated mean flow is just such that the fluctuations neither grow nor decay. The procedure is used to compute exact coherent states of a flow introduced by Drazin and Reid [Hydrodynamic Stability (Cambridge University Press, Cambridge, UK, 1981)] and studied by Waleffe [Phys. Fluids 9, 883 (1997)]: a linearly stable, plane parallel shear flow confined between stationary stress-free walls and driven by a sinusoidal body force. Numerical continuation of the lower-branch states to lower Reynolds numbers reveals the presence of a saddle node; the saddle node allows access to upper-branch states that are, like the lower-branch states, self-consistently described by the reduced equations. Both lower- and upper-branch states are characterized in detail.


[Coding part of the son gene small transcript contains four areas of complete tandem repeats].
Overlapping cDNA clones for the smaller son gene transcript were isolated by several steps of human placenta cDNA library walking. Here we report the structure of repeats that exist at the long open reading, present in the structure of this smaller (5.6 kb) transcript of human gene son. We were able to identify in this transcript four areas of complete tandem repeats, formed by several steps of duplication. For three of them the extent of homology between amino acid sequences of repeated elements is higher than between their nucleic acid sequences. It means that amino acid sequences of repeated elements are conserved, that could reflect the structural significance for the function of hypothetical protein product of human gene son. On the basis of the results of analysis we proposed the model for the formation of repeats by processes of duplication, mutation and natural selection pressure at the expressed protein level.


Malignant inflammatory fibrous histiocytoma of bone and acute lymphoblastic leukaemia.
A patient is described who developed a malignant inflammatory fibrous histiocytoma of vertebral bone (MFH) 4 months after the onset of acute lymphoblastic leukaemia. This is the first report of the simultaneous occurrence of these two conditions. Similarities to the more frequent occurrence of another histiocytic malignancy, histiocytic medullary reticulosis, following acute lymphoblastic leukaemia, are noted. The usefulness of gallium scanning to monitor the response of this tumour to treatment is demonstrated.


Molecular biology of the Rh blood group system.
Rh molecular biology has made many advances since the first Rh cDNA was cloned in 1990. This review summarizes the current knowledge concerning the molecular basis of Rh antigenicity, D-epitope expression, and the structures of the Rh genes and proteins. Although many recent reviews have appeared regarding these subjects, advances in Rh protein function that have been published within the last 12 months have had a fundamental impact on the future direction of Rh research. In November 2000, an article described the role of Rh proteins in ammonium transport, which has remained undescribed in vertebrates, except for non-specific transport via K+ channels. The recent identification of nonerythroid Rh proteins, their expression in diverse tissues, and notably polarized epithelial and endothelial cells will be of broad functional significance and will greatly increase our understanding of the role of Rh in ammonium transport and the biology of ammonium metabolism as a whole. The advances in Rh molecular genetics have enabled the development of diagnostic tests in the clinic. At present, this is largely confined to the prenatal diagnosis of fetal blood group status in alloimmunized pregnancies, but could be extended to the noninvasive prenatal testing of all D-negative pregnant women and eventually, perhaps, to all patient and donor blood.


Comparative clinico-morphological investigations of the CNS of monkeys and of the eye teguments of guinea pigs infected with different measles virus strains.
Measles virus strains Edmonston and L-16 have been studied in 10 intracerebrally (i.c.) infected monkeys and in 155 guinea pigs infected into the anterior eye chamber. The strains appeared to differ in pathogenicity for monkeys and guinea pigs. The more pathogenic Edmonston strain caused encephalitis in monkeys, whereas in guinea pigs it caused iridocyclitis, keratoconjunctivitis and follicular conjunctivitis. Strain L-16 was not neurovirulent for monkeys, while in guinea pigs it caused follicular conjunctivitis. Specific pathohistological changes detected in the CNS of monkeys and in the eye teguments of guinea pigs were confirmed by virologic and serologic findings.


PROBATION AND MONETARY SANCTIONS IN GEORGIA: EVIDENCE FROM A MULTI-METHOD STUDY.
Georgia leads the nation in probation supervision, which has been the subject of recent legislative reforms. Probation supervision is the primary mechanism for monitoring and collecting legal financial obligations (LFOs) from people sentenced in Georgia courts. This Article analyzes how monetary sanctions and probation supervision intersect in Georgia using quantitative data from the Department of Community Supervision as well as interviews with probationers and probation officers gathered as part of the Multi-State Study of Monetary Sanctions between 2015 and 2018. Several key findings emerge: (1) there is substantial variation between judicial districts in the amount of fines and fees ordered to felony probationers in Georgia, with fines and fees in rural areas much higher than those in urban areas; (2) probationers express fear of incarceration solely for lack of ability to pay; (3) probation officers consider collecting LFOs as a distraction from their true mission of public safety; and (4) both probationers and probation officers question the purpose, effectiveness, and fairness of monetary sanctions in Georgia. This Article concludes with a discussion of reforms to date and further options for reform based on the findings from this research.


Acute pancreatitis: value and impact of CT severity index.
Acute pancreatitis is a disease with a broad spectrum of findings that varies in severity from mild interstitial or edematous pancreas to severe forms with significant local and systemic complications that are associated with a substantial degree of morbidity and mortality. Several scoring systems are used to assess the severity and predict the outcome and prognosis of acute pancreatitis. These include the Ranson, Acute Physiology And Chronic Health Evaluation II (APACHE II) and Glasgow scales. The CT severity index (CTSI) derived by Balthazar et al. has become widely used for description of CT findings in acute pancreatitis. The purpose of this project was to examine the current best evidence about regarding the effect of using a CTSI on patient outcome and its value in comparison with other widely used scoring systems.


Methylome profiling of healthy and central precocious puberty girls.
Recent studies demonstrated that changes in DNA methylation (DNAm) and inactivation of two imprinted genes (MKRN3 and DLK1) alter the onset of female puberty. We aimed to investigate the association of DNAm profiling with the timing of human puberty analyzing the genome-wide DNAm patterns of peripheral blood leukocytes from ten female patients with central precocious puberty (CPP) and 33 healthy girls (15 pre- and 18 post-pubertal). For this purpose, we performed comparisons between the groups: pre- versus post-pubertal, CPP versus pre-pubertal, and CPP versus post-pubertal. Analyzing the methylome changes associated with normal puberty, we identified 120 differentially methylated regions (DMRs) when comparing pre- and post-pubertal healthy girls. Most of these DMRs were hypermethylated in the pubertal group (99%) and located on the X chromosome (74%). Only one genomic region, containing the promoter of ZFP57, was hypomethylated in the pubertal group. ZFP57 is a transcriptional repressor required for both methylation and imprinting of multiple genomic loci. ZFP57 expression in the hypothalamus of female rhesus monkeys increased during peripubertal development, suggesting enhanced repression of downstream ZFP57 target genes. Fourteen other zinc finger (ZNF) genes were related to the hypermethylated DMRs at normal puberty. Analyzing the methylome changes associated with CPP, we demonstrated that the patients with CPP exhibited more hypermethylated CpG sites compared to both pre-pubertal (81%) and pubertal (89%) controls. Forty-eight ZNF genes were identified as having hypermethylated CpG sites in CPP. Methylome profiling of girls at normal and precocious puberty revealed a widespread pattern of DNA hypermethylation, indicating that the pubertal process in humans is associated with specific changes in epigenetically driven regulatory control. Moreover, changes in methylation of several ZNF genes appear to be a distinct epigenetic modification underlying the initiation of human puberty.


Copper(i) complexes based on ligand systems with two different binding sites: synthesis, structures and reaction with O2.
The synthesis of the ligand systems L1 and L2 with two different N3-binding sites linked through a dibenzofuran spacer and their coordination properties towards a variety of CuI precursors are reported. The reaction of L1 with copper halides leads to the formation of a bimetallic species [(L1)(CuICl)2] (1), and metallodimers [((L1)(CuIX)2)2(μ-(Cu)(μ-X)2)] (2: X = Br, 3: X = I) in which two dicopper complexes are bridged by a (μ-(Cu)(μ-X)2)-moiety whereas L2 reacts with copper chloride to afford {[Cu(L2)Cl2]}n (8). Furthermore, starting from L1 in combination with copper(i) salts of weakly coordinating anions the dicopper complexes [(L1)(CuI(NCCH3))2](BF4)2 (4), [(L1)(CuI(NCCH3))(Cu(Y))](Y) (5: Y = OTf, 6: Y = ClO4) and [(L1)(Cu(dppe))](PF6)2 (7) were isolated, and employing L2, the complexes [(L2)(CuI(NCCH3))2](Z)2 (9: Z = PF6, 10: Z = OTf) and [(L2)(Cu(dppe))](PF6)2 (11) were obtained. Complexes 4-6 as well as 9 and 10 react rapidly with O2 to form metastable O2 adducts in acetone at -90 °C, where O2 is bound between the two copper centers within one dicopper molecule, as evidenced by UV/Vis spectroscopy, kinetic investigations, Raman spectroscopy and studies with ligands containing the isolated donor sites. The reactivity of the O2 adducts towards selected substrates was also investigated, showing their ability to act as electrophiles as well as nucleophiles.


Abnormal regulation of interleukin 6 in systemic juvenile idiopathic arthritis.
To evaluate the in vitro production of interleukin 6 (IL-6) by peripheral blood mononuclear cells (PBMC) of patients with systemic juvenile idiopathic arthritis (JIA), its regulation by IL-10, and the association of abnormal regulation of IL-6 production with presence of polymorphisms in the regulatory sequence of the IL-6 gene. PBMC were cultured in the absence or presence of lipopolysaccharide (LPS). IL-6 and IL-10 levels were measured by ELISA. Polymorphisms in the regulatory sequences of the IL-6 gene were assessed by restriction fragment length polymorphism analysis and sequencing of amplified regions. Patients' PBMC produced high amounts of IL-6 compared to controls in unstimulated conditions. The IL-10 50% inhibitory dose of LPS stimulated IL-6 production was significantly higher in patients than controls. IL-10 levels produced in the absence or presence of LPS were comparable between patients and controls. The -174 G/C polymorphism in the IL-6 gene does not appear to be correlated with the high unstimulated IL-6 production or with the reduced inhibition by IL-10 observed in patients with JIA. No differences in patients compared to controls and with respect to the published sequence were found in the 3' untranslated region (UTR) of the IL-6 gene. Most patients with JIA have increased unstimulated production of IL-6 and reduced inhibition of IL-6 production by IL-10. This abnormal regulation of IL-6 production is not secondary to a defect in IL-10 production, and is not associated with polymorphism of alleles at position -174 of the 5' flanking region or with mutations in the 3' untranslated region of the IL-6 gene.


Field evaluation of mercury vapor analytical methods: comparison of the "double amalgam method" and ISO 17733.
In this study, a gold amalgam method called the "Double amalgam method" was compared with the ISO 17733 method for mercury vapor analysis method. In terms of sensitivity and ease of operation, the amalgamation method is superior to the oxidation method. Two parallel samplings were carried out in this research at a button battery factory, where the mercury vapor level in the air was about 0.001 mg/m3 and at a fluorescent lamp factory, where the mercury vapor level was about 0.015 mg/m3. In the both cases, the measured values of the two showed good agreement with each other. As these two workplaces represent typical mercury levels in industries today, the double amalgam method is applicable to working environment measurement.


Mitochondrial Activity in Human White Adipocytes Is Regulated by the Ubiquitin Carrier Protein 9/microRNA-30a Axis.
The acquisition of beige adipocyte features by white fat cells corresponds to protection against obesity-induced metabolic diseases in humans and animal models of type 2 diabetes. In adipose tissue, expression of the E2 small ubiquitin-like modifier ligase ubiquitin carrier protein 9 (Ubc9) is positively correlated with markers of insulin resistance and corresponds with impaired browning of human white adipocytes. However, the molecular regulation of Ubc9 expression in adipocytes and other cells remains unclear. In this study, we demonstrate that the mRNA and protein expression of Ubc9 are regulated by the microRNA miRNA-30a (miR-30a) in human subcutaneous adipocytes. Ubc9 and miR-30a exhibit inverse expression in adipose tissue, with miR-30a robustly elevated in brown fat. Depletion of Ubc9 by siRNA or enforced expression of a miR-30a mimic augments mitochondrial volume and respiration in human white adipocytes, reflecting features of brown fat cells. Furthermore, Ubc9 depletion induces a brown fat gene program in human subcutaneous adipocytes. Induction of the beige-selective gene program corresponds to stabilization of the PR domain-containing 16 (PRDM16) protein, an obligate transcriptional regulator of the brown/beige fat metabolic program in white adipocytes that interacts with Ubc9. Taken together, our data demonstrate a previously unappreciated molecular axis that controls browning of human white adipocytes.


Efficient quantum walk on a quantum processor.
The random walk formalism is used across a wide range of applications, from modelling share prices to predicting population genetics. Likewise, quantum walks have shown much potential as a framework for developing new quantum algorithms. Here we present explicit efficient quantum circuits for implementing continuous-time quantum walks on the circulant class of graphs. These circuits allow us to sample from the output probability distributions of quantum walks on circulant graphs efficiently. We also show that solving the same sampling problem for arbitrary circulant quantum circuits is intractable for a classical computer, assuming conjectures from computational complexity theory. This is a new link between continuous-time quantum walks and computational complexity theory and it indicates a family of tasks that could ultimately demonstrate quantum supremacy over classical computers. As a proof of principle, we experimentally implement the proposed quantum circuit on an example circulant graph using a two-qubit photonics quantum processor.


Axonal regrowth is impaired during digit tip regeneration in mice.
Mice are intrinsically capable of regenerating the tips of their digits after amputation. Mouse digit tip regeneration is reported to be a peripheral nerve-dependent event. However, it is presently unknown what types of nerves and Schwann cells innervate the digit tip, and to what extent these cells regenerate in association with the regenerative response. Given the necessity of peripheral nerves for mammalian regeneration, we investigated the neuroanatomy of the unamputated, regenerating, and regenerated mouse digit tip. Using immunohistochemistry for β-III-tubulin (β3T) or neurofilament H (NFH), substance P (SP), tyrosine hydroxylase (TH), myelin protein zero (P0), and glial fibrillary acidic protein (GFAP), we identified peripheral nerve axons (sensory and sympathetic), and myelinating- and non-myelinating-Schwann cells. Our findings show that the digit tip is innervated by two digital nerves that each bifurcate into a bone marrow (BM) and connective tissue (CT) branch. The BM branches are composed of sympathetic axons that are ensheathed by non-myelinating-Schwann cells whereas the CT branches are composed of sensory and sympathetic axons and are ensheathed by myelinating- and non-myelinating-Schwann cells. The regenerated digit neuroanatomy differs from unamputated digit in several key ways. First, there is 7.5 fold decrease in CT branch axons in the regenerated digit compared to the unampuated digit. Second, there is a 5.6 fold decrease in myelinating-Schwann cells in the regenerated digit compared to the unamputated digit that is consistent with the decrease in CT branch axons. Importantly, we also find that the central portion of the regenerating digit blastema is aneural, with axons and Schwann cells restricted to peripheral and distal blastema regions. Finally, we show that even with impaired innervation, digits maintain the ability to regenerate after re-amputation. Taken together, these data indicate that nerve regeneration is impaired in the context of mouse digit tip regeneration.


Relationships between Cattell-Horn-Carroll (CHC) cognitive abilities and math achievement within a sample of college students with learning disabilities.
This study examined the relationship between cognitive abilities and math achievement within a sample of college students with learning disabilities (LD). The cognitive abilities were seven areas identified by Stratum II of the Cattell-Horn-Carroll (CHC) theory of cognitive abilities, in addition to the eighth area of Working Memory. Math performance was assessed via math calculation and math reasoning tasks. Instruments include the Woodcock-Johnson III Tests of Cognitive Abilities and Tests of Achievement. Participants were 158 college students with a diagnosed LD in math. Multiple regression analyses found that Processing Speed and Working Memory were related to Math Calculation scores and that Comprehension-Knowledge, Fluid Reasoning, and Working Memory were related to Math Reasoning. Implications for the assessment of math LD in the college populations are discussed.


Regulation of the Membrane Trafficking of the Mechanosensitive Ion Channels TRPV1 and TRPV4 by Zonular Tension, Osmotic Stress and Activators in the Mouse Lens.
Lens water transport generates a hydrostatic pressure gradient that is regulated by a dual-feedback system that utilizes the mechanosensitive transient receptor potential vanilloid (TRPV) channels, TRPV1 and TRPV4, to sense changes in mechanical tension and extracellular osmolarity. Here, we investigate whether the modulation of TRPV1 or TRPV4 activity dynamically affects their membrane trafficking. Mouse lenses were incubated in either pilocarpine or tropicamide to alter zonular tension, exposed to osmotic stress, or the TRPV1 and TRPV4 activators capsaicin andGSK1016790A (GSK101), and the effect on the TRPV1 and TRPV4 membrane trafficking in peripheral fiber cells visualized using confocal microscopy. Decreases in zonular tension caused the removal of TRPV4 from the membrane of peripheral fiber cells. Hypotonic challenge had no effect on TRPV1, but increased the membrane localization of TRPV4. Hypertonic challenge caused the insertion of TRPV1 and the removal of TRPV4 from the membranes of peripheral fiber cells. Capsaicin caused an increase in TRPV4 membrane localization, but had no effect on TRPV1; while GSK101 decreased the membrane localization of TRPV4 and increased the membrane localization of TRPV1. These reciprocal changes in TRPV1/4 membrane localization are consistent with the channels acting as mechanosensitive transducers of a dual-feedback pathway that regulates lens water transport.


HOMOLOGOUS DISEASE IN THE ADULT RAT, A MODEL FOR AUTOIMMUNE DISEASE. I. GENERAL FEATURES AND CUTANEOUS LESIONS.
The cutaneous lesions of adult rats with homologous disease are described, and evidence is presented to indicate that they have an immunologic basis. The skin changes included erythema, purpura, edema, and a variety of inflammatory lesions. In the more active lesions, dermal infiltration, hydropic degeneration, acanthosis, and atrophy of the epidermis with hyperkeratosis and follicular plugging were present. In some cases, ulceration and sloughing were also observed. More chronic lesions were characterized by atrophy of the epidermis and collagenization of the dermis with disappearance of the skin appendages. Rejection of autografts was observed simultaneously with acceptance of homografts. The histologic appearance of autografts undergoing rejection was similar to that of the spontaneous skin lesions, suggesting that the latter, too, had an immunologic basis. In favor of this, also, was the specificity of the dermatitis for the skin of the host, with sparing of neighboring homograft tissue. There was a histologic similarity between the spontaneous skin lesions of homologous disease and those of lupus erythematosus on the one hand, and scleroderma on the other, thus supporting the possibility that the cutaneous lesions of these connective tissue diseases of man may also have an immunologic basis. It was concluded that the adult rat with homologous disease may furnish a model for human autoimmune disease.


How Can We Actually Change Help-Seeking Behaviour for Mental Health Problems among the General Public? Development of the 'PLACES' Model.
Good treatment uptake is essential for clinically effective interventions to be fully utilised. Numerous studies have examined barriers to help-seeking for mental health treatment and to a lesser extent, facilitators. However, much of the current research focuses on changing help-seeking attitudes, which often do not lead to changes in behaviour. There is a clear gap in the literature for interventions that successfully change help-seeking behaviour among the general public. This gap is particularly relevant for early intervention. Here we describe the development of a new model which combines facilitators to treatment and an engaging, acceptable intervention for the general public. It is called the 'PLACES' (Publicity, Lay, Acceptable, Convenient, Effective, Self-referral) model of treatment engagement. It is based on theoretical work, as well as empirical research on a low intensity psychoeducational cognitive behavioural therapy (CBT) intervention: one-day workshops for stress and depression. In this paper, we describe the development of the model and the results of its use among four different clinical groups (adults experiencing stress, adults experiencing depression, adolescents (age 16-18) experiencing stress, and mothers with postnatal depression). We recorded high rates of uptake by people who have previously not sought help and by racial and ethnic minority groups across all four of these clinical groups. The clinical and research implications and applications of this model are discussed.


The natural history of main duct-involved, mixed-type intraductal papillary mucinous neoplasm: parameters predictive of progression.
As such, the natural history of MPD-involved IPMN is poorly understood. The high-risk of malignancy associated with main pancreatic duct (MPD)-involved intraductal papillary mucinous neoplasm (IPMN) has been established by surgical series. The International Consensus Guidelines recommend surgical resection of MPD-involved IPMN in fit patients. A review of a prospectively collected database (1992-2012) of patients with IPMN undergoing primary surveillance was performed. Invasive progression was defined as invasive carcinoma on pathology and/or positive cytopathology. Analyses included univariate, logistic regression, and receiver operating characteristic curve analyses. A total of 503 patients with IPMN underwent primary surveillance, 70 for MPD-involved, mixed-type IPMN. Indications for intensive surveillance of these 70 high-risk patients were comorbidities, patient choice, and early/borderline MPD dilation (42%, 51%, and 7%, respectively). Mean follow-up was 4.7 years. Nine patients (13%) progressed at a mean of 3.5 (range, 1-9) years during follow-up. Univariate analyses yielded weight loss, interval (from isolated branch-duct IPMN) to MPD involvement, diffuse MPD dilation, increase of MPD diameter, absence of extra pancreatic cysts, elevated serum CA19-9 levels, and elevated serum alkaline phosphatase levels as significant. Maximum MPD and/or branch-duct diameter were not significant. In logistic regression, diffuse MPD dilation, serum CA19-9 and serum alkaline phosphatase levels, and absence of extra pancreatic cysts were predictors of invasiveness. The receiver operating characteristic curve indicated that the combination of these 4 factors achieved an accuracy of 98% in predicting progression. Primary surveillance of mixed-type IPMN may be a reasonable strategy in select patients. Diffuse MPD dilation, serum CA19-9, serum alkaline phosphatase, and absence of extrapancreatic cysts predict patients likely to progress during primary surveillance.


Stress and psychological distress among SARS survivors 1 year after the outbreak.
Our study examined the stress level and psychological distress of severe acute respiratory syndrome (SARS) survivors 1 year after the outbreak. During the SARS outbreak in 2003, we used the 10-item Perceived Stress Scale (PSS-10) to assess SARS survivors treated in 2 major hospitals (non-health care workers, n = 49; health care workers, n = 30). We invited SARS survivors from the same hospitals (non-health care workers, n = 63; health care workers, n = 33) to complete the PSS-10 again in 2004. At that time, they were also asked to complete the General Health Questionnaire (GHQ-12) and measures of depression, anxiety, and posttraumatic symptoms. PSS-10 scores were also obtained from matched community control subjects during the outbreak (n = 145) and again in 2004 (n = 112). SARS survivors had higher stress levels during the outbreak, compared with control subjects (PSS-10 scores = 19.8 and 17.9, respectively; P < 0.01), and this persisted 1 year later (PSS-10 scores = 19.9 and 17.3, respectively; P < 0.01) without signs of decrease. In 2004, SARS survivors also showed worrying levels of depression, anxiety, and posttraumatic symptoms. An alarming proportion (64%) scored above the GHQ-12 cut-off that suggests psychiatric morbidity. During the outbreak, health care worker SARS survivors had stress levels similar to those of non-health care workers, but health care workers showed significantly higher stress levels in 2004 (PSS-10 score = 22.8, compared with PSS-10 score = 18.4; P < 0.05) and had higher depression, anxiety, posttraumatic symptoms, and GHQ-12 scores. One year after the outbreak, SARS survivors still had elevated stress levels and worrying levels of psychological distress. The situation of health care worker SARS survivors is particularly worrying. The long-term psychological implications of infectious diseases should not be ignored. Mental health services could play an important role in rehabilitation.


Collagenase immunolocalization in cultures of rheumatoid synovial cells.
Cultures of rheumatoid synovial cells that have been enzymatically dissociated and are adherent to a culture vessel are morphologically heterogeneous. When these cells are cultured on a collagenous substrate for 2 to 6 days at 37 degrees C in serum-free medium, they produce collagenase. A monospecific antibody to human collagenase has localized the enzyme extracellularly around cytoplasmic extensions of dendritic cells and intracellularly within a few macrophage-like and fibroblast-like cells.


Reduced Isocyanate Release Using a Waterproof, Resin-Based Cast Alternative Relative to Fiberglass Casts.
The effects of occupational isocyanate exposure range from asthma and contact dermatitis to neurotoxicity and cancer. Respiratory sensitization due to orthopedic cast application has been well documented. This study aims to compare the safety of standard-of-care fiberglass casts and a novel waterproof cast alternative by measuring the amount of isocyanate released during off-gassing over time. A 3D-printed arm simulator with comparable casing material amounts was placed in a sealed chamber. An isocyanate-sensing color-changing (SafeAir) tag was used to measure the levels of toxic exposure. Triplicate trials were conducted across all time periods (15 min, 1 h, and 24 h) and conditions. The bare arm simulator and freshly opened tags served as negative controls. Normalized pixel intensity indexes and isocyanate release estimates in ppb were derived from ImageJ-analyzed SafeAir tag photos. Fiberglass casts exhibited greater isocyanate release than both the waterproof alternative (p = 0.0002) and no-cast controls (p = 0.0006), particularly at 24 h. The waterproof alternative and no-cast control did not statistically differ (p = 0.1603). Therefore, the waterproof alternative released less isocyanate than the fiberglass casts. Waterproof cast alternatives may be safer than fiberglass by limiting medical professionals' exposure to toxic isocyanates and, thus, decreasing their risk of suffering occupational asthma.


The phage phi29 membrane protein p16.7, involved in DNA replication, is required for efficient ejection of the viral genome.
It is becoming clear that in vivo phage DNA ejection is not a mere passive process. In most cases, both phage and host proteins seem to be involved in pulling at least part of the viral DNA inside the cell. The DNA ejection mechanism of Bacillus subtilis bacteriophage phi29 is a two-step process where the linear DNA penetrates the cell with a right-left polarity. In the first step approximately 65% of the DNA is pushed into the cell. In the second step, the remaining DNA is actively pulled into the cytoplasm. This step requires protein p17, which is encoded by the right-side early operon that is ejected during the first push step. The membrane protein p16.7, also encoded by the right-side early operon, is known to play an important role in membrane-associated phage DNA replication. In this work we show that, in addition, p16.7 is required for efficient execution of the second pull step of DNA ejection.


Ethanol enhances collective dynamics of lipid membranes.
From inelastic neutron-scattering experiments and all atom molecular dynamics simulations we present evidence for a low-energy dynamical mode in the fluid phase of a 1,2-dimyristoyl-sn-glycero-3-phoshatidylcholine (DMPC) bilayer immersed in a 5% water/ethanol solution. In addition to the well-known phonon that shows a liquidlike dispersion with energies up to 4.5 meV, we observe an additional mode at smaller energies of 0.8 meV, which shows little or no dispersion. Both modes show transverse properties and might be related to molecular motion perpendicular to the bilayer.


Service user's actual involvement in mental health research practices: A scoping review.
Service user involvement in mental health research is on the international political agenda, for example mirrored by an emphasis on user involvement in funding of research. The idea is that service users contribute with their lived experiences of mental distress to the research process and thereby heighten the quality and relevance of the research. The purpose of this scoping review was to identify and evaluate empirical research of how mental health service users actually partake in collaborative research processes and to summarize this research in dialogue with mental health user-researchers. The review included 32 studies. Main findings indicated that actual involvement of service user-researchers in research processes encompassed a complex set of precarious negotiation practices, where academics and service user-researchers were positioned and positioned themselves in alternative ways. The review accounts for how mental health service users were involved in collaborative research processes. The extracted themes concerned: (i) Expectations of research processes, (ii) Contribution to research processes, and (iii) Training and learning from research processes. The study reveals that collaborative research in mental health requires changes to traditional research practices to create and support genuine collaborative partnerships and thereby avoid tokenism and power inequalities.


Periodontal disease in mothers indicates risk in their children.
It is well established that severe periodontitis clusters in families, but there are no data about the relationship between mothers with chronic periodontitis and their children's periodontal status. To evaluate a risk for periodontal diseases in children of periodontally diseased and healthy mothers. Four study groups were included: (I) 20 female patients with untreated generalized severe chronic periodontitis, (II) their children (34), (III) 13 periodontally healthy mothers and (IV) their children (13). Material was collected from years 2004-2006. The clinical examination included registration of visible plaque index, modified gingival index and, bleeding sites on probing. Periodontal microbiological samples were obtained from all study subjects and the isolates were identified according to morphology and biochemical profiles; similar interfamilial pathogens were compared by PCR-technique. The children of diseased mothers more frequently had periodontal diseases, especially gingivitis. In addition, clinical parameters of gingival inflammation were more expressed and oral hygiene was worse in this group of children. VPI and VPI% of the diseased and healthy mothers differed significantly. The most common oral pathogens were P. intermedia/nigrescens and A. actinomycetemcomitans. The children of healthy mothers harboured pathogens less frequently than the children of diseased mothers. The sharing of P. intermedia/nigrescens was more frequent (5 families) than A. actinomycetemcomitans (2 families). Maternal indicators, such as periodontitis, hygiene habits, and periodontal microflora are risk factors for childhood periodontal diseases, and might be predictive of future childhood and adolescent periodontitis.


Combining EEG and fMRI in the study of epileptic discharges.
The combining of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) is a unique noninvasive method for investigating the brain regions involved at the time of epileptic discharges. The neuronal discharges taking place during an interictal spike or spike-wave burst result in an increase in metabolism and blood flow, which is reflected in the blood oxygen-level dependent (BOLD) signal measured by fMRI. This increase is most intense in the region generating the discharge but is also present in regions affected by the discharge. On occasion, epileptic discharges result in decreased metabolism, the origin of which is only partially understood. EEG-fMRI applied to focal epilepsy results in maxima of the BOLD signal most often concordant with other methods of localization and has been shown to help in localizing epileptic foci in nonlesional frontal lobe epilepsy. It has also demonstrated the involvement of the thalamus in generalized epileptic discharges. In patients with new-onset epilepsy it could be used to evaluate the source and extent of the brain structures involved during discharges and their evolution as the disease progresses.


Functional consequences of the deletion mutation deltaGlu160 in human cardiac troponin T.
To explore the functional consequences of a deletion mutation of troponin T (DeltaGlu160) found in familial hypertrophic cardiomyopathy, the mutant human cardiac troponin T, and wild-type troponins T, I, and C were expressed in Escherichia coli and directly incorporated into isolated porcine cardiac myofibrils using our previously reported troponin exchange technique. The mutant troponin T showed a slightly reduced potency in replacing the endogenous troponin complex in myofibrils and did not affect the inhibitory action of troponin I but potentiated the neutralizing action of troponin C, suggesting that the deletion of a single amino acid, Glu-160, in the strong tropomyosin-binding region affects the tropomyosin binding affinity of the entire troponin T molecule and alters the interaction between troponin I and troponin C within ternary troponin complex in the thin filament. This mutation also increased the Ca(2+) sensitivity of the myofibrillar ATPase activity, as in the case of other mutations in troponin T with clinical phenotypes of poor prognosis similar to that of Glu160. These results provide strong evidence that the increased Ca(2+) sensitivity of cardiac myofilament is a typical functional consequence of the troponin T mutation associated with a malignant form of hypertrophic cardiomyopathy.


Longitudinal Measurements of Cerebrospinal Fluid Biomarkers in Parkinson's Disease.
The purpose of this study was to investigate whether cerebrospinal fluid (CSF) levels of tau, phosphorylated tau, β-amyloid42 , α-synuclein, neurofilament light, and YKL-40 change over time and if changes correlate with motor progression and/or cognitive decline in patients with PD and controls. We included 63 patients with PD (nondemented) and 21 neurologically healthy controls from the prospective and longitudinal Swedish BioFINDER study, all of whom had clinical assessments and lumbar punctures at baseline and after 2 years. CSF tau levels correlated strongly with α-synuclein. The levels of CSF α-synuclein, tau, phosphorylated tau, neurofilament light, and YKL-40, but not β-amyloid42 , increased in CSF over 2 years in PD. No changes were seen in the control group. Studying patients with a short disease duration ( ≤ 5 years) and patients with a long disease duration ( > 5 years) separately, α-synuclein and tau only increased in the PD group with long disease duration. In the PD group, an increase in phosphorylated tau over 2 years correlated with faster motor progression and faster cognitive decline. An increase in YKL-40 over 2 years correlated with faster cognitive decline. CSF biomarkers reflecting Lewy body pathology and neurodegeneration (α-synuclein), neuronal degeneration (tau, phosphorylated tau, and neurofilament light), and inflammation (YKL-40) increase significantly over 2 years in PD. CSF levels of α-synuclein and tau correlate and remain stable in the early symptomatic phase of PD but increase in the later phase. We hypothesize that CSF α-synuclein levels might increase as a result of more intense neurodegeneration in PD with long disease duration. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.


Genomic structures of synaptotagmin II protein: comparison of exon-intron organization of the synaptotagmin gene family.
Synaptotagmin (Syt) I (or II) is thought to be a Ca(2+) sensor for neurotransmitter release in the rostral (or caudal) region of the mammalian brain. In this study, we first report the genomic structures and the transcription initiation site of the mouse syt II gene. Syt II protein coding regions consist of 8 exons with a total size of about 7 kbp. Exon 2 encodes the transmembrane domain, and exons 3-5 and 6-8 encode the C2A and C2B domains, respectively, although the precise intron positions within the two C2 domains are different. The syt II gene structures are quite similar to the mouse syt VIII and human syt IX genes, but not Caenorhabditis elegans syt I, human syt VII, or the mouse syt III genes, indicating that the exon-intron patterns of the functional domain of synaptotagmins (especially the C2A domain) have not been as well conserved during evolution as among isoforms. The only conserved feature among the synaptotagmin gene family seems to have a single exon that encodes the whole transmembrane domain.


Competition between ant species: outcome controlled by parasitic flies.
Experimental evidence demonstrates that the parasitic phorid fly Apocephalus shifts the competitive balance between the ant species Pheidole dentata and Solenopsis texana by interfering with the defensive behavior of Pheidole dentata major workers (soldiers). This represents one of the first examples of a parasite affecting competitive interactions anmong terrestrial animals in natural communities. Similar complex interactions are probably common in many ant communities.


A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.
Circadian rhythm abnormalities in bipolar disorder (BD) have led to a search for genetic abnormalities in circadian "clock genes" associated with BD. However, no significant clock gene findings have emerged from genome-wide association studies (GWAS). At least three factors could account for this discrepancy: complex traits are polygenic, the organization of the clock is more complex than previously recognized, and/or genetic risk for BD may be shared across multiple illnesses. To investigate these issues, we considered the clock gene network at three levels: essential "core" clock genes, upstream circadian clock modulators, and downstream clock controlled genes. Using relaxed thresholds for GWAS statistical significance, we determined the rates of clock vs. control genetic associations with BD, and four additional illnesses that share clinical features and/or genetic risk with BD (major depression, schizophrenia, attention deficit/hyperactivity). Then we compared the results to a set of lithium-responsive genes. Associations with BD-spectrum illnesses and lithium-responsiveness were both enriched among core clock genes but not among upstream clock modulators. Associations with BD-spectrum illnesses and lithium-responsiveness were also enriched among pervasively rhythmic clock-controlled genes but not among genes that were less pervasively rhythmic or non-rhythmic. Our analysis reveals previously unrecognized associations between clock genes and BD-spectrum illnesses, partly reconciling previously discordant results from past GWAS and candidate gene studies.


An energy model of interframe interval effects in single-step apparent motion.
A computational model was developed to explain the effects of an interframe interval (IFI) in single-step apparent motion experiments. In these experiments a stimulus appears in one position, disappears, and then reappears in a shifted position after a short or long IFI. If the luminance during the IFI matches the mean luminance of the stimulus frames, long IFIs result in perceived motion opposite the short-IFI conditions. Brighter or darker IFIs, however, do not support the reversed motion effect. The model possess the following defining characteristics: (1) a biphasic ("transient") channel whose signalled direction of motion reverses with changes of IFI duration; (2) a combined direction-opponent output which is the sum of directional responses developed in two channels--biphasic ("transient") and monophasic ("sustained"); (3) a signal/noise weighting of the contributions of the two channels to the final directional output of the system. Predictions of the model about the effects of IFI intensity and viewing eccentricity were tested and confirmed in two new psychophysical experiments. The interpretations of past studies which included a role for second-order motion mechanisms in explaining IFI duration effects were reexamined. Further empirical tests of the model were outlined.


Genetic basis of prune belly syndrome: screening for HNF1β gene.
Although the cause of prune belly syndrome is unknown, familial evidence suggests a genetic component. Recently 2 nonfamilial cases of prune belly syndrome with chromosome 17q12 deletions encompassing the HNF1β gene have made this a candidate gene for prune belly syndrome. To date, there has been no large-scale screening of patients with prune belly syndrome for HNF1β mutations. We assessed the role of HNF1β in prune belly syndrome by screening for genomic mutations with functional characterization of any detected mutations. We studied patients with prune belly syndrome who were prospectively enrolled in our Pediatric Genitourinary DNA Repository since 2001. DNA from patient samples was amplified by polymerase chain reaction, sequenced for coding and splice regions of the HNF1β gene, and compared to control databases. We performed functional assay testing of the ability of mutant HNF1β to activate a luciferase construct with an HNF1β DNA binding site. From 32 prune belly syndrome probands (30 males, 2 females) HNF1β sequencing detected a missense mutation (V61G) in 1 child with prune belly syndrome. Absent in control databases, V61G was previously reported in 2 patients without prune belly syndrome who had congenital genitourinary anomalies. Functional testing showed similar luciferase activity compared to wild-type HNF1β, suggesting the V61G substitution does not disturb HNF1β function. One genomic HNF1β mutation was detected in 3% of patients with prune belly syndrome but found to be functionally normal. Thus, functionally significant HNF1β mutations are uncommon in prune belly syndrome, despite case reports of HNF1β deletions. Further genetic study is necessary, as identification of the genetic basis of prune belly syndrome may ultimately lead to prevention and improved treatments for this rare but severe syndrome.


Phylogenetic and Structural Identification of a Novel Magnetotactic Deltaproteobacteria Strain, WYHR-1, from a Freshwater Lake.
Magnetotactic bacteria (MTB) are phylogenetically diverse prokaryotes that are able to biomineralize intracellular, magnetic chains of magnetite or greigite nanocrystals called magnetosomes. Simultaneous characterization of MTB phylogeny and biomineralization is crucial but challenging because most MTB are extremely difficult to culture. We identify a large rod, bean-like MTB (tentatively named WYHR-1) from freshwater sediments of Weiyang Lake, Xi'an, China, using a coupled fluorescence and scanning electron microscopy approach at the single-cell scale. Phylogenetic analysis of 16S rRNA gene sequences indicates that WYHR-1 is a novel genus from the Deltaproteobacteria class. Transmission electron microscope observations reveal that WYHR-1 cells contain tens of magnetite magnetosomes that are organized into a single chain bundle along the cell long axis. Mature WYHR-1 magnetosomes are bullet-shaped, straight, and elongated along the [001] direction, with a large flat end terminated by a {100} face at the base and a conical top. This crystal morphology is distinctively different from bullet-shaped magnetosomes produced by other MTB in the Deltaproteobacteria class and the Nitrospirae phylum. This indicates that WYHR-1 may have a different crystal growth process and mechanism from other species, which results from species-specific magnetosome biomineralization in MTB.IMPORTANCE Magnetotactic bacteria (MTB) represent a model system for understanding biomineralization and are also studied intensively in biogeomagnetic and paleomagnetic research. However, many uncultured MTB strains have not been identified phylogenetically or investigated structurally at the single-cell level, which limits comprehensive understanding of MTB diversity and their role in biomineralization. We have identified a novel MTB strain, WYHR-1, from a freshwater lake using a coupled fluorescence and scanning electron microscopy approach at the single-cell scale. Our analyses further indicate that strain WYHR-1 represents a novel genus from the Deltaproteobacteria class. In contrast to bullet-shaped magnetosomes produced by other MTB in the Deltaproteobacteria class and the Nitrospirae phylum, WYHR-1 magnetosomes are bullet-shaped, straight, and highly elongated along the [001] direction, are terminated by a large {100} face at their base, and have a conical top. Our findings imply that, consistent with phylogenetic diversity of MTB, bullet-shaped magnetosomes have diverse crystal habits and growth patterns.


Reliability of wear measurements of CAD-CAM restorative materials after artificial aging in a mastication simulator.
The purpose of this in vitro study was to assess the 2-body wear behavior of computer-aided design and computer-aided manufacturing (CAD-CAM) restorative materials and additionally to validate an automatic approach to wear quantification as provided by newly developed software. Two composite resins (Experimental Composite, Shofu Block HC), 1 polymethyl methacrylate- (PMMA)-based material (Telio CAD), and 1 dual-network material (VITA Enamic) were tested (n = 12). The materials were stored in distilled water at 37 °C for 14 days, then aged in a mastication simulator (cycles: 400 000, 50 N, 1.2 Hz, 5/55 °C) for 2-body wear testing with human molars as antagonists. Software was developed as a freely available function in R for automatic wear quantification and was applied to 2 (vertical and horizontal) images obtained by an optical laser scanner (SDM). Wear measurements were validated with a reference confocal laser scanning microscope (LSM) system. The Kruskal-Wallis with Tukey-Kramer post hoc test (α = 0.05), coefficient of variation, Bland-Altman method, and intraclass correlation were applied. Shofu Block HC showed the greatest wear, and no differences were found among other materials. The automatic wear measurements agreed well with the reference LSM system. The reliability of the SDM scans was 98.5%. The wear resistance caused by two-body wear differed among the restorative materials tested, with the mean wear resistance of the 2 composite resin materials differing significantly. Wear quantification with R software based on SDM scans showed satisfactory agreement with the reference LSM system.


An outbreak of multidrug-resistant Serratia marcescens: the importance of continuous monitoring of nosocomial infections.
Serratia marcescens is a well-established as a nosocomial pathogen, resulting in considerable morbidity and mortality in immunocompromised patients. The aim of this study was to investigate an outbreak of Serratia marcescens at the Orthopaedic Clinic of the Clinical Center University of Sarajevo. A total of 96 strains from 79 patients were isolated. The isolates were identified by conventional methods. Susceptibility testing was performed by the discdiffusion method following CLSI guidelines. Results were confirmed by VITEC-2 Compact. From January to December 2010, 96 strains from 79 patients were isolated at the Orthopaedic Clinic of the Clinical Center, University of Sarajevo.The strains were isolated from wound swabs, blood cultures and cerebrospinal fluid. The strains were identifed using current phenotypic methods as Serratia marcescens with identical biochemical characteristics and antibiotic susceptibility patterns. All strains were susceptible to imipenem, meropenem, amikacin, ciprofloxacin, levofloxacin and piperacillin/tazobactam. The infection control team was alerted and after investigation they discovered the same phenotype of Serratia marcescens in the anaesthetic vials used in procedures. This outbreak was extremely difficult to terminate, even with cohorting of patients, sterilisation of equipment, reinforcement of handwashing and deep-cleaning of facilities. The implementation of new control measures terminated the outbreak in February 2011. Continuous monitoring of nosocomial infections is indispensable. Phenotypic characterization of the isolates is useful for studying the relationship of microbial pathogens. The relationship of one clinical isolate to another during an outbreak is important in motivating the search for a common source or mode of transmission.


Evolutionary analyses of European H1N2 swine influenza A virus by placing timestamps on the multiple reassortment events.
A novel H1N2 swine influenza A virus emerged in Europe since 1994. Previous phylogenetic analyses revealed that its genome segments were derived from H1N1 human virus, H3N2 human virus and avian-like H1N1/H3N2 swine virus, indicating the possibility of multiple reassortments events. However, dates of these reassortment events have not been investigated systematically. In this study, we used both global and local molecular clock concepts in a maximum likelihood framework to extrapolate the times of origins of the genome segments in European H1N2 swine viruses, and deduced that novel neuraminidase, hemagglutinin and other internal protein genes were introduced to the European H1N2 lineage at the 1970s, early 1980s and late 1980s, respectively through reassortments. Furthermore, in light of the evolutionary timescale reconstructed for the H1N2 viruses, we argue that further reassortments, in addition to those responsible for the introductions of novel genome segments, might have also occurred among the viruses prior to the outbreaks arose in United Kingdom at 1994. Our results confirm that the viral genes of various origins have stably maintained in swine population for many years before the multiple genetic reassortant was detected. Our evolutionary analyses also suggested that the HA and NA genes evolved in a significantly higher rate of synonymous substitutions after they were introduced from human to swine and established the European H1N2 swine lineage.


Towards mainstream anammox: lessons learned from pilot-scale research at WWTP Dokhaven.
The aim of this research was to study the biological feasibility of the Partial Nitritation/Anammox (PN/A) technology to remove nitrogen from municipal mainstream wastewaters. During stable process operations at summer temperatures (23.2 ± 1.3°C), the total nitrogen removal rate was 0.223 ± 0.029 kg N (m3 d)-1 while at winter temperatures (13.4 ± 1.1°C) the total nitrogen removal rate was 0.097 ± 0.016 kg N (m3 d)-1. Nitrite-oxidizing bacteria (NOB) suppression was successfully achieved at the complete temperature range of municipal mainstream wastewater. Despite the presence of NOB as observed in activity tests, their activity could be successfully suppressed due to a relative low dissolved oxygen concentration. An overcapacity of ammonia-oxidizing bacteria and anammox activity was always present. Long-term stability is a focus point for future research, especially in relation to the stability of the biological oxygen demand removing step, preceding the PN/A reactor.


Biomechanical testing of microblasted, acid-etched/microblasted, anodized, and discrete crystalline deposition surfaces: an experimental study in beagle dogs.
Modifications in implant surface topography and chemistry may alter the early bone response at different levels. This study characterized four implant surfaces and evaluated the biomechanical fixation and histologic response at early implantation times in a canine radius model. External-hexagon Branemark-type implants were used with four experimental surfaces: microblasted (MI), acid-etched and microblasted (AAM), anodized (A), and discrete crystalline deposition (DCD). Surface topography was assessed by scanning electron microscopy, interferometry, and x-ray photoelectron spectroscopy. The implants were placed in the central region of the radii of eight beagle dogs and remained in vivo for 10 or 30 days. The implants were torqued to interface failure, and a general linear statistical model with torque as the dependent variable and implant surface and time in vivo as independent variables was used. All surfaces presented were textured, and different surface chemistries were observed. No significant differences between implant surfaces were observed for torque at 10 days. However, at 30 days, the AAM surface presented significantly higher torque values compared to the DCD and A surfaces. Significantly higher torque values were observed at 30 days compared to 10 days (P < .001). Significantly different biomechanical fixation dependent on surface preparation was observed after 30 days, and all surfaces were biocompatible and osteoconductive.


Long-term stability (21-30 years) of root coverage outcomes using sub-epithelial connective tissue grafts at single or multiple gingival recessions: A longitudinal case series.
To evaluate outcomes and predictive factors for the long-term stability of root coverage using a sub-epithelial connective tissue graft. One-hundred and two healthy subjects (221 gingival recessions, GRs) were treated from 1987 to 1996. Keratinized tissue width (KTW), GR depth (RD), GR width (RW) and GR area (RA) were evaluated at baseline (M0) and at 1 month (M1), 1 year (M2), 11 years (M3), 21 years (M4) and 27 years (M5) after surgery. Primary outcomes consisted of complete root coverage (cRC) and relative dimensional changes in recession depth (measured in mm [c%-RD]), recession width (measured in mm [c%-RW]) and recession area (measured in mm2 [c%-RA]). cRC was 88.7% at 1 year (M2), 59.8% at M3, 44.4% at M4 and 51.9% at M5. Average c%-RD was 95.2% at 1 year, 81.9% at M3, 71.5% at M4 and 81.7% at M5. KTW increased after surgery and over time and was positively correlated with favourable outcomes. Increased baseline RA was associated with less favourable clinical outcomes. The sub-epithelial connective tissue graft is effective in the treatment of GRs and facilitates long-term stability of clinical outcomes. Wider baseline RA was a strong predictor of unfavourable short- and long-term RC outcomes.


The symmetries of image formation by scattering. II. Applications.
We show that the symmetries of image formation by scattering enable graph-theoretic manifold-embedding techniques to extract structural and timing information from simulated and experimental snapshots at extremely low signal. The approach constitutes a physically-based, computationally efficient, and noise-robust route to analyzing the large and varied datasets generated by existing and emerging methods for studying structure and dynamics by scattering. We demonstrate three-dimensional structure recovery from X-ray diffraction and cryo-electron microscope image snapshots of unknown orientation, the latter at 12 times lower dose than currently in use. We also show that ultra-low-signal, random sightings of dynamically evolving systems can be sequenced into high quality movies to reveal their evolution. Our approach offers a route to recovering timing information in time-resolved experiments, and extracting 3D movies from two-dimensional random sightings of dynamic systems.


Novel circular DNA virus identified in Opuntia discolor (Cactaceae) that codes for proteins with similarity to those of geminiviruses.
Viral metagenomic studies have enabled the discovery of many unknown viruses and revealed that viral communities are much more diverse and ubiquitous than previously thought. Some viruses have multiple genome components that are encapsidated either in separate virions (multipartite viruses) or in the same virion (segmented viruses). In this study, we identify what is possibly a novel bipartite plant-associated circular single-stranded DNA virus in a wild prickly pear cactus, Opuntia discolor, that is endemic to the Chaco ecoregion in South America. Two ~1.8 kb virus-like circular DNA components were recovered, one encoding a replication-associated protein (Rep) and the other a capsid protein (CP). Both of the inferred protein sequences of the Rep and CP are homologous to those encoded by members of the family Geminiviridae. These two putatively cognate components each have a nonanucleotide sequence within a likely hairpin structure that is homologous to the origins of rolling-circle replication (RCR), found in diverse circular single-stranded DNA viruses. In addition, the two components share similar putative replication-associated iterative sequences (iterons), which in circular single-stranded DNA viruses are important for Rep binding during the initiation of RCR. Such molecular features provide support for the possible bipartite nature of this virus, which we named utkilio virus (common name of the Opuntia discolor in South America) components A and B. In the infectivity assays conducted in Nicotiana benthamiana plants, only the A component of utkilio virus, which encodes the Rep protein, was found to move and replicate systemically in N. benthamiana. This was not true for component B, for which we did not detect replication, which may have been due to this being a defective molecule or because of the model plants (N. benthamiana) used for the infection assays. Future experiments need to be conducted with other plants, including O. discolor, to understand more about the biology of these viral components.


Improvement in Smell Using Monoclonal Antibodies Among Patients With Chronic Rhinosinusitis With Nasal Polyps: A Systematic Review.
Impairment of smell is more commonly related to chronic rhinosinusitis with nasal polyps (CRSwNP) than without, especially when asthma and/or NSAID-exacerbated respiratory disease and type 2 inflammation are also present. Therapeutic options include intranasal and systemic corticosteroids, surgery, and, more recently, biological therapy. We summarize current knowledge on the effect of biologics on olfaction in patients with CRSwNP. We performed a systematic search of the PubMed and Cochrane databases from January 2001 to June 2022. The inclusion criteria were as follows: adult patients with CRS treated with dupilumab, omalizumab, mepolizumab, benralizumab, or reslizumab; and studies published in English reporting outcomes for sense of smell based on psychophysical and/or subjective tools. We excluded reports that did not assess CRSwNP, loss of smell evaluated with a method other than those accepted in the inclusion criteria, review articles, and expert opinions. No funding was received. Dupilumab has demonstrated rapid and sustained long-term improvement in smell in clinical trials and in real life. Omalizumab improves smell at 24 weeks. This improvement is maintained in the long-term, although it is not clinically relevant. Mepolizumab and benralizumab improved smell in the long term based on a subjective scale. No studies examining the improvement in smell in patients with CRSwNP treated with reslizumab were found. Indirect comparisons by meta-analysis consistently conclude that dupilumab is the most effective biologic for improving impaired sense of smell. Dupilumab seems to be more efficacious for improving the sense of smell than omalizumab, mepolizumab, and benralizumab.


Further Reflections: Surrogate Decisionmaking When Significant Mental Capacities are Retained.
Mackenzie Graham has made an important contribution to the literature on decisionmaking for patients with disorders of consciousness. He argues, and I agree, that decisions for unresponsive patients who are known to retain some degree of covert awareness ought to focus on current interests, since such patients likely retain the kinds of mental capacities that in ordinary life command our current respect and attention. If he is right, then it is not appropriate to make decisions for such patients by appealing to the values they had in the past, either the values expressed in an advance directive or the values recalled by a surrogate. There are two things I wish to add to the discussion. My first point is somewhat critical, for although I agree with his general conclusion about how, ideally, such decisions should be approached, I remain skeptical about whether his conclusion offers decisionmakers real practical help. The problem with these cases is that the evidence we have about the nature of the patient's current interests is minimal or nonexistent. However-and this is important-Graham's conclusion will be extremely relevant if in the future, our ability to communicate with such patients improves, as I hope it will. This leads to my second point. Graham's conclusion illustrates a more general problem with our standard framework for decisionmaking for previously competent patients, a problem that has not been adequately recognized. So, in what follows, I explain the problem I see and offer some brief thoughts about solutions.


Educators' implicit perspectives on wisdom: a comparison between interpersonal and intrapersonal perspectives.
This research aimed to investigate educators' implicit perspectives on wisdom in order to compare interpersonal and intrapersonal perspectives and to help identify similarities or differences between these two theoretical perspectives. A total of 56 educators in Taiwan were interviewed individually. We utilised the grounded theory method to analyse the qualitative data. Results showed that both interpersonal and intrapersonal perspectives converged on four core components of wisdom: intrapsychic integration, actions in service of problem solving and ideal implementation, positive results and feedback and adjustments. The interpersonal perspective referred to external characteristics, and admiration and influence, whereas the intrapersonal perspective included greater detail about intrapsychic integration and action strategies than did the interpersonal perspective. We close with a discussion both of how wisdom appears to span across different fields and how the present results might feed into the teaching of wisdom in schools.


Is clinical intervention in the ultra high risk phase effective?
Recent research suggests that early intervention in psychosis might improve the chances of recovery and may even be able to prevent the onset of psychotic disorders. Clinical intervention in subjects at ultra high risk (UHR) of psychosis can have three different objectives. The first aim is to improve the 'prodromal' symptoms and problems that subjects usually present with. The second is to reduce the risk of the subsequent onset of frank psychosis. The third objective is to minimize the delay before the initiation of antipsychotic treatment in the subgroup of UHR subjects that go on to develop a first episode of psychosis. Both pharmacological and psychological interventions appear to be effective in reducing the severity of presenting symptoms in UHR subjects. Clinical trials of the impact of these interventions on the risk of subsequent transition to psychosis have been positive, but have involved small samples, and thus the issue of whether the effects persist in the long term remains to be determined. The monitoring of UHR subjects for the first signs of frank psychosis is an effective means of reducing the delay between the onset of the first episode and the start of antipsychotic treatment. Follow-up studies are required to test whether the reduction in this delay leads to an improved long term outcome. To date, the majority of the interventions that have been used in UHR subjects, such as case management, antipsychotic medication, and cognitive behavior therapy have previously been employed in patients with established psychosis. However, it is possible that treatments that are not normally used in patients with psychotic disorders may prove effective when applied at this stage.


Securing a future for responsible neuromodulation in children: The importance of maintaining a broad clinical gaze.
This perspective paper provides an overview of several key tensions and challenges within the social context of neuromodulation, and it suggests a means of securing the future of paediatric neuromodulation in light of these. Tensions and challenges relate to: the considerable clinical and economic need for new therapies to manage neurological diseases; significant commercial involvement in the field; funding pressures; public perceptions (particularly unrealistic expectations); and the emerging Responsible Research and Innovation initiative. This paper argues that managing these challenges and tensions requires that clinicians working within the field adopt what could be called a broad clinical gaze. This paper will define the broad clinical gaze, and it will propose several ways in which a broad clinical gaze can be - and indeed is being - operationalised in recent advances in neuromodulation in children. These include the use of multidisciplinary and interdisciplinary clinical team structures, the adoption of clinical assessment tools that capture day-to-day functionality, and the use of patient registries. By adopting a broad clinical gaze, clinicians and investigators can ensure that the field as a whole can responsibly and ethically deliver on its significant clinical potential.


The effect of exercise-induced localised hyperthermia on tendon cell survival.
Tendons that store energy during locomotion, such as the equine superficial digital flexor tendon (SDFT) and human Achilles tendon, suffer a high incidence of central core degeneration which is thought to precede tendon rupture. Although energy storage contributes to the efficiency of locomotion, tendons are not perfectly elastic and some energy is lost in the form of heat. Recent studies have shown that the central core of equine SDFT reaches temperatures as high as 45 degrees C during high-speed locomotion. In this study, we test the hypothesis that hyperthermia causes tendon cell death and results in tendon central core degeneration. Tendon fibroblasts cultured from the core of the equine SDFT were subjected to a temperature of 45 degrees C in an in vitro system for 0-180 min, and cell survival fraction was measured and compared with that for equine dermal fibroblasts and a commercial rat kidney fibroblast cell line (NRK 49F). Tendon fibroblasts were significantly more resistant to hyperthermia than NRK 49F cells after 30, 45 and 60 min of heating and significantly more resistant than dermal fibroblasts after 45 and 60 min of heating. After 10 min of heating at 45 degrees C, the tendon fibroblast cell survival fraction was 91 +/- 4%, whereas heating for 10 min at 48 degrees C resulted in a drop in the cell survival fraction to 22 +/- 4%. In conclusion, while temperatures experienced in the central core of the SDFT in vivo are unlikely to result in tendon cell death, repeated hyperthermic insults may compromise cell metabolism of matrix components, resulting in tendon central core degeneration.


Rationale for establishing a mechanism to increase reimbursement to hypertension specialists.
Hypertension is an important public health problem both in the United States and worldwide, contributing to many forms of cardiovascular and renal diseases. Although great strides have been made in the proportion of the US population that achieves recommended blood pressure targets, many Americans still have undertreated and uncontrolled blood pressure that increases the risk of expensive strokes, heart attacks, heart failure, and dialysis. Because hypertension is a common but heterogeneous and sometimes complex condition, the American Society of Hypertension (ASH) has, since 1999, designated physicians as "ASH Hypertension Specialists." Such Hypertension Specialists (as defined by ASH's Specialist Program) are fully licensed physicians with a primary board certification who are competent in all aspects of the diagnosis and treatment of hypertension, as evidenced by passing a specific examination on these topics offered by ASH's Specialist Program. These physicians have a proven track record of controlling blood pressure in "resistant hypertensive" patients, the general population whom they serve, and educating other physicians to help them achieve higher blood pressure control rates among their patient populations. This report sets out a rationale for increased reimbursement for care of hypertensive patients by ASH-Designated Hypertension Specialists.


Optimization of analgesia for piglet castration under isoflurane anaesthesia with parenteral butorphanol, meloxicam or intratesticular lidocaine.
This blinded prospective study investigated analgesic effects of intramuscular (IM) butorphanol, meloxicam or intratesticular (IT) lidocaine for castration of 7-14 days old piglets under isoflurane anaesthesia. 66 piglets were randomly injected with: meloxicam IM (0.4 mg/kg; group M), butorphanol IM (0.2 mg/kg; group B), or both (group BM) 20 minutes prior to castration, or lidocaine IT (4 mg/kg (group ML4) or 8 mg/kg (group ML8)) together with meloxicam IM (0.4 mg/kg) under anaesthesia with 1.8% end-tidal isoflurane. Heart rate, respiratory rate, mean arterial blood pressure and end-tidal carbon dioxide were recorded. Anaesthesia quality was scored and postoperative behaviour assessed. As butorphanol caused unacceptable side effects, its use was stopped. Group M showed worse anaesthesia quality than ML4 and ML8 (higher incidence of movements: 11/17, 3/18 and 4/17, respectively). There were no significant differences between groups regarding parameters measured during castration. Postoperative behaviour did not differ between groups. For castration of 7-14 days old piglets under isoflurane anaesthesia, IT lidocaine provides an additional side effect free analgesia.


Recurrent transient anterior subluxation of the shoulder. The "dead arm" syndrome.
The recurrent transient anterior subluxation (the "dead arm" syndrome) is an accepted clinical syndrome seen most commonly in young athletes or individuals whose arms have been forcefully hyperextended in elevation and external rotation. Care must be taken to differentiate other causes of painful shoulder. With an accurate diagnosis, the results of conservative or operative treatment are most favorable. If surgical treatment is carried out, careful layer-by-layer dissection is required to properly identify and correct anatomic abnormalities.


New subunits NDH-M, -N, and -O, encoded by nuclear genes, are essential for plastid Ndh complex functioning in higher plants.
In higher plants, the Ndh complex reduces plastoquinones and is involved in cyclic electron flow around photosystem I, supplying extra-ATP for photosynthesis, particularly under environmental stress conditions. Based on plastid genome sequences, the Ndh complex would contain 11 subunits (NDH-A to -K), but homologies with bacterial complex indicate the probable existence of additional subunits. To identify missing subunits, tobacco (Nicotiana tabacum) NDH-H was His tagged at its N terminus using plastid transformation. A functional Ndh subcomplex was purified by Ni(2+) affinity chromatography and its subunit composition analyzed by mass spectrometry. Five plastid encoded subunits (NDH-A, -H, -I, -J, and -K) were identified as well as three new subunits (NDH-M, -N, and -O) homologous to cyanobacterial and higher plant proteins. Arabidopsis thaliana mutants missing one of these new subunits lack a functional Ndh complex, and NDH-M and NDH-N are not detected in a tobacco transformant lacking the Ndh complex. We discuss the involvement of these three nuclear-encoded subunits in the functional integrity of the plastidial complex.


In vivo injectable gels for tissue repair.
The desire to reduce healthcare costs while improving outcomes drives minimally invasive methods to replacing traditional surgical procedures. Various treatments that would previously have needed open-type surgeries can be carried out using endoscopes, catheters, and needles. These advantages have become especially obvious for tissue engineering and regenerative medicine with in vivo gel injectable nanomaterials. In this review, the state of the art in this rapidly developing field is given. This is done by contrasting functional evaluation in vitro with in vivo followed by describing (1) synthetic materials, (2) the body's own polymers, (3) polymers in nature, (4) self-assembled peptides, and (5) new innovations and combinations. With increased understanding of the relationship between material characteristics and the outcome in vivo more rational design criteria are emerging.


Polyphenols downregulate PAI-1 gene expression in cultured human coronary artery endothelial cells: molecular contributor to cardiovascular protection.
Epidemiologic data have indicated that the intake of polyphenols is inversely associated with mortality from cardiovascular disease. Mitogen-activated protein kinases (MAPKs) are ubiquitous signaling proteins that have been associated with gene regulation. This study determined whether polyphenols (catechin and quercetin) activated kinase-signaling cascades that suppress PAI-1 expression and whether this suppression is at the transcription level in human coronary artery endothelial cells (ECs) remains unresolved. ECs were incubated in the absence/presence of polyphenols and RNA and protein were analyzed by real-time PCR and Western blot analysis. MAPKs were analyzed using antibodies to active form of p38, JNK, and ERK1/2. ECs were transiently transfected with a 1.1-kb PAI-1 promoter (pPAI110/luc) and promoter activity were assays after treatment with polyphenols. Catechin and quercetin decreased EC PAI-1 mRNA in a time- and dose-dependent manner, reaching a maximum at 4 and 2 h, respectively. These polyphenols activated EC p38 and ERK1/2 within 2.5 and 5 min, respectively, while maximal JNK activation occurred at 10-15 min. An inhibitor of p38 MAPK had no effect on polyphenol-induced repression of PAI-1. Inhibitors of ERK or JNK prevented polyphenol repression of EC PAI-1 gene expression. Exposing ECs transiently transfected with pPAI110/luc to polyphenols decreased promoter activity 50%. Polyphenols repress EC PAI-1 expression, in part, by activating ERK and JNK signaling pathways and this repression is at transcriptional levels. Thus MAPK seem to play an important role in polyphenol-induce repression of PAI-1 expression in ECs.