Conservative treatment of genu valgus and varum with medial/lateral heel wedges.
Symptomatic bowlegs and knock-knees are common in the aging person and aging athlete secondary to knee trauma. Diagnosis is made by observation and in mild degrees by a standing alignment x-ray that shows narrowing of the joint surface on the appropriate side. The patients complained of pain on the convexity side of the deformity. Treatment consisted of a simple exercise program, non-steroidal anti-inflammatory drugs and appropriate 1/8-inch wedges on the lateral side of the heel for bowlegs or on the medial side of the heel for knock-knees. The effect of a simple heel wedge formed the basis for conservative treatment of symptomatic knee deformities.


Lacunar infarcts. Pathogenesis and validity of the clinical syndromes.
In this study, we investigated the lacunar hypothesis to answer three questions: 1) Is the lacunar syndrome valid for diagnosing lacunar infarction? 2) What is the frequency of potential cardiac versus carotid sources of embolism in patients with lacunar versus cortical infarct? 3) What is the frequency of vascular risk factors in these two groups of patients? The study was performed in a well-defined prospective series of 103 patients with a first-ever lacunar infarct and 144 other patients with a first-ever infarct involving the cortex. Sensitivity and specificity of the lacunar syndromes in diagnosing lacunar infarction were 95% and 93%, respectively. Positive and negative predictive values of diagnosing lacunar infarction in patients with lacunar syndromes were 90% and 97%, respectively. Risk factor analysis showed no differences for either group of cerebral infarction. A cardiac source of embolism was significantly less frequent in patients with lacunar infarction (odds ratio = 0.32, 95% confidence interval = 0.17-0.61, p less than 0.001). Significant carotid stenosis (diameter reduction greater than or equal to 50%) was also less frequent in patients with lacunar infarction (odds ratio = 0.35, 95% confidence interval = 0.16-0.76, p less than 0.001). These findings show that the lacunar syndrome is an excellent clinical test for diagnosing lacunar infarction and that cardiac and carotid embolism are unlikely causes of lacunar infarction, supporting the hypothesis that lacunar infarcts are usually caused by small vessel disease.


Sublytic concentrations of the membrane attack complex of complement induce endothelial interleukin-8 and monocyte chemoattractant protein-1 through nuclear factor-kappa B activation.
Activation of the complement cascade and subsequent assembly of the membrane attack complex (MAC) occur in a number of pathophysiological settings. When formed on the surface of endothelial cells in sublytic concentrations, the MAC can induce a number of proinflammatory activities, including the secretion of soluble mediators (eg, interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1) and the up-regulation of cell surface adhesion molecules. Available data indicate that MAC-induced cell activation may occur through several complex signal transduction pathways, but little is known about the intranuclear mechanisms by which complement-derived products promote the up-regulation of inflammatory mediators. Using purified distal complement proteins (C5-9) to assemble functional MAC on early-passage human umbilical vein endothelial cells (HUVECs), we examined mechanisms of MCP-1 and IL-8 induction. Formation of sublytic concentrations of MAC promoted an increase in nuclear factor (NF)-kappa B DNA binding activity within 60 minutes as determined by serial electrophoretic mobility shift assay. Cytosolic to nuclear translocation of NF-kappa B was confirmed by Western immunoblot and immunocytochemical analyses. Formation of the C5b-8 complex also promoted NF-kappa B translocation but to a lesser degree than observed in HUVECs containing complete MAC. No cytosolic to nuclear translocation of the p65 NF-kappa B subunit was observed in unstimulated HUVECs or in cells incubated with the MAC components devoid of C7. Preincubation of HUVECs with pyrrolidine dithiocarbamate prevented MAC-induced increases in IL-8 and MCP-1 mRNA concentrations and protein secretion. A direct cause and effect linkage between MAC assembly and NF-kappa B activation was established through examination of the pharmacological effect of the peptide SN50 on IL-8 and MCP-1 expression. SN50 is a recently engineered 26-amino-acid peptide that contains a lipophilic cell-membrane-permeable motif and a nuclear localization sequence that specifically competes with the nuclear localization sequence of the NF-kappa B p50 subunit. This study provides direct in vitro evidence that the distal complement system (MAC) can promote proinflammatory endothelial cell activation, specifically, increases in IL-8 and MCP-1 mRNA concentrations and protein secretion, and that cytosolic to nuclear translocation of NF-kappa B is necessary for this response.


Simulating environmental and psychological acoustic factors of the operating room.
In this study, an operating room simulation environment was adapted to include quadraphonic speakers, which were used to recreate a composed clinical soundscape. To assess validity of the composed soundscape, several acoustic parameters of this simulated environment were acquired in the presence of alarms only, background noise only, or both. These parameters were also measured for comparison from size-matched operating rooms at Jackson Memorial Hospital. The parameters examined included sound level, reverberation time, and predictive metrics of speech intelligibility in quiet and noise. It was found that the sound levels and acoustic parameters were comparable between the simulated environment and the actual operating rooms. The impact of the background noise on the perception of medical alarms was then examined, and was found to have little impact on the audibility of the alarms. This study is a first in kind report of a comparison between the environmental and psychological acoustical parameters of a hospital simulation environment and actual operating rooms.


[Effect of Curcumol on the Biological Behavior of Multiple Myeloma Cells].
Objective To observe the effect of curcumol on the biological behavior of multiple myeloma (MM) cells, thus studying its possible mechanisms for MM treatment. Methods Bone marrow mesenchymal stem cells (BMSCs) and multiple myeloma cell line 8226 (RPMI 8226) were taken as sub- jects, which were then divided into the RMPI 8226 group (cultured by RMPI 8226 alone) and the BMSCs + RMPI 8226 group (cultured by BMSCs and RMPI 8226). Curcumol in different concentrations (0. 1, 0.5, 1. 0 , 10.0 μg/mL) was added to cells in the two groups respectively. Cell proliferation, cell cycle, and ap' optosis induced by curcumol were examined by flow cytometry. The expressions of receptor activator of nuclear factor Kb ligand ( RANKL ) and osteoprotegerin ( OPG) were detected using reverse tran- scriptase-polymerase chain reaction (RT-PCR). Results Curcumol induced arrested cell cycle of RMPI 8226. The arrest of RMPI 8226 cell cycle was more obviously in the RMPI 8226 group than in the BMSCs + RMPI 8226 group. After curcumol treatment the cell proliferation of RPMI 8226 was significantly inhibited (P <0. 01) and its apoptosis was increased (P <0. 01). Co-cultured with BMSCs decreased curcumol in- duced apoptosis of RPMI 8226. Curcumol down-regulated the expression of osteogenic differentiation related gene RANKL, and up-regulated the expression of OPG. Conclusions Curcumol disturbed the cell cycle and induced apoptosis of RPMI 8226 cells. Curcumol up-regulated the expression of OPG as well as down-regulated the expression of RANKL. Co-culture with BMSCs could obviously inhibit curcumol in- duced apoptosis of MM cells, which might be associated with drug resistance of MM cells.


Functional characterization of the α5(Asn398) variant associated with risk for nicotine dependence in the α3β4α5 nicotinic receptor.
Smoking is a major cause for premature death. Work aimed at identifying genetic factors that contribute to nicotine addiction has revealed several single nucleotide polymorphisms (SNPs) that are linked to smoking-related behaviors such as nicotine dependence and level of smoking. One of these SNPs leads to an aspartic acid-to-asparagine substitution in the nicotinic receptor α5 subunit at amino acid position 398 [rs16969968; α5(Asn398)]. The α5 subunit is expressed both in the brain and in the periphery. In the brain, it associates with the α4 and β2 subunits to form α4β2α5 receptors. In the periphery, the α5 subunit combines with the α3 and β4 subunits to form the major ganglionic postsynaptic nicotinic receptor subtype. The α3β4α5 receptor regulates a variety of autonomic responses such as control of cardiac rate, blood pressure, and perfusion. In this paradigm, the α5(Asn398) variant may act by regulating autonomic responses that may affect nicotine intake by humans. Here, we have investigated the effect of the α5(Asn398) variant on the function of the α3β4α5 receptor. The wild-type or variant α5 subunits were coexpressed with the α3 and β4 subunits in human embryonic kidney 293 cells. The properties of the receptors were studied using whole-cell and single-channel electrophysiology. The data indicate that the introduction of the α5(Asn398) mutation has little effect on the pharmacology of receptor activation, receptor desensitization, or single-channel properties. We propose that the effect of the α5(Asn398) variant on nicotine use is not mediated by an action on the physiological or pharmacological properties of the α3β4α5 subtype.


Natural history of pure ground-glass opacity lung nodules detected by low-dose CT scan.
Although focal ground-glass opacity (GGO) lung nodules are generally reported to grow slowly, their natural course is unclear. The purpose of this study was to elucidate the natural course of screening-detected pure GGO lung nodules in patients with no history of malignancy. We retrospectively reviewed the database of subjects who had undergone screenings involving low-dose CT scans. We included patients with pure GGO lung nodules who were followed for > 2 years after the initial screening. Between June 1997 and September 2006, 122 pure GGO nodules were found in 89 patients. The median nodule size was 5.5 mm (range, 3-20 mm) in the largest diameter on initial low-dose CT scan. The median follow-up period per patient was 59 months. On a per-person basis, the frequency of growth was 13.5% (12 of 89 patients). On a per-nodule basis, the frequency of growth was 9.8% (12 of 122 nodules). Nodule growth was significantly associated with initial size and new development of an internal solid portion. The median volume doubling time was 769 days for growing pure GGO nodules. A total of 11 growing nodules were surgically validated, and all lesions were confirmed as primary lung cancer. About 90% of the screening-detected pure GGO lung nodules did not grow during long-term follow-up in subjects with no history of malignancy and most growing nodules had an indolent clinical course. A strategy of long-term follow-up and selective surgery for growing nodules should be considered for pure GGO lung nodules.


Unraveling the Unimolecular Ion Chemistry of Protonated Isoprene and Prenol.
The atmospheric chemistries of isoprene and prenol have been studied extensively; however, much of that research has focused on neutral or radical chemistry. Recent studies have demonstrated that under acidic conditions, isoprene and prenol can become protonated in the atmosphere, and we have explored the unimolecular chemistry of protonated isoprene and prenol with tandem mass spectrometry (using a triple-quadrupole mass spectrometer) and density functional theory. The collision-induced dissociation of protonated isoprene revealed two product ion channels: the neutral losses of C2H4 and H2, the former dominating over the latter. Protonated prenol dissociates by four product ion channels: the neutral losses of water, formaldehyde, methanol, and propene, with the former two being minor channels and the latter two being major channels. Density functional theory supplemented with CBS-QB3 single-point calculations revealed the underlying mechanisms to explain the breakdown behavior. The two competing channels from protonated isoprene could easily be rationalized due to the relative energy difference between key transition states along the reaction coordinates. However, in the case of protonated prenol, it was revealed that the minor products observed in the breakdown of protonated prenol had significantly lower reaction barriers when compared to the major products, an apparent contradiction. This could be rationalized if the initial ion population entering the collision cell is comproed of several isomeric species on the minimum energy reaction pathway, species populated by collisional excitation in the ion source region.


Agonistic and antagonistic bivalent ligands for serotonin and dopamine receptors including their transporters.
This review deals with the literature (1982-2006) concerning bivalent ligands for dopamine (D) and serotonin (5-HT) receptors, as well as for their respective transporters. The design, synthesis, and pharmacological evaluation of bivalent agonists and antagonists for dopamine and serotonin receptors have been successfully pursued. Increased potencies for 5-HT(1B/1D) receptor agonists were achieved as well as improved selectivities. At these receptors, selectivity seems to depend strongly on spacer length, whereas the improved affinities seem to be based on the presence of two pharmacophores within one molecule. Intrinsic activities and pharmacokinetic properties may differ from those of the respective monovalent ligands. Additionally, improved central nervous system penetration was achieved. Bivalent dopamine receptor agonists and antagonists can exhibit selectivity profiles different from their monomeric analogues with no loss in potency. For dopamine antagonists, affinities depend strongly on spacer length. For agonistic dimers different pharmacokinetic properties were observed. Bivalency was also applied to inhibitors of monoamine re-uptake transporters. Selectivity profiles and affinities depend strongly on the length of the alkylene-spacer: For some dimeric inhibitors the norepinephrine transporter (NET) and the dopamine transporter (DAT) affinities changed gradually, but for the serotonin transporter (SERT) a pentamethylene spacer showed the highest potency. Because the bivalent ligand approach has just begun to be applied to these versatile, therapeutically important targets, many advances in affinity enhancement, as well as the achievement of novel selectivity profiles and improved pharmacokinetics can be expected.


Polarized photoluminescence from single GaN nanorods: effects of optical confinement.
By measuring linearly polarized photoluminescence (PL) from single, isolated gallium nitride (GaN) nanorods with the rod diameters in the subwavelength regime (30-90 nm), we present clear evidence for size dependence of polarization anisotropy. The maximum polarization ratio at room temperature (approximately 0.9 with emission and excitation light polarized parallel to the long axis of nanorod) occurs at the rod diameter of approximately 40 nm. The experimental data are compared with the recent theoretical model proposed for thick semiconductor nanowires. It is concluded that the optical confinement effects in this size regime play an important role in the observed giant polarization anisotropy. Furthermore, we have performed a temperature-dependent study of polarized PL to show the importance of internal emission anisotropy at low temperatures.


Canine parvovirus detected from a serval (Leptailurus serval) in South Africa.
Canine parvovirus first emerged in domestic dogs (Canis familiaris), most likely as a variant of the feline panleucopaenia virus. Relatively recently, canine parvovirus-2a and canine parvovirus-2b infections have been identified in both symptomatic and asymptomatic domestic cats, while canine parvovirus infections have also been demonstrated in wild felids. This report documents the first known case of canine parvovirus-2b detected in unvaccinated serval (Leptailurus serval) from South Africa. The serval presented with clinical signs of vomiting, anorexia and diarrhoea that responded to symptomatic treatment. Two weeks later, severe leucopaenia, thrombocytopenia and death occurred. Typical enteric histological lesions of parvovirus infection were not observed on histopathological examination of the small intestine; however, histological lesions consistent with septicaemia were present. Canine parvovirus was detected in formalin-fixed paraffin-embedded small intestine using polymerase chain reaction. Phylogenetic analysis of the sequence of the canine parvovirus viral capsid protein gene showed similarities between the sample from the serval and canine parvovirus-2b isolates from domestic dogs in Argentina and South Africa. A case of canine parvovirus-2b in a domestic dog from South Africa in 2012 that fell within the same clade as the serval sample appears distantly related because of the long branch length. The significance of these findings is explored. More extensive surveys of canine parvovirus in domestic and wild felids and canids are needed to understand the epidemiology of canine parvovirus in non-domestic felids in South Africa.


Structural dependence of flavonoid interactions with Cu2+ ions: implications for their antioxidant properties.
The flavonoids constitute a large group of polyphenolic phytochemicals with antioxidant properties in vitro. The interactions of four structurally related flavonoids (quercetin, kaempferol, rutin and luteolin) with Cu2+ ions were investigated in terms of the extent to which they undergo complex formation through chelation or modification through oxidation, as well as in their structural dependence. The ortho 3',4'-dihydroxy substitution in the B ring is shown to be important for Cu2+-chelate formation, thereby influencing the antioxidant activity. The presence of a 3-hydroxy group in the flavonoid structure enhances the oxidation of quercetin and kaempferol, whereas luteolin and rutin, each lacking the 3-hydroxy group, do not oxidize as readily in the presence of Cu2+ ions. The results also demonstrate that the reactivities of the flavonoids in protecting low-density lipoprotein (LDL) against Cu2+ ion-induced oxidation are dependent on their structural properties in terms of the response of the particular flavonoid to Cu2+ ions, whether chelation or oxidation, their partitioning abilities between the aqueous compartment and the lipophilic environment within the LDL particle, and their hydrogen-donating antioxidant properties.


Targeting the oligomerization domain of ETO interferes with RUNX1/ETO oncogenic activity in t(8;21)-positive leukemic cells.
About 12% of all de novo acute myeloid leukemias are characterized by the translocation t(8;21), which generates the oncogenic fusion protein RUNX1/ETO. RUNX1/ETO has a modular structure and contains several docking sites for heterologous proteins, including transcriptional co-repressors like N-CoR, SMART, and mSIN3A. RUNX1/ETO is found in high molecular weight complexes, which are crucial for the block in myeloid differentiation observed in RUNX1/ETO-transformed cells. Essential for high molecular weight complex formation is the nervy homology region 2 (NHR2) within ETO, which serves as interacting surface for oligomerization as well as association with members of the ETO protein family. Here, we show that the expression of a fusion peptide consisting of 128 amino acids (NC128), including the entire NHR2 domain of ETO, disrupts the stability of the RUNX1/ETO high molecular weight complexes, restores transcription of RUNX1/ETO target genes, and reverts the differentiation block induced by RUNX1/ETO in myeloid cells. In the presence of NC128, RUNX1/ETO-transformed cells lose their progenitor cell characteristics, are arrested in cell cycle progression, and undergo cell death. Our results indicate that selective interference with the oligomerization domain of ETO could provide a promising strategy to inhibit the oncogenic properties of the leukemia-associated fusion protein RUNX1/ETO.


Disparities in staging prostate magnetic resonance imaging utilization for nonmetastatic prostate cancer patients undergoing definitive radiation therapy.
There is growing evidence supporting incorporating multiparametric (mp) magnetic resonance imaging (MRI) scans into risk stratification, active surveillance, and treatment paradigms for prostate cancer. The purpose of our study was to determine whether demographic disparities exist in staging MRI utilization for prostate cancer patients. An institutional database of 705 nonmetastatic prostate cancer patients treated with radiation therapy from 2005 through 2013 was used to identify patients undergoing versus not undergoing pretreatment diagnostic prostate mpMRI. Uni- and multivariable logistic regression evaluated the relationship of clinical and demographic characteristics with MRI utilization. All demographic variables assessed, except the other race category, were significantly associated with MRI utilization (all P < .05), including age (odds ratio [OR], 0.92), black race (OR, 0.51), poverty (OR, 0.53), closer distance to radiation facility (OR, 1.79), and nonprivate primary insurance (OR, 0.57) on univariable analysis, while clinical stage T3 (OR, 3.37) was the only clinical characteristic. On multivariable analysis stratified by D'Amico risk group, age remained significant across all risk groups, whereas the black versus white racial (OR, 0.21; 95% confidence interval, 0.08-0.55) and nonprivate versus private insurance type (OR, 0.37; 95% confidence interval, 0.16-0.86) disparities persisted in the low-risk group. Clinical stage T3 remained associated in the high-risk group. For race specifically, the percentages of whites, blacks, and others undergoing MRI in the overall cohort and by risk group were, respectively: overall, 80% (343/427), 68% (156/231), and 85% (40/47); low risk, 86%, 56%, and 63%; intermediate risk, 79%, 72%, and 95%; and high risk, 72%, 72%, and 100%. In this urban, academic center cohort, older patients across all risk groups and black or nonprivate insurance patients in the low risk group were less likely to undergo staging prostate MRI scans. Further research should investigate these differences to ensure equitable utilization across all demographic groups considering the burden of prostate cancer disparities.


Tolerization of dendritic cells by HLA-G.
The expression of HLA-G at the fetal-maternal interface during pregnancy and in transplanted tissue makes this a key molecule in the acceptance of a semiallogeneic fetus and allogeneic transplant. Dendritic cells (DC) play a critical role in the control of innate and adaptive immune responses. DC are present in maternal decidua, but must be kept under tight control. Here we describe the mechanism of tolerization of DC by HLA-G through inhibitory receptor interactions. The HLA-G-ILT (immunoglobulin-like transcript) interaction leads to development of tolerogenic DC with the induction of anergic and immunosuppressive T cells. Using human monocyte-derived DC and ILT4-transgenic mice, we show that (i) HLA-G induces the development of tolerogenic DC with arrest maturation/activation of myeloid DC, (ii) HLA-G-modified DC induce differentiation of anergic and immunosuppressive CD4(+) and CD8(+) effector T cells, and (iii) the gene expression profile provides evidence that HLA-G induces tolerogenic DC by disruption of the MHC class II presentation pathway. Ligation of ILT4 receptor on DC from transgenic mice diminished peptide presentation by MHC class II molecules and significantly prolonged allograft survival. These findings provide support that HLA-G is an important tolerogenic molecule on DC for the acceptance of a semiallogeneic fetus and transplanted tissue/organ.


Associations of Anger and Fear to Later Self-Regulation and Problem Behavior Symptoms.
The mediating and moderating roles of self-regulation in the associations of dispositional anger and fear to later conduct and anxiety symptoms were tested. Mothers and teachers rated children's anger and fear at 54 months (N = 191), and mothers reported on children's symptoms of anxiety and conduct disorders at 72 and 84 months (Ns = 169 and 144). Children's self-regulatory ability was assessed using the Tower of Hanoi task at 72 months. Children's self-regulation mediated the association between early dispositional fear and 84-month mother-reported anxiety disorder symptoms above and beyond the effects of earlier generalized anxiety symptoms. Children's anger directly predicted relatively high mother-reported conduct and anxiety disorder symptoms. Findings are discussed in terms of the importance of considering self-regulation as potential mechanism relating early childhood dispositional reactivity to later psychopathology symptoms.


In vitro phosphorylation of the movement protein of tomato mosaic tobamovirus by a cellular kinase.
The movement protein (MP) of tomato mosaic virus (ToMV) was produced in E. coli as a soluble fusion protein with glutathione S-transferase. When immobilized on glutathione affinity beads, the recombinant protein was phosphorylated in vitro by incubating with cell extracts of Nicotiana tabacum and tobacco suspension culture cells (BY-2) in the presence of [gamma-(32)P]ATP. Phosphorylation occurred even after washing the beads with a detergent-containing buffer, indicating that the recombinant MP formed a stable complex with some protein kinase(s) during incubation with the cell extract. Phosphoamino acid analysis revealed that the MP was phosphorylated on serine and threonine residues. Phosphorylation of the MP was decreased by addition of kinase inhibitors such as heparin, suramin and quercetin, which are known to be effective for casein kinase II (CK II). The phosphorylation level was not changed by other types of inhibitor. In addition, as shown for animal and plant CK II, [gamma-(32)P]GTP was efficiently used as a phosphoryl donor. Phosphorylation was not affected by amino acid replacements at serine-37 and serine-238, but was completely inhibited by deletion of the carboxy-terminal 9 amino acids, including threonine-256, serine-257, serine-261 and serine-263. These results suggest that the MP of ToMV could be phosphorylated in plant cells by a host protein kinase that is closely related to CK II.


[Method of epiglottis reconstruction].
A new technique of epiglottis reconstruction is proposed because of its loss at laryngeal resection for tumor or severe laryngeal injury or scarring. New epiglottis is created from a full-thickness graft taken from oral fundus in the projection of the lower edge of the root of the tongue. Outline of the epiglottis with the petal up is cut on the skin in this region (2.5 x 3.5 cm). The anterior margin of the outline is round, the bottom is square. Hairy skin inside the outline is removed. A cut is made throughout the layers of the oral cavity fundus only in that part of the outline which belongs to the petal. Along the outline only skin and subcutaneous fat are cut horizontally. The created petal is pushed to the pharyngeal cavity. The hole in the oral bottom is closed with connection of its upper edge with the lower one using two thick silk sutures through all thickness of the wall. Illustrations are provided for reconstruction of the epiglottis and lateral wall of the larynx removed during laryngeal resection for tumor.


Electrostrictive properties of nanosize PbTiO(3).
Properties of nanosize PbTiO(3) are discussed from the standpoint of the effects of crystallite size on electrostrictive behavior. Experimental results based on crystallite size-dependent primary and secondary order parameters (spontaneous polarization and strain) show that the critical crystallite size (CCS) for the stabilization of the cubic paraelectric phase at 298 K is around 15 nm. The CCS inversely scales with the cubic-tetragonal transition temperature (T(tr)). Electrostrictive coefficients exhibit an order of magnitude increase at 28 nm, which is attributed to the anharmonicity of the perovskite lattice. First order calculations indicate that the increase in the electrostrictive coefficients offsets the decrease in spontaneous polarization and results in an increase in piezoelectric moduli suggesting that piezoelectric activity could, in principle, be observed in the nanosize regime.


[Rapid Expansion of Distal Aortic Arch Aneurysm with the Short Elephant Trunk;Report of a Case].
A 78-year-old female patient was introduced to our hospital with chief complaint of massive hemoptysis. She had a history of total arch replacement using a short elephant trunk for acute Stanford type A aortic dissection 3 years before. A contrast-enhanced computed tomography (CT) revealed kinking of the short elephant trunk and distal aortic arch aneurysm which caused aortobronchial fistula. She was treated by emergency thoracic endovascular aortic repair and long-term administration of antibiotics. Three years later, distal aortic arch aneurysm disappeared by CT and there was no recurrence of hemoptysis. This is the aortic aneurysm was considered to be caused by the short elephant trunk.


Major bleeding after hospitalization for deep-venous thrombosis.
Most studies of oral anticoagulant-related bleeding have analyzed the incidence of adverse outcomes among patients with a variety of different conditions and without any comparison with a control group. We determined the incidence, time course, and risk factors associated with major bleeding after hospital discharge among patients with deep-vein thrombosis, and estimated the excess risk of bleeding associated with oral anticoagulant therapy. A total of 22,000 adults were hospitalized in California for 3 or more days with a diagnosis of deep-venous thrombosis between January 1, 1992, and September 30, 1994. We determined the risk factors associated with readmission for bleeding. We compared the incidence of readmission for bleeding with comparison cohorts of patients with pneumonia or cellulitis who were matched for age, gender, race, and length of hospital stay. Of 21,250 patients with deep-venous thrombosis who were discharged without bleeding, 1.4% were readmitted for bleeding within 91 days; the rate was 2.7 times greater in the first 30 days than in the next 61 days. Risk factors for bleeding included hospitalization with gastrointestinal bleeding during the previous 18 months (relative hazard [RH] = 2.6, 95% confidence interval [CI]: 1.6 to 4.1), hospitalization with an alcohol-related diagnosis during the previous 18 months (RH = 2.6, 95% CI: 1.4 to 4.8), chronic renal disease (RH = 2.4, 95% CI: 1.4 to 4.2), female gender (RH = 1.7, 95% CI: 1.3 to 2.2), presence of a malignancy (RH = 1.6, 95% CI: 1.2 to 2.2), nonwhite race (RH = 1.6, 95% CI: 1.2 to 2.1), and age over 65 years (RH = 1.3, 95% CI: 1.0 to 1.7). Significantly more women (n = 40) had intracranial bleeding than men (n = 18, P = 0.02). In the comparison cohorts, the incidence of readmission for bleeding within 3 months of discharge was 0.7%, and the relative risk (RR) of readmission was greater in those with deep-venous thrombosis than in those with cellulitis (RR = 2.0, 95% CI: 1.6 to 2.5) or pneumonia (RR = 2.0, 95% CI: 1.7 to 2.5). The incidence of rehospitalization for bleeding was greatest in the first 30 days after discharge, and was approximately twice that seen in patients hospitalized for cellulitis or pneumonia. Further studies are needed to determine why women and nonwhite patients are at increased risk for anticoagulant-related bleeding.


Dopamine causes inhibition of Na+-K+-ATPase activity in rat proximal convoluted tubule segments.
We studied the effect of dopamine (DA) on Na+-K+-ATPase activity in proximal convoluted tubule (PCT) segments dissected from perfused rat kidneys. DA inhibited Na+-K+-ATPase activity in a dose-dependent manner. Inhibition was significant with 10(-7) M DA and maximal with 10(-4) M DA. The inhibition was reversible. Enzyme inhibition occurred in the presence of DA and a DA antagonist, metoclopramide, but not when 10(5) M of the DA1 and DA2 agonists fenoldopam mesylate and LY 171555 were added in the absence of DA. In PCT segments incubated with the DA precursor dopa, Na+-K+-ATPase activity was also inhibited. However, dopa did not inhibit the sodium pump if dopa decarboxylase activity was blocked with benserazide. These findings suggest an intracellular site of action of DA. In tubules incubated in different K concentrations, 10(-5) DA decreased the maximal activity (Vmax) and increased the Km. DA 10(-5) M caused an almost immediate swelling of PCT segments. Swelling did not occur in the presence of both DA and 10(-5) M amiloride. The DA-induced tubular swelling was probably due to inhibition of Na+-K+-ATPase-mediated Na+-transport. We conclude that in rat PCT segments, DA causes a rapid and reversible inhibition of apparent Na+-K+-ATPase activity and an apparent reduction in the affinity for K. The site of action appears to be intracellular.


Upper abdominal surgery: does a lung function test exist to predict early severe postoperative respiratory complications?
We evaluated the capacity to predict severe respiratory complications (SRCs) following upper abdominal surgery (UAS) by using the results of a respiratory questionnaire and preoperative pulmonary function tests. Lung volumes, flows and transfer factor of the lung for carbon monoxide (TL,CO,sb) were assessed in 361 consecutive adult patients (248 males and 113 females). SRCs were diagnosed 24 h after UAS by clinical examination and chest radiography. Univariate and stepwise multiple logistic regression analyses were performed to estimate the odds ratio (OR) and 95% confidence interval (95% CI) of each single input variable, and to determine which indices best predicted outcome. These patients had a 1% mortality rate and 14% incidence of SRCs, with a male:female ratio of 0.86. The best predictors for SRCs by multiple analysis were: preoperative current hypersecretion of mucus (OR=133; p<0.0001); an increase in residual volume (RV) (OR=3.11; p=0.01); and, to a lesser extent, low percentage of predicted values both of forced expiratory volume in one second (FEV1 % pred) and TL,CO,sb. The algorithm thus obtained (logit theta) was extremely sensitive (84%), specific (99%), and accurate (95%) for preoperative prediction of SRCs. We have found that preoperative current hypersecretion of mucus and pulmonary hyperinflation, and to a lesser extent percentage predicted values both of forced expiratory volume in one second and transfer factor of the lung for carbon monoxide, have a significant predictive capacity for severe respiratory complications following upper abdominal surgery.


Current perspectives on the surgical management of mandibular third molars in the United Kingdom: the need for further research.
This survey of expert opinion regarding the management of mandibular third molar (M3M) impaction and its clinical sequelae was circulated to all members of the British Association of Oral and Maxillofacial Surgeons (BAOMS). It was completed by 289 clinicians who reported treating 60003 patients annually. Respondents included 199 (69%) specialists and 58 (20%) primary care clinicians. Most (99%) of the clinicians treated at least one M3M with complete surgical removal (CSR) annually. Only 69% performed one or more coronectomies (COR). Advocates of coronectomy reported lower rates of inferior alveolar nerve (IAN) injury, but IAN, lingual nerve, and adjacent second molar damage were rare, occurring in less than 0.5% of cases, with small differences between the COR and CSR groups. Although these differences are not statistically significant, they are likely to be clinically important. Also, the COR group would have comprised mainly high-risk teeth, while the CSR group would include many teeth at low risk of complications. This might have skewed the results. Those clinicians performing no coronectomies cited three main reasons for being low adopters of COR: the lack of irrefutable evidence to support its benefit, the increased need for a second operation, and more non-IAN complications. Although COR may prevent permanent IAN damage in high-risk cases, this paper highlights clinicians' views that there is a gap in evidence and knowledge to support COR. As a result, 47% of the clinicians surveyed recommended, and were prepared to participate in, further studies to determine the effectiveness and safety of COR.


Intrathyroidal ectopic thymus in 8-year-old girl: a case report.
We provide a case report of two thyroid nodules in an 8-year-old girl, which revealed malignant ultrasonographic findings and which were confirmed as ectopic thymic tissue by total thyroidectomy. The ultrasound presentations of intrathyroidal thymus glands were similar to those of the malignant thyroid nodules. In addition, in this case, there were two ectopic thymus lesions in the thyroid gland, which undoubtedly increased the difficulty of diagnosis. The occurrence of multiple ectopic thymic lesions in the thyroid gland was different from previous reports. Therefore, clinicians should take into consideration this rare entity, and should not mistake it as a thyroid neoplasm; moreover, they should not perform extensive thyroid resection.


Autohemotherapy with ozone as a possible effective treatment for Fibromyalgia.
The objective of this study is to evaluate the effectiveness of autohemotherapy with ozone in the management of fibromyalgia (FM). 20 FM patients (according to the criteria of the American College of Rheumatology), were treated with 10 sessions of ozone hemotherapy (2 sessions per week) with a concentration of 30-60 mcgr/ml. The health condition of the patients was evaluated before and after treatment, through the Fibromyalgia Impact Questionnaire (FIQ). Blood samples were obtained from all patients by venous puncture for biochemical routine analysis and serotonin levels in serum and the following peripheral blood mononuclear cells (BMCs) were isolated for oxidative stress quantification: reactive oxygen species (ROS) generation, and lipid peroxidation (LP) and protein carbonyl (PC) content, as these are signs of oxidative cell damage. All patients treated with ozone reported an improvement in sleep and mental alertness, a marked decrease of asthenia accompanied by a decrease of FIQ as well as tender points, and a moderate increase of serotonin levels. Also, an important decrease of LP and PC was observed; ROS also decreased, although less obvious, which indicates a reduction in oxidative stress levels. The autohemotherapy with ozone in patients with FM showed an important decline of tender points and FIQ score, as well as a decrease of oxidative stress levels. This treatment allows patients to face life with greater vitality and less drug use, diminishing harmful side effects. Further investigation should be carried out, including groups with more patients and clinical trials, to elucidate the effect of ozone therapy in patients suffering from FM.


Role of melatonin in reduction of lipid peroxidation and peroxynitrite formation in non-septic shock induced by zymosan.
Zymosan, a non-bacterial agent, causes inflammation by inducing the production of a variety of cytokines and pro-inflammatory mediators, wherein reactive oxygen species including nitric oxide and peroxynitrite are known to play a crucial role in the inflammatory process. The current study was designed to investigate the protective effect of melatonin, a radical scavenger and antioxidant, on non-septic shock induced by zymosan in the rat. Four groups of rats (controls, melatonin-injected [5 mg/kg x 6], zymosan-injected [500 mg/kg], and zymosan + melatonin) were used in this experiment. Thiobarbituric acid reactive substances (malondialdehyde [MDA] + 4-hydroxyalkenals [4-HDA]), as an index of lipid peroxidation, were measured in the liver, lung, small intestine (ileum), kidney and pancreas. Twenty-four hours after zymosan administration, MDA + 4-HDA levels were significantly increased in the liver, lung, small intestine, and kidney while the increase in the pancreas was not statistically significant compared to levels in control rats. The percentage increases in lipid peroxidation products were 34.3%, 39.2%, 48.5%, 32.5%, and 17.4% for the liver, lung, small intestine, kidney, and pancreas, respectively. In animals given melatonin 30 minutes before zymosan, and 5 more times after zymosan (i.e., every 4 hours), the increase in MDA + 4-HDA levels was reduced in all organs studied. There was also a significant increase in the volume of peritoneal exudate in zymosan-treated rats that was reduced when the zymosan-shocked rats received melatonin. After zymosan administration, immunohistochemical and histological examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine, a specific "footprint" of peroxynitrite, and tissue damage in the liver, lung, and small intestine of zymosan-shocked rats. Again, melatonin treatment reduced both nitrotyrosine immunoreactivity and tissue damage associated with zymosan administration.


Smoking control in restaurants: the effectiveness of self-regulation in Australia.
The provision of smoke-free areas in restaurants has been a controversial issue; the restaurant industry largely opts for a self-regulation approach. This study aimed to examine the effectiveness of self-regulation as a strategy in meeting the industry's and customers' perceived needs. Restaurateur and customer perspectives on the provision of smoke-free areas in restaurants were examined by survey among 365 restaurateurs and 1327 customers in New South Wales, Australia. Less than 2% of restaurants were totally smoke-free; 22% provided some smoke-free areas. Customers were much more likely than owners to think that smoke-free areas should be provided. Owners appeared to be unaware of customers' views about smoke-free areas in restaurants. Little evidence was found to support the effectiveness of the self-regulation policy adopted by the restaurant industry. Characteristics of restaurants and owners associated with the provision of smoke-free areas are presented and implications of the findings are discussed.


Very long-term follow-up of autologous pubovaginal fascia slings in women with stress urinary incontinence.
The objective was to report on the very long-term outcome of a published series of autologous pubovaginal slings (PVS) in women with stress urinary incontinence (SUI). Following institutional review board approval, a cohort of well characterized, non-neurogenic women who underwent an autologous PVS (primary [PVS1] and secondary [PVS2]) for SUI was re-evaluated for their very long-term outcome status. Data collected included demographics, validated questionnaires (Urogenital Distress Inventory - short form [UDI-6], Incontinence Impact Questionnaire - short form 7, quality of life), SUI retreatment/operations, and subjective patient-reported SUI improvement (%) and symptom recurrence. The primary outcome was success defined as UDI-6 question 3 (SUI) ≤ 1 and no SUI retreatment/operation. Patients not seen in clinic for 2 years were contacted via a standardized phone interview. From 83 patients with 7-year intermediate follow-up data, 34 (PVS1 = 18, PVS2 = 16) had very long-term follow-up based on clinic visit (7) or phone interviews (27). Those lost to follow-up (49), including 5 deceased, did not differ in demographics and intermediate outcomes from the followed cohort, but lived further away (>75 miles). At a mean age of 74 years, and with a median follow-up of 14.5 years, 53% met the success criteria (PVS1 = 44%, PVS2 = 63%). Mean postoperative questionnaire scores did not differ significantly between intermediate and very long-term follow-ups, and long-term outcomes between PVS1 and PVS2 remained similar. A majority of women with long-term follow-up after PVS for primary and secondary SUI remained successful more than 14 years after their surgery. Both groups, PVS1 and PVS2, fared equally well, confirming the durability of PVS as a treatment alternative for SUI.


Photoredox-Catalyzed α-C-H Monoalkylation of Symmetric Polyols in the Presence of CO2.
Achieving the selective modification of symmetric poly-hydroxylated compounds presents a significant challenge due to the presence of identical active sites. Herein, we address this challenge through the design of a ternary catalytic system that includes a photoredox catalyst, a hydrogen atom transfer promotor and a carbonation catalyst. This catalytic system enables the reversible carbonation of acyclic polyols under CO2 atmosphere, which modulates the reactivity of its distinct C-H bonds toward hydrogen atom transfers. An exquisite selectivity for the monoalkylation is achieved in a variety of unprotected light polyols, yielding valuable building blocks in short reaction times. Mechanistic and computational studies demonstrate that the formation of an intramolecular hydrogen bond between the transient carbonate and the free alcohol is pivotal for the kinetic and thermodynamic activation of a specific alcohol.


Biocatalytic degradation of pharmaceuticals, personal care products, industrial chemicals, steroid hormones and pesticides in a membrane distillation-enzymatic bioreactor.
Laccase-catalyzed degradation of a broad spectrum of trace organic contaminants (TrOCs) by a membrane distillation (MD)-enzymatic membrane bioreactor (EMBR) was investigated. The MD component effectively retained TrOCs (94-99%) in the EMBR, facilitating their continuous biocatalytic degradation. Notably, the extent of TrOC degradation was strongly influenced by their molecular properties. A significant degradation (above 90%) of TrOCs containing strong electron donating functional groups (e.g., hydroxyl and amine groups) was achieved, while a moderate removal was observed for TrOCs containing electron withdrawing functional groups (e.g., amide and halogen groups). Separate addition of two redox-mediators, namely syringaldehyde and violuric acid, further improved TrOC degradation by laccase. However, a mixture of both showed a reduced performance for a few pharmaceuticals such as primidone, carbamazepine and ibuprofen. Mediator addition increased the toxicity of the media in the enzymatic bioreactor, but the membrane permeate (i.e., final effluent) was non-toxic, suggesting an added advantage of coupling MD with EMBR.


Temporal and spatial expression of cuticular proteins of Anopheles gambiae implicated in insecticide resistance or differentiation of M/S incipient species.
Published data revealed that two of the 243 structural cuticular proteins of Anopheles gambiae, CPLCG3 and CPLCG4, are implicated in insecticide resistance and a third, CPF3, has far higher transcript levels in M than in S incipient species. We studied the distribution of transcripts for these three genes in the tissues of An. gambiae and the location of the proteins in the cuticle itself to gain information about how these cuticular proteins contribute to their important roles. Our data are consistent with CPLCG3/4 contributing to a thicker cuticle thus slowing penetration of insecticides and CPF3 possibly having a role in the greater desiccation tolerance of the M form. Using RT-qPCR, we established the temporal expression of the genes and by in situ hybridization we revealed the main tissues where their mRNAs are found. Electron microscopy immunolocalization, using secondary antibodies labeled with colloidal gold, allowed us to localize these proteins within different regions of the cuticle. The temporal expression of these genes overlaps, albeit with higher levels of transcripts from CPF3 in pharate adults and both CPLCG3 and CPLCG4 are higher in animals immediately after adult eclosion. The main location of mRNAs for all three genes is in appendages and genitalia. In contrast, the location of their proteins within the cuticle is completely different. CPF3 is found exclusively in exocuticle and CPLCG3/4 is restricted to the endocuticle. The other CPF gene expressed at the same times, CPF4, in addition to appendages, has message in pharate adult sclerites. The temporal and spatial differences in transcript abundance and protein localization help to account for An. gambiae devoting about 2% of its protein coding genes to structural cuticular proteins. The location of CPLCG3/4 in the endocuticle may contribute to the thickness of the cuticle, one of the recently appreciated components of insecticide resistance, while the location of CPF3 might be related to the greater desiccation resistance of the M form.


Prolonged inhibitory effect of 9-(1,3-dihydroxy-2-propoxymethyl)guanine against replication of Epstein-Barr virus.
The effects of 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG), a new antiviral drug, and acyclovir (ACV) [9-(2-hydroxyethoxymethyl)guanine] on the replication of Epstein-Barr virus (EBV) were compared. Both drugs inhibited EBV DNA replication in P3HR-1 cells and superinfected Raji cells, but neither inhibited replication of the plasmid form of the EBV genome in latently infected Raji cells. However, DHPG had a more prolonged inhibitory effect than ACV. Although the effect of the drugs is prompt, the kinetics of inhibition of EBV replication indicated that a drug exposure of 14 days was needed to reduce the EBV genome copy number to the residual plasmid level (30 copies per cell). The inhibitory effect of ACV was readily reversed within 11 days after removal of the drug, in contrast to the more prolonged effect exerted by DHPG, which persisted for more than 21 days. The 50% inhibitory doses for cell growth of ACV and DHPG were estimated to be 250 and 200 microM, respectively. The viral 50% and 90% effective doses of inhibition were, respectively, 0.3 and 9 microM for ACV and 0.05 and 3 microM for DHPG. The therapeutic indices (50% inhibitory dose/50% effective dose) for ACV and DHPG were 833 and 4,000, respectively. Synthesis of EBV-associated polypeptides was also affected. In superinfected Raji cells, ACV (100 microM) and DHPG (30 microM) inhibited synthesis of polypeptides with molecular weights of 145,000 and 140,000; in addition, synthesis of polypeptides with molecular weights of 110,000 and 85,000 was markedly reduced by DHPG but not by ACV. However, after drug removal, the inhibitory effect of ACV on polypeptide synthesis was abolished in contrast to the more persistent effect of DHPG.


ST-GREED: Space-Time Generalized Entropic Differences for Frame Rate Dependent Video Quality Prediction.
We consider the problem of conducting frame rate dependent video quality assessment (VQA) on videos of diverse frame rates, including high frame rate (HFR) videos. More generally, we study how perceptual quality is affected by frame rate, and how frame rate and compression combine to affect perceived quality. We devise an objective VQA model called Space-Time GeneRalized Entropic Difference (GREED) which analyzes the statistics of spatial and temporal band-pass video coefficients. A generalized Gaussian distribution (GGD) is used to model band-pass responses, while entropy variations between reference and distorted videos under the GGD model are used to capture video quality variations arising from frame rate changes. The entropic differences are calculated across multiple temporal and spatial subbands, and merged using a learned regressor. We show through extensive experiments that GREED achieves state-of-the-art performance on the LIVE-YT-HFR Database when compared with existing VQA models. The features used in GREED are highly generalizable and obtain competitive performance even on standard, non-HFR VQA databases. The implementation of GREED has been made available online: https://github.com/pavancm/GREED.


The contribution of malaria control interventions on spatio-temporal changes of parasitaemia risk in Uganda during 2009-2014.
In Uganda, malaria vector control interventions and case management with Artemisinin Combination Therapies (ACTs) have been scaled up over the last few years as a result of increased funding. Data on parasitaemia prevalence among children less than 5 years old and coverage of interventions was collected during the first two Malaria Indicator Surveys (MIS) conducted in 2009 and 2014, respectively. In this study, we quantify the effects of control interventions on parasitaemia risk changes between the two MIS in a spatio-temporal analysis. Bayesian geostatistical and temporal models were fitted on the MIS data of 2009 and 2014. The models took into account geographical misalignment in the locations of the two surveys and adjusted for climatic changes and socio-economic differentials. Parasitaemia risk was predicted over a 2 × 2 km2 grid and the number of infected children less than 5 years old was estimated. Geostatistical variable selection was applied to identify the most important ITN coverage indicators. A spatially varying coefficient model was used to estimate intervention effects at sub-national level. The coverage of Insecticide Treated Nets (ITNs) and ACTs more than doubled at country and sub-national levels during the period 2009-2014. The coverage of Indoor Residual Spraying (IRS) remained static at all levels. ITNs, IRS, and ACTs were associated with a reduction in parasitaemia odds of 19% (95% BCI: 18-29%), 78% (95% BCI: 67-84%), and 34% (95% BCI: 28-66%), respectively. Intervention effects varied with region. Higher socio-economic status and living in urban areas were associated with parasitaemia odds reduction of 46% (95% BCI: 0.51-0.57) and 57% (95% BCI: 0.40-0.53), respectively. The probability of parasitaemia risk decline in the country was 85% and varied from 70% in the North-East region to 100% in Kampala region. The estimated number of children infected with malaria declined from 2,480,373 in 2009 to 825,636 in 2014. Interventions have had a strong effect on the decline of parasitaemia risk in Uganda during 2009-2014, albeit with varying magnitude in the regions. This success should be sustained by optimizing ITN coverage to achieve universal coverage.


Innovations in health care services: the CAALYX system.
This paper describes proposed health care services innovations, provided by a system called CAALYX (Complete Ambient Assisted Living eXperiment). CAALYX aimed to provide healthcare innovation by extending the state-of-the-art in tele-healthcare, by focusing on increasing the confidence of elderly people living autonomously, by building on the knowledge base of the most common disorders and respective characteristic vital sign changes for this age group. A review of the state-of-the-art on health care services was carried out. Then, extensive research was conducted on the particular needs of the elderly in relation to home health services that, if offered to them, could improve their day life by giving them greater confidence and autonomy. To achieve this, we addressed issues associated with the gathering of clinical data and interpretation of these data, as well as possibilities of automatically triggering appropriate clinical measures. Considering this initial work we started the identification of initiatives, ongoing works and technologies that could be used for the development of the system. After that, the implementation of CAALYX was done. The innovation in CAALYX system considers three main areas of contribution: (i) The Roaming Monitoring System that is used to collect information on the well-being of the elderly users; (ii) The Home Monitoring System that is aimed at helping the elders independently living at home being implemented by a device (a personal computer or a set top box) that supports the connection of sensors and video cameras that may be used for monitoring and for interaction with the elder; (iii) The Central Care Service and Monitoring System that is implemented by a Caretaker System where attention and care services are provided to elders, where actors as Caretakers, Doctors and Relatives are logically linked to elders. Innovations in each of these areas are presented here. The ageing European society is placing an added burden on future generations, as the 'elderly-to-working-age-people' ratio is set to steadily increase in the future. Nowadays, quality of life and fitness allows for most older persons to have an active life well into their eighties. Furthermore, many older persons prefer to live in their own house and choose their own lifestyle. The CAALYX system can have a clear impact in increasing older persons' autonomy, by ensuring that they do not need to leave their preferred environment in order to be properly monitored and taken care of.


Nicotine suppression of gustatory responses of neurons in the nucleus of the solitary tract.
This study investigated effects of nicotine applied to the tongue surface on responses of gustatory neurons in the nucleus of the solitary tract (NTS) in rats. In pentobarbital-anesthetized rats, single-unit recordings were made from NTS units responsive to one or more tastants (sucrose, NaCl, citric acid, monosodium glutamate, quinine). Application of nicotine (0.87, 8.7, or 600 mM) excited gustatory NTS units and significantly attenuated NTS unit responses to their preferred tastant in a dose-dependent manner. The depressant effect of nicotine was equivalent regardless of which tastant best excited the NTS unit. Nicotinic excitation of NTS units and depression of their tastant-evoked responses were both significantly attenuated by the nicotinic antagonist mecamylamine, which itself did not excite NTS units. In rats with bilateral trigeminal ganglionectomy, nicotine still excited nearly all NTS units but no longer depressed tastant-evoked responses. Nicotine did not elicit plasma extravasation when applied to the tongue. The results indicate that nicotine directly excites NTS units by gustatory nerves and inhibits their tastant-evoked responses by a nicotinic acetylcholine receptor-mediated excitation of trigeminal afferents that inhibit NTS units centrally.


Specialized Dynamical Properties of Promiscuous Residues Revealed by Simulated Conformational Ensembles.
The ability to interact with different partners is one of the most important features in proteins. Proteins that bind a large number of partners (hubs) have been often associated with intrinsic disorder. However, many examples exist of hubs with an ordered structure, and evidence of a general mechanism promoting promiscuity in ordered proteins is still elusive. An intriguing hypothesis is that promiscuous binding sites have specific dynamical properties, distinct from the rest of the interface and pre-existing in the protein isolated state. Here, we present the first comprehensive study of the intrinsic dynamics of promiscuous residues in a large protein data set. Different computational methods, from coarse-grained elastic models to geometry-based sampling methods and to full-atom Molecular Dynamics simulations, were used to generate conformational ensembles for the isolated proteins. The flexibility and dynamic correlations of interface residues with a different degree of binding promiscuity were calculated and compared considering side chain and backbone motions, the latter both on a local and on a global scale. The study revealed that (a) promiscuous residues tend to be more flexible than nonpromiscuous ones, (b) this additional flexibility has a higher degree of organization, and (c) evolutionary conservation and binding promiscuity have opposite effects on intrinsic dynamics. Findings on simulated ensembles were also validated on ensembles of experimental structures extracted from the Protein Data Bank (PDB). Additionally, the low occurrence of single nucleotide polymorphisms observed for promiscuous residues indicated a tendency to preserve binding diversity at these positions. A case study on two ubiquitin-like proteins exemplifies how binding promiscuity in evolutionary related proteins can be modulated by the fine-tuning of the interface dynamics. The interplay between promiscuity and flexibility highlighted here can inspire new directions in protein-protein interaction prediction and design methods.


Clinical and pathologic features of lineage 2 West Nile virus infections in birds of prey in Hungary.
In the southeast of Hungary a sparrow hawk (Accipiter nisus) and several goshawk (Accipiter gentilis) fledglings succumbed to encephalitis manifesting as an acute neurological disease during the summers of 2004 and 2005. Both years the causative agent was identified as a lineage 2 West Nile virus. This is the first description of clinical, pathological and immunohistochemical findings of infection caused by a neuroinvasive, lineage 2 West Nile virus and the first evidence of its circulation in continental Europe.


A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle.
The endocrine system dynamically controls tissue differentiation and homeostasis, but has not been studied using dynamic tissue culture paradigms. Here we show that a microfluidic system supports murine ovarian follicles to produce the human 28-day menstrual cycle hormone profile, which controls human female reproductive tract and peripheral tissue dynamics in single, dual and multiple unit microfluidic platforms (Solo-MFP, Duet-MFP and Quintet-MPF, respectively). These systems simulate the in vivo female reproductive tract and the endocrine loops between organ modules for the ovary, fallopian tube, uterus, cervix and liver, with a sustained circulating flow between all tissues. The reproductive tract tissues and peripheral organs integrated into a microfluidic platform, termed EVATAR, represents a powerful new in vitro tool that allows organ-organ integration of hormonal signalling as a phenocopy of menstrual cycle and pregnancy-like endocrine loops and has great potential to be used in drug discovery and toxicology studies.


Genomic and proteomic approaches towards an understanding of sleep.
The basic functions of sleep are still unclear, however, recent advances in genomics and proteomics have begun to contribute to our understanding of both normal and pathological sleep. In this review, we focus primarily on normal sleep and wake that have been studied in model organisms such as mice. Mice have been especially valuable since many different inbred strains exist that differ in sleep-related traits, and genes can be altered by either mutagenesis or targeted approaches. Advances in QTL (Quantitative Trait Loci) analysis have also helped to identify important sleep related genes, and several other QTLs have been mapped as a first step toward finding the genes that underlie basic sleep traits. In addition to more traditional genetic approaches, the abundance of different mRNAs across sleep and wake can now be studied and compared in different brain regions much more thoroughly using microarray methods. Progress at the protein level has been more difficult, but a few studies have begun to investigate changes in proteins during sleep and wake, and we present some of our own preliminary data in this area. A knowledge of which genes and proteins control or respond to changes in sleep will not only help answer fundamental questions, but may also suggest novel drug targets for improving multiple aspects of sleep and wake.


MXD3 regulation of DAOY cell proliferation dictated by time course of activation.
MXD3 is a basic-helix-loop-helix-leucine-zipper transcription factor involved in cellular proliferation. In previous studies we demonstrated that knock-down of MXD3 in the human medulloblastoma cell line DAOY resulted in decreased proliferation. Surprisingly, overexpression of MXD3 in DAOY cells also decreased proliferation and increased cell death, suggesting that persistent expression of MXD3 triggers an apoptotic response, perhaps as a fail-safe mechanism. To investigate this apparent paradox in detail we developed a tamoxifen inducible system to analyze the temporal effects of MXD3 in the proliferation and transcriptional response of DAOY cells upon acute induction compared with long-term expression of MXD3. We find that acute induction of MXD3 initially promotes cell cycle progression as assessed by a transient increase in bromodeoxyuridine incorporation. However, persistent induction of MXD3 ultimately results in decreased proliferation based on cell counts. Finally, with microarray expression profiling and gene ontology analysis we identify several major pathways enriched in response to acute (immune response, apoptosis, cell cycle) versus persistent (cell adhesion) MXD3 activation. In this study, we demonstrate that acute MXD3 activation results in a transient increase in cell proliferation while persistent activation of MXD3 eventually results in an overall decrease in cell number, suggesting that the time course of MXD3 expression dictates the cellular outcome. Microarray expression profiling and gene ontology analysis indicate that MXD3 regulates distinct genes and pathways upon acute induction compared with persistent expression, suggesting that the cellular outcome is specified by changes in MXD3 transcriptional program in a time-dependent manner.


Contested Practice: Political Activism in Nursing and Implications for Nursing Education.
Canadian nurses have a social mandate to address health inequities for the populations they serve, as well as to speak out on professional and broader social issues. Although Canadian nursing education supports the role of nurses as advocates for social justice and leadership for health care reform, little is known about how nurse educators understand activism and how this translates in the classroom. A comparative life history study using purposeful sampling and a critical feminist lens was undertaken to explore political activism in nursing and how nurse educators foster political practice among their students. Findings from interviews and focus groups with 26 Ontario nurse educators and nursing students suggested that neoliberal dynamics in both the practice setting and in higher education have constrained nurses' activist practice and favour a technical rational approach to nursing education. Implications and strategies to inspire political action in nursing education are discussed.


Creatine kinase-overexpression improves myocardial energetics, contractile dysfunction and survival in murine doxorubicin cardiotoxicity.
Doxorubicin (DOX) is a commonly used life-saving antineoplastic agent that also causes dose-dependent cardiotoxicity. Because ATP is absolutely required to sustain normal cardiac contractile function and because impaired ATP synthesis through creatine kinase (CK), the primary myocardial energy reserve reaction, may contribute to contractile dysfunction in heart failure, we hypothesized that impaired CK energy metabolism contributes to DOX-induced cardiotoxicity. We therefore overexpressed the myofibrillar isoform of CK (CK-M) in the heart and determined the energetic, contractile and survival effects of CK-M following weekly DOX (5 mg/kg) administration using in vivo (31)P MRS and (1)H MRI. In control animals, in vivo cardiac energetics were reduced at 7 weeks of DOX protocol and this was followed by a mild but significant reduction in left ventricular ejection fraction (EF) at 8 weeks of DOX, as compared to baseline. At baseline, CK-M overexpression (CK-M-OE) increased rates of ATP synthesis through cardiac CK (CK flux) but did not affect contractile function. Following DOX however, CK-M-OE hearts had better preservation of creatine phosphate and higher CK flux and higher EF as compared to control DOX hearts. Survival after DOX administration was significantly better in CK-M-OE than in control animals (p<0.02). Thus CK-M-OE attenuates the early decline in myocardial high-energy phosphates and contractile function caused by chronic DOX administration and increases survival. These findings suggest that CK impairment plays an energetic and functional role in this DOX-cardiotoxicity model and suggests that metabolic strategies, particularly those targeting CK, offer an appealing new strategy for limiting DOX-associated cardiotoxicity.


Inflammatory mimetic microfluidic chip by immobilization of cell adhesion molecules for T cell adhesion.
Leukocyte adhesion to adhesion molecules on endothelial cells is important in immune function, cancer metastasis and inflammation. This cell-cell binding is mediated via cell adhesion molecules such as E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) found on endothelial cells. Because these adhesion molecules on endothelial cells vary significantly across several disease conditions such as autoimmune diseases, inflammation or cancer metastasis, investigations of therapeutic agents that down-regulate leukocyte-endothelial interactions have been based on in vitro models using endothelial cell lines. Here we report a new model, an inflammatory mimetic microfluidic chip, which emulates leukocyte binding to cell adhesion molecules (CAM) by controlling the types and ratio of adhesion molecules. In our model, E-selectin was essential for the synergic binding of Jurkat T cells. Immunosuppressive drugs, such as tacrolimus (FK506) and cyclosporine A (CsA), were used to inhibit T cell interactions under the physiologic model of T cell migration at a ratio of 5 : 4.3 : 3.9 (E-selectin : ICAM-1 : VCAM-1). Our results support the potential usefulness of the inflammatory mimetic microfluidic chip as a T cell adhesion assay tool with modified adhesion molecules for applications such as immunosuppressive drug screening. The inflammatory mimetic microfluidic chip can also be used as a biosensor in clinical diagnostics, drug efficacy tests and high throughput drug screening due to the dynamic monitoring capability of the microfluidic chip.


Hitting the brakes: pathological subthalamic nucleus activity in Parkinson's disease gait freezing.
Gait freezing is a complex and devastating paroxysmal motor arrest commonly suffered in Parkinson's disease that causes significant impairment to mobility, commonly resulting in falls and subsequent injury. The neurobiological basis of gait freezing in Parkinson's disease is poorly understood and thus, currently available therapies are partially effective at best. We used a validated virtual reality gait paradigm to elicit freezing behaviour intraoperatively in eight patients undergoing subthalamic nucleus deep brain stimulation surgery while microelectrode recordings were obtained. This allowed us to directly test the hypothesis that increases in pathological multi-unit activity in the subthalamic nucleus are associated with freezing onset in real time, manifest as dysfunctional firing of lower limb muscles typical of freezing that were detected by EMG. We present evidence that freezing is related to transient increases in pathological subthalamic nucleus activity. We performed time-frequency analysis to characterize the oscillatory dynamics of subthalamic nucleus activity coincident with freezing onset, demonstrating an increase in pathological beta and theta rhythms that are followed by a temporal chain of activity culminating in characteristically abnormal lower limb muscle firing detected by EMG. Finally, we interrogate the potential clinical utility of our findings by contrasting the subthalamic nucleus activity signature during pathological freezing against purposeful stopping. These results advance our understanding of the neurobiological basis of gait freezing in Parkinson's disease, highlighting the role of the subthalamic nucleus and emergent synchronous activity in basal ganglia circuits in driving non-purposeful motor arrests in individuals with Parkinson's disease. Pathological subthalamic nucleus activity identified in association with freezing is discernible from that of volitional stopping, paving the way towards more effective therapeutics such as adaptive closed-loop deep brain stimulation protocols.


Behavioral performance of tfm mice supports the beneficial role of androgen receptors in spatial learning and memory.
In adulthood, androgens and androgen receptors might contribute to the sexually dimorphic performance in spatial learning and memory, but their roles seem complex. To study the potential role of androgen receptors in spatial learning and memory, we tested adult 6-8-month-old mutant mice with a naturally occurring defect in the androgen receptor gene (testicular feminization mutant or tfm) and C57Bl/6J wild-type mice. Because the trait is X-linked, only tfm males are completely androgen insensitive while female tfm mice are heterozygous, carrying one wild-type and one tfm copy of the androgen receptor. Here we show that female tfm carrier mice outperform tfm male mice in the water maze, while there are no gender differences in water maze performance in wild-type mice. In tfm mice, there were no gender differences in measures of anxiety in the open field or plus maze or sensorimotor function, indicating that potential differences in these measures did not contribute to the differences observed in the water maze. There were no differences in tfm and wild-type female and male mice in emotional learning and memory in the passive avoidance test. These findings support a beneficial role for androgen receptors in spatial learning and memory.


Enumeration and characterization of human memory T cells by enzyme-linked immunospot assays.
The enzyme-linked immunospot (ELISPOT) assay has advanced into a useful and widely applicable tool for the evaluation of T-cell responses in both humans and animal models of diseases and/or vaccine candidates. Using synthetic peptides (either individually or as overlapping peptide mixtures) or whole antigens, total lymphocyte or isolated T-cell subset responses can be assessed either after short-term stimulation (standard ELISPOT) or after their expansion during a 10-day culture (cultured ELISPOT). Both assays detect different antigen-specific immune responses allowing the analysis of effector memory T cells and central memory T cells. This paper describes the principle of ELISPOT assays and discusses their application in the evaluation of immune correlates of clinical interest with a focus on the vaccine field.


Circulating Tumor DNA to Interrogate the Safety of Letrozole-Associated Controlled Ovarian Stimulation for Fertility Preservation in Breast Cancer Patients.
Current fertility preservation strategies for young breast cancer patients planning a future motherhood include the association of controlled ovarian stimulation with the aromatase inhibitor letrozole (let-COS) to harvest mature oocytes while maintaining low estradiol levels. Despite this is a widely adopted protocol, the safety of let-COS on breast cancer outcomes has been poorly investigated and its use remains off-label. We assessed the safety of let-COS in breast cancer patients using circulating tumor DNA (ctDNA) as a surrogate biomarker of disease recurrence. BROVALE is an interventional non-randomized prospective study designed to evaluate the efficacy and safety of let-COS for fertility preservation in early breast cancer patients before starting (neo)adjuvant chemotherapy. Letrozole was administered throughout the COS cycle, until ovulation triggering. Safety was a secondary endpoint. Data on oncological outcomes were collected during the follow-up as well as plasma and whole blood for evaluation of ctDNA levels at the time of enrollment (i.e. before starting let-COS) and oocyte retrieval (i.e. 48 hours after the last administration of letrozole). Targeted gene sequencing on the primary tumor samples was performed to identify specific mutations used for ctDNA analysis by digital PCR. DNA extracted from whole blood samples was used to discriminate between somatic and germline mutations. From April 2014 to May 2017, 29 young early breast cancer patients enrolled in the BROVALE study who had available tissue samples participated to the ctDNA substudy. Among them, 15 had at least one validated somatic mutation. ctDNA was undetectable neither before nor after let-COS in 9 of them. Six patients had detectable ctDNA in the plasma samples collected before Let-COS. No change in ctDNA level after let-COS was observed in 3 patients and the level decreased (fold-change ≤ 0.5) in two women. One patient experienced an increased (fold-change ≥ 2) in ctDNA level but without disease relapse 34 months after diagnosis. No increase in ctDNA level was observed in 93% (14/15) of the patients receiving let-COS supporting its use as a safe strategy for young women with early breast cancer interested in fertility preservation before chemotherapy.


[Vaccinations of the traveller].
Travelers' immunization has 2 aims: for the traveler, to prevent the risk of contracting an endemic disease during his stay abroad; for the community to prevent the risk of importing an infectious agent yet unknown in the country. Travelling offers an opportunity to update routine immunizations: tetanus, diphtheria, poliomyelitis, hepatitis B; for young people: measles and rubella; for elderly people: influenza. Two vaccinations are compulsory: yellow fever for travelers to tropical Africa and Amazonian forest; meningococcus A + C for Mecca pilgrims. Other vaccines are recommended for travelers to specific areas: typhoid fever, hepatitis A, cholera in countries with poor hygiene; rabies for exposed travelers (expatriates, trekkers...); Japanese encephalitis for persons spending a month or longer in rural agricultural areas during the monsoon season; tickborne encephalitis for persons visiting forested areas of central Europe from may to september. Yet, most of travelers' diseases such as malaria cannot be prevented by vaccination and appropriate preventive measures (chemoprophylaxis and protection against insects) should be taken.


Cell growth with trans fatty acids is affected by adenosine 3',5'-monophosphate and membrane fluidity.
Two positional isomers (9 and 11) of trans octadecenoates did not support growth on glucose of an Escherichia coli mutant that requires unsaturated fatty acids. However, the trans fatty acids provided sufficient fluidity to produce much higher cell yields when the concentration of adenosine 3',5'-monophosphate was raised. The effectiveness of the trans acids rose from 0 to 1 cell per femtomole to 15 to 20 cells per femtomole as the concentration of adenosine 3',5'-monophosphate was increased. The corresponding cis positional isomers supported high yields (35 to 40 cells per femtomole) independent of supplementation. The enhanced growth with adenosine 3',5'-monophosphate supplementation is not due to an increased uptake and incorporation of the trans isomers relative to the cis isomers, since the 9-trans isomer was incorporated more rapidly than the 9-cis isomer into the membrane phospholipids under all growth conditions and represented 21 +/- 2 mole percent of the acids. The finding that cells growing with trans fatty acid isomers have a higher requirement for adenosine 3',5'-monophosphate may indicate that some fatty acids can alter the metabolic regulation normally exerted by the cyclic nucleotide.


Using Patterns to Encode Color Information for Dichromats.
Color is one of the most common ways to convey information in visualization applications. Color vision deficiency (CVD) affects approximately 200 million individuals worldwide and considerably degrades their performance in understanding such contents by creating red-green or blue-yellow ambiguities. While several content-specific methods have been proposed to resolve these ambiguities, they cannot achieve this effectively in many situations for contents with a large variety of colors. More importantly, they cannot facilitate color identification. We propose a technique for using patterns to encode color information for individuals with CVD, in particular for dichromats. We present the first content-independent method to overlay patterns on colored visualization contents that not only minimizes ambiguities but also allows color identification. Further, since overlaying patterns does not compromise the underlying original colors, it does not hamper the perception of normal trichromats. We validated our method with two user studies: one including 11 subjects with CVD and 19 normal trichromats, and focused on images that use colors to represent multiple categories; and another one including 16 subjects with CVD and 22 normal trichromats, which considered a broader set of images. Our results show that overlaying patterns significantly improves the performance of dichromats in several color-based visualization tasks, making their performance almost similar to normal trichromats'. More interestingly, the patterns augment color information in a positive manner, allowing normal trichromats to perform with greater accuracy.


Arguments for the presence of a Na-K ATPase pump inhibitor in the plasma of uremic and essential hypertensive patients.
The effect of salt and/or volume depletion has been tested in 6 end-stage renal disease and 11 essential hypertensive patients (HTA) on red blood cell (RBC) ionic fluxes. Volume depletion promotes an increase in the RBC Na-K ATPase activity with, as a result, a significant decrease in intracellular sodium concentration [Na)ic). Moreover, a factor has been found in the plasma of uremic subjects which causes natriuresis when injected in rat renal arteries. The concentration of this factor decreases during dialysis in relation to the weight loss and the increase in the RBC Na-K pump activity. In essential hypertension, the effect of a low salt diet on the blood pressure is correlated with the improvement of RBC Na-K ATPase activity. These experiments illustrate the presence of a Na-K ATPase inhibitor in the plasma of these subjects, dependent on sodium and water balance.


Bothrops asper snake venom and its metalloproteinase BaP-1 activate the complement system. Role in leucocyte recruitment.
The venom of the snake Bothrops asper, the most important poisonous snake in Central America, evokes an inflammatory response, the mechanisms of which are not well characterized. The objectives of this study were to investigate whether B. asper venom and its purified toxins--phospholipases and metalloproteinase--activate the complement system and the contribution of the effect on leucocyte recruitment. In vitro chemotaxis assays were performed using Boyden's chamber model to investigate the ability of serum incubated with venom and its purified toxins to induce neutrophil migration. The complement consumption by the venom was evaluated using an in vitro haemolytic assay. The importance of complement activation by the venom on neutrophil migration was investigated in vivo by injecting the venom into the peritoneal cavity of C5-deficient mice. Data obtained demonstrated that serum incubated with crude venom and its purified metalloproteinase BaP-1 are able to induce rat neutrophil chemotaxis, probably mediated by agent(s) derived from the complement system. This hypothesis was corroborated by the capacity of the venom to activate this system in vitro. The involvement of C5a in neutrophil chemotaxis induced by venom-activated serum was demonstrated by abolishing migration when neutrophils were pre-incubated with antirat C5a receptor antibody. The relevance of the complement system in in vivo leucocyte mobilization was further demonstrated by the drastic decrease of this response in C5-deficient mice. Pre-incubation of serum with the soluble human recombinant complement receptor type 1 (sCR 1) did not prevent the response induced by the venom, but abolished the migration evoked by metalloproteinase-activated serum. These data show the role of the complement system in bothropic envenomation and the participation of metalloproteinase in the effect. Also, they suggest that the venom may contain other component(s) which can cause direct activation of C5a.


Patient, observer and instrument variation in the measurement of strength of shoulder abductor muscles in patients with rheumatoid arthritis using a modified sphygmomanometer.
We describe the use of a modified sphygmomanometer to measure the strength of shoulder abductor muscles. Using a 5 x 5 Greco-Latin square design we compared the measurements of 5 physical therapists taken on 5 patients with rheumatoid arthritis with 2 cuff adaptations. The design variables explained 96.4% of the pressure readings, with patients accounting for 76.6%. There was no significant variation due to order of testing, cuff preparations or observers. The method is simple, portable, inexpensive, comfortable and safe to use. It can also be applied to 26 different muscle groups.


Cutaneous mucinosis in a strain of brown-egg laying chickens.
Cutaneous mucinosis is a cutaneous disorder described in humans, dogs, and rarely cats but never reported in birds. Twenty-six brown egg-laying chickens between ages 43 and 46 weeks had a history of feather loss, scaly, dry skin, weight loss, and decreased egg production. Microscopic findings in the skin included fragmentation of collagen bundles and interstitial, periadnexal, and perivascular dermal accumulation of wispy, mildly basophilic material that was also occasionally observed within the follicular epithelium. A moderate lymphoplasmacytic and heterophilic perivascular dermatitis was also observed. The wispy to granular material was diffusely Alcian blue positive and periodic acid-Schiff negative (consistent with mucin), suggesting a diagnosis of primary or secondary cutaneous mucinosis. The cause of this condition could not be determined.


ermA, ermC , tetM and tetK are essential for erythromycin and tetracycline resistance among methicillin-resistant Staphylococcus aureus strains isolated from a tertiary hospital in Malaysia.
The objective of this study was to determine the expression and transferability of tetracycline and erythromycin resistance among 188 MRSA strains from a Malaysian tertiary hospital. The minimum inhibitory concentrations (MICs) for oxacillin, erythromycin, tetracycline and ciprofloxacin ranged from 4 to 512 μg/ml, 0.25 to 256 μg/ml, 0.5 to 256 μg/ml and 0.5 to 512 μg/ml, respectively. Tetracycline-resistant strains showed co-resistance towards ciprofloxacin and erythromycin. There was a significant increase (P<0.05) of high-level tetracycline (≥MIC 256 μg/ml) and erythromycin (≥MIC 128 μg/ml) resistant strains in between the years 2003 and 2008. All erythromycin-resistant strains harboured ermA or ermC gene and all tetracycline-resistant strains harboured tetM or tetK gene. The blaZ was detected in all MRSA strains, whereas ermA, tetM, ermC, tetK and msrA genes were detected in 157 (84%), 92 (49%), 40 (21%), 39 (21%) and 4 (2%) MRSA strains, respectively. The blaZ, tetM, ermC and tetK genes were plasmid-encoded, with ermC gene being easily transmissible. Tn5801-like transposon was present in 78 tetM-positive strains. ermA and tetM genes were the most prevalent erythromycin and tetracycline resistance determinants, respectively, in MRSA strains. The association of resistance genes with mobile genetic elements possibly enhances the spread of resistant traits in MRSA.


Satisfactory outcomes after one-stage revision anterior cruciate ligament reconstruction using rectangular tunnel technique.
One-stage revision anterior cruciate ligament reconstruction (ACLR) with the anatomic rectangular tunnel (RT) technique using bone-patellar tendon-bone (BTB) grafts results in anatomically precise tunnel placement and secure graft fixation. This study evaluated knee joint laxity and clinical outcomes in terms of femoral tunnel overlap. It was hypothesised that there would be no significant differences in knee joint laxity or clinical outcomes regardless of femoral tunnel overlap. Between 2012 and 2021, a single surgeon conducted 196 one-stage revision ACLRs with the RT technique using BTB grafts. Patients were divided based on the presence of femoral tunnel overlap. Knee joint laxity was evaluated using the Lachman test, pivot shift test, and side-to-side difference measured with a KT-1000 arthrometer. Clinical outcomes were assessed using the Lysholm score, Knee Injury and Osteoarthritis Outcome Score (KOOS), and International Knee Documentation Committee (IKDC) Knee Examination Form 2000. Knee joint laxity and clinical outcomes were compared between groups after a median follow-up of 2.5 years (range 2.0-8.0). The study included 30 and 73 patients in the overlap and non-overlap groups, respectively. No significant differences were observed in the results of the Lachman test, pivot shift test, or KT-1000 arthrometer as well as in the Lysholm, KOOS, or IKDC scores between the two groups. Based on the IKDC scores, all patients were graded as normal or nearly normal. One-stage revision ACLR with the RT technique using BTB grafts improved knee joint laxity and had favourable clinical outcomes regardless of femoral tunnel overlap. To achieve optimal results in one-stage revision ACLR, it is crucial to create a tunnel within the anatomical attachment area and ensure proper graft fixation and tensioning. III.


Inducible miR-145 expression by HIF-1a protects cardiomyocytes against apoptosis via regulating SGK1 in simulated myocardial infarction hypoxic microenvironment.
Myocardial infarction (MI) is partly due to myocardial cell damage caused by hypoxia. MicroRNAs (miRNAs) have been proved to be closely related to the development and progression of many cardiovascular diseases. This study investigated the role of miR-145 in cardiomyocytes under hypoxic condition. The quantitative real-time polymerase chain reaction (qRT-PCR) was performed to test miR-145 expression in H9c2 cells with hypoxia-inducible factor (HIF)-a abnormal expression under hypoxic condition. The 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyltetrazolium bromide (MTT), Tran-swell assay and flow cytometry were used to investigate the effects of miR-145 on cell viability, migration and apoptosis under normoxic or hypoxic condition, respectively. Meanwhile, reactive oxygen species (ROS) content in hypoxic H9c2 cells was analyzed. Western blotting was used to explore the potential mechanism of miR-145 protective effects on cardiomyocytes. Expression levels of miR-145 and SGK1 in rat MI model were also assessed. Results showed that miR-145 was upregulated in H9c2 and HL-1 cells under hypoxic condi-tion, which was promoted by HIF-1a. MiR-145 overexpression enhanced cell viability and migration under normoxic condition. Under hypoxic condition, miR-145 overexpression promoted cell viability, inhibited apoptosis and ROS activity. Western blotting results proved that miR-145 overexpression inhibited the activation of apoptotic related factors, and promoted activation of PI3K/AKT signaling pathway via SGK1 upregulation. Expression levels of miR-145 and SGK1 were both upregulated in rat MI models. HIF-1a could induce miR-145 upregulation in hypoxic H9c2 and HL-1 cells. MiR-145 protected H9c2 cells against hypoxic damage. SGK1 upregulation and activated PI3K/AKT may have participated in the protective effects of miR-145 on cardiomyocytes.


Interlaboratory study of immunochromatography for the rapid determination of cadmium concentrations in cereals and soybeans.
Cadmium (Cd) is one of the most toxic heavy metals to humans. To prevent the distribution of Cd-contaminated food, a simple and quick on-site test for measuring Cd concentrations in agricultural products is needed. Recently, an immunochromatography kit developed for determining Cd in rice was reported to be useful for determining Cd in many other crops. We conducted an interlaboratory study to evaluate the kit for determining Cd in cereals (wheat and rice) and soybeans. Ten test materials were used, and 12 test samples including two sets of blind duplicates were distributed to 12 laboratories in Japan. The Cd recoveries (relative to certified values or values determined by inductively coupled plasma-MS) from all test materials were 84.6-125.1%. Repeatability RSD values of the test materials ranged from 8.8 to 14.8%. Reproducibility RSD values ranged from 13.4 to 27.6%, averaging 21.3%. The Horwitz ratio ranged from 0.61 to 1.36. The reproducibility was within the range of ELISA results for measuring toxins and allergens in food. Our results indicated that the kit was an inexpensive, reliable tool for quick and easy on-site determination of Cd in cereals and soybeans.


Adhesion of salivary components to Streptococcus mutans peptides.
Streptococcus mutans is the main microorganism associated to dental caries; it adheres to the dental enamel by interacting with the acquired film's proteins and the cell surface adhesin, called variously antigen PAc. At least two distinct sites in PAc interact with salivary receptors in vitro, these are within residues 816-1213, the most conserved portion of PAc, and within residues 186-469, the alanine-rich sequence. Our purpose was to establish differences or similarities in PAc's peptides interactions with the salivary components of individuals with and without previous caries experience. 40 saliva samples were obtained from patients with (n=20) and without (n=20) caries. The acquired film's proteins were extracted using hydroxyapatite, and subjected to interaction with three synthetic PAc peptides (PAc (301-319), PAc (365-377), and PAc (1025-1044)) synthesized from PAc's bonding sites to the salivary components. The results show low interaction between the acquired pellicle components and the peptides in all patients. This suggests that the examined PAc's are not relevant as far as the initial adhesion of Streptococcus mutans to the tooth's surface is concerned, as defined by the similarities in the results for healthy and affected individuals.


Minocycline Extended-Release Comparison with Doxycycline for the Treatment of Rosacea: A Randomized, Head-to-Head, Clinical Trial.
Minocycline efficacy for the treatment of papulopustular rosacea (PPR) has not been evaluated in clinical trials at levels demonstrated to stay below the antimicrobial threshold. We assessed the efficacy, safety, and dose response of DFD-29, a minocycline extended-release oral capsule. Two studies are reported (NCT03340961). A single-center open-label, three-arm, Phase I pharmacokinetic study randomized 24 healthy subjects aged 18 to 45 years to receive 21 days of once-daily dosing with DFD-29 40 or 20mg, or doxycycline 40mg. Blood samples were collected over 24 hours on Days 1 and 21 to plot mean plasma concentration levels. A multicenter Phase II clinical trial randomized 205 subjects with mild-to-severe PPR 1:1:1:1 to receive once-daily DFD-29 40 or 20mg, doxycycline 40mg, or placebo for 16 weeks. Co-primary endpoints were the proportion of subjects achieving treatment success (IGA grade 0 or 1 and ≥2-grade improvement) at Week 16, and a reduction in total inflammatory lesion count at Week 16. Pharmacokinetic analysis demonstrated that minocycline plasma levels of DFD-29 40mg were approximately half those of doxycycline 40mg after 21 days, with DFD-29 20mg even lower, demonstrating a dose response. In the Phase II trial, DFD-29 40mg met both co-primary endpoints, achieving IGA treatment success in 66.0 percent subjects versus 11.5 percent placebo (p<0.0001), 31.9 percent DFD-29 20mg (p=0.007), and 33.3 percent doxycycline 40mg (p<0.0010), and a mean reduction in lesion counts of -19.2 versus -7.3 placebo (p<0.0001), -12.6 DFD-29 20mg (p=0.0070), and -10.5 doxycycline 40mg (p=0.0004). MIC values and plasma concentrations shown for antibacterial threshold data are mean values; fast absorbers/slow metabolizers could exceed the threshold, causing resistance selection pressure. DFD-29 40mg demonstrated significantly greater efficacy than placebo, DFD-29 20mg, and doxycycline 40mg at plasma concentrations predicted to be below the antimicrobial threshold for the treatment of PPR.


[Utility of quetiapine in tardive dyskinesia].
Neuroleptic induced tardive dyskinesia is a late appearing extrapyramidal disorder of involuntary, choreoatetoid movements. It may appear during chronic treatment with classical neuroleptics or a short time after its prolonged administration is interrupted. At present, there is no agreement on what would be the best way to treat dyskinesias. Clozapine is an alternative treatment to take into account, although the risk of agranulocytosis may be excessive to use it when there is a mild or moderate form of dyskinesia. Cases of improvement of dyskinesias both with olanzapine as well as with risperidone, although in a lower number, have been reported. Due to its receptor profile, quetiapine is the atypical antipsychotic that is most similar to clozapine, which leads us to consider it for the treatment of dyskinesias. The first patient is a 66 year old woman with schizoaffective disorder of 16 years of evolution who has received many classical neuroleptics and who presents a picture or orolingual dyskinesias with a score of 28 on the AIMS scale. Treatment was substituted with Quetiapine until reaching a dose of 400 mg/day over 4 months, obtaining a decrease in the AIMS score up to 9. The second patient is a 60 year old woman diagnosed of bipolar disorder under treatment since 26 years of age with delusional jealousy ideation. Different atypical antipsychotics were used, all of them causing dyskinetic symptoms in the orolingual region, that disappeared with low doses of quetiapine, with good stabilization of her psychopathology. The third patient is a 33 old male diagnosed of paranoid schizophrenia when he was 18 years old. He was under maintenance treatment with haloperidol, biperiden and lorazepam, until 27 years of age, when the treatment was changed to risperidone, after presenting an orofacial tardive dyskinesia with masticatory type movements and lingual protrusion, with a 19 score on the AIMS scale. The change to quetiapine 600 mg/day reduced the score on the AIMS scale to 3. Our experience, based on 3 cases, shows an early and lasting improvement of the tardive dyskinesia with quetiapine. This experience is reinforced by other investigators with similar cases. In all, we have 12 cases that support the efficacy of quetiapine in the treatment of tardive dyskinesias.