[Mast cells and antitumor resistance].
Data on the possible participation of mast cells in the immunological surveillance are presented. Results of the investigations are adduced testifying to participation of mast cells as regulatory ones in the rejection of tumours by means of the development of the delayed hypersensitivity and as effector killer cells with cytolytic activity.


Cardiovascular effects of noradrenaline microinjected into the insular cortex of unanesthetized rats.
The insular cortex (IC) has been reported to be involved in central cardiovascular control. In the present study, we investigated the cardiovascular responses evoked by microinjection of noradrenaline into the IC as well as the central and peripheral mechanisms involved in their mediation. Microinjection of noradrenaline into the IC (3, 7, 10, 15, 30 and 45 nmol/100 nL) caused long-lasting dose-related pressor and bradycardiac responses. The cardiovascular responses evoked by 15 nmol of noradrenaline were blocked by IC pretreatment with WB4101 or 5-methyl-urapidil, selective α(1)-adrenoceptor antagonists. IC pretreatment with either the selective α(2)-adrenoceptor antagonists RX821002 or the β-adrenoceptor antagonist propranolol did not affect noradrenaline cardiovascular responses. Noradrenaline cardiovascular responses were mimicked by microinjection of the selective α(1)-adrenoceptor agonist phenylephrine into the IC, thus reinforcing the idea that α(1)-adrenoceptors mediate cardiovascular responses to noradrenaline microinjected into the IC. The pressor response to noradrenaline microinjection was potentiated by i.v. pretreatment with the ganglion blocker pentolinium and inhibited by i.v. pretreatment with the selective V(1)-vasopressin receptor antagonist dTyr(CH(2))(5)(Me)AVP. The bradycardiac response to noradrenaline microinjection into the IC was abolished by pretreatment with either pentolinium or the V(1)-vasopressin receptor antagonist, indicating its reflex origin. In conclusion, our results suggest that pressor response evoked by microinjection of noradrenaline into the IC involve the activation of IC α(1)-adrenoceptors to cause the release of vasopressin into the circulation.


SEXUAL SELECTION BY THE HANDICAP MECHANISM.
The handicap mechanism of sexual selection by female choice has been strongly criticized because it does not cause sexual selection to reinforce viability selection and it cannot account for the origin of mating preferences. However, several models indicate that the handicap mechanism can have important effects when operating in conjunction with Fisher's mechanism in polygynous populations. These models have been criticized because they require that fitness remains heritable indefinitely. I develop a simple haploid model of the handicap mechanism based on nonheritable variation in paternal investment, thus eliminating the problem of heritable fitness. This model produces the same evolutonary dynamics as both simple and quantitative genetic models of the handicap mechanism based on heritable fitness. If the parameters are such that Fisherian runaway selection does not occur in the null model (i.e., the polymorphic equilibria, which lie along the "Fisher line," are stable), then the handicap mechanism turns the Fisher line into an evolutionary trajectory upon which all other trajectories converge. This occurs because Fisher's mechanism generates no net selection on female preference when the population is on the Fisher line, so that any additional source of selection (direct or indirect) on female choice causes the population to evolve deterministically along the Fisher line. This change in the evolutionary dynamics has the important consequence of eliminating the potential for rapid population divergence for mating systems via genetic drift along the Fisher line.


Influence of feeding supplemental fat by age sequence on the performance of growing turkeys.
Large White toms were used in an experiment to determine the response of turkeys to feeding supplemental fat by age sequence. The eight treatments tested consisted of a factorial arrangement of dietary animal-vegetable fat blend (A-V fat) at 0 and 4% and four age periods (0 to 20, 6 to 20, 9 to 20, and 12 to 20 weeks). The concentrations of nutrients were kept constant within an age period, irrespective of level of dietary fat. On an age-period basis, improvements in feed efficiency resulting from supplemental fat increased with increasing age. During the 0- to 6-week period, feed efficiency was improved 1.6% per 1% added fat, while during the 12- to 20-week period, feed efficiency of toms previously fed no added fat was improved 3.6% for 1% added fat. Improvements in weight gains through 12 weeks of age followed a similar pattern but of lesser magnitude. The overall data through 20 weeks of age demonstrated that nearly all of the increases in weight gain and much of the improvements in feed efficiency obtained by feeding supplemental fat from 0 to 6, 0 to 9, and 0 to 12 weeks of age were lost after these treatment groups were fed a diet with no added fat for the rest of the growing period. Conversely, 20-week feed efficiencies and efficiencies of metabolizable energy and protein utilization were similar for all treatment groups that received no supplemental fat from 0 to 6, 0 to 9, or 0 to 12 weeks of age but were then fed 4% supplemental fat thereafter. A small numerical advantage in 20-week body weights was observed for toms fed supplemental fat from 0 or 6 to 20 weeks of age as compared with those fed fat-supplemented diets from 9 or 12 to 20 weeks of age.


Targeting Adult Neurogenesis to Optimize Hippocampal Circuits in Aging.
Millions of individuals suffer from age-related cognitive decline, defined by impaired memory precision. Increased understanding of hippocampal circuit mechanisms underlying memory formation suggests a role for computational processes such as pattern separation and pattern completion in memory precision. We describe evidence implicating the dentate gyrus-CA3 circuit in pattern separation and completion, and examine alterations in dentate gyrus-CA3 circuit structure and function with aging. We discuss the role of adult hippocampal neurogenesis in memory precision in adulthood and aging, as well as the circuit mechanisms underlying the integration and encoding functions of adult-born dentate granule cells. We posit that understanding these circuit mechanisms will permit generation of circuit-based endophenotypes that will edify new therapeutic strategies to optimize hippocampal encoding during aging.


The key role of polymer grafted nanoparticles in the phase miscibility of an LCST mixture.
Blends of bromo-terminated polystyrene (PS-Br) and poly(vinyl methylether) (PVME) exhibit lower critical solution temperatures. In this study, PS-Br was designed by atom transfer radical polymerization and was converted to thiol-capped polystyrene (PS-SH) by reacting with thiourea. The silver nanoparticles (nAg) were then decorated with covalently bound PS-SH macromolecules to improve the phase miscibility in the PS-Br-PVME blends. Thermally induced demixing in this model blend was followed in the presence of polystyrene immobilized silver nanoparticles (PS-g-nAg). The graft density of the PS macromolecules was estimated to be ca. 0.78 chains per nm(2). Although the matrix and the grafted molecular weights were similar, PS-g-nAg particles were expelled from the PS phase and were localized in the PVME phase of the blends. This was addressed with respect to intermediate graft density and favourable PS-PVME contacts from microscopic interactions point of view. Interestingly, blends with 0.5 wt% PS-g-nAg delayed the spinodal decomposition temperature in the blends by ca. 18 °C with respect to the control blends. The scale of cooperativity, as determined by differential scanning calorimetry, increased only marginally in the case of PS-g-nAg; however, it increased significantly in the presence of bare nAg particles.


Evaluation of accuracy of computer-aided intraoperative positioning of endosseous oral implants in the edentulous mandible.
The overall accuracy of a novel surgical computer-aided navigation system for placement of endosseous implants was evaluated. Five dry cadaver mandibles were scanned using high resolution computed tomography (HRCT). The position of four interforaminal dental implants was planned on the computer screen and transferred to the cadaver mandibles using VISIT, a surgical navigation software developed at the Vienna General Hospital. The specimens were HRCT-scanned again to compare the position of the implants with the preoperative plan on reformatted slices after matching of the pre- and postoperative data sets using the mutual information technique. The overall accuracy was 0.96 +/- 0.72 mm (range 0.0-3.5 mm). No perforation of the mandibular cortex or damage to the mandibular canal occurred. We conclude that computer-aided implant surgery can reach a level of accuracy where further clinical developments are feasible.


Can optic nerve sheath diameter assessment be used as a non-invasive tool to dynamically monitor intracranial pressure?
This study aims to detect whether the optic nerve sheath diameter (ONSD) can be used to dynamically monitor intracranial pressure (ICP). Adult patients undergoing invasive ICP monitoring on the day of admission are included in this study. For each patient, the ONSD is first measured in the supine position and then in the 30° head-up position. Subsequently, a dynamic test is conducted on 16 patients. The ONSD is measured in the supine position once a day for three consecutive days starting on the day of admission. There is a strong correlation between the ONSD and ICP values in the supine position on admission (r = 0.799), and when patients are changed from the supine to the 30° head-up position, the ICP and ONSD values decrease correspondingly. However, the change in ICP is not strongly correlated with the change in ONSD (r = 0.358). In the dynamic test, a good agreement between the ICP and ONSD only exists in three patients (18.8%), and three patients have completely different profiles for ICP and ONSD. These results suggest that the changes in the ONSD and ICP values are not closely correlated after dynamic observation. Therefore, measurement of the ONSD may not be a suitable tool to dynamically monitor ICP.


Embedding for bulk systems using localized atomic orbitals.
We extend projection-based embedding techniques to bulk systems to treat point defects in semiconductors and insulators. To avoid non-additive kinetic energy contributions, we construct the density partition using orthogonal subsets of orbitals. We have implemented our approach in the popular Vienna ab initio simulation package software package. We demonstrate its power for defect structures in silicon and polaron formation in titania, two challenging cases for conventional Kohn-Sham density functional theory.


[Rational treatment of hypertensive crises].
The Hypertensive Crisis can be divided into Emergencies and Urgencies. Hypertension may be unknown at presentation. The Emergencies have acute or ongoing end-organ damage (neurological, renal or cardiovascular). It is crucial to recognize one from another already at the emergency room evaluation. There is no arbitrary level of blood pressure separating hypertensive emergencies and urgencies. Ideally, this patients must be treated in an intensive care unit. The level to which the blood pressure should be lowered and the election of the treatment, parenteral versus oral, depends on the patient's general condition and should be individualized. The general recommendation is to reduce the mean arterial pressure gradually in the first 48 hours by no more than 20 percent or to a diastolic blood pressure not lower than 100 mmHg. A relatively asymptomatic patient, even with high diastolic lectures does not need to be treated with parenteral drugs. The patient should be evaluated for possible factors that may have contributed to the high of blood pressure and the progression of hypertension.


A Study on the Morphometry of a Medial Meniscus in the Knee Joint of Human Cadavers in the South Indian Population.
Introduction The knee joint is a complex system containing various hard and soft tissue components necessary for functioning in a coordinated manner. The menisci help to deepen the tibial plateau. Knowledge of the dimension of menisci in the knee joint is of paramount importance in arthroscopic surgery and the management of injuries due to sports or degeneration. The present study aims to describe the morphometric data of the medial meniscus and document the morphometric variation in the medial menisci. Methodology This study was conducted in the department of anatomy in two medical colleges under MGR University by measuring the dimensions of 100 medial menisci taken from 50 formalin-fixed embalmed cadavers. The width and thickness of the medial menisci were measured using digital vernier calipers. The outer and inner circumferences were measured using a measuring tape, non-elastic threads, and metallic pins. The area of the medial meniscus and the tibial plateau was measured by counting the small squares present in the circumference of the menisci drawn over the graph paper. The weight of the medial menisci was measured using the electronic weigh scale. Results The widest part of the medial meniscus was the posterior one-third, and the narrowest part was the anterior one-third. The thickest part was the middle one-third, followed by the anterior one-third. The average inner and outer circumferences of the menisci were 6.25 cm and 10.05 cm, respectively. The medial meniscus covers more than half of the area of the tibial plateau. Conclusion The present study provides a good understanding of the morphometric features of the medial menisci and will be of great help for managing knee joint pathologies and designing prostheses.


Spatial coupling of JNK activation to the B cell antigen receptor by tyrosine-phosphorylated ezrin.
The ezrin-radixin-moesin proteins regulate B lymphocyte activation via their effect on BCR diffusion and microclustering. This relies on their ability to dynamically tether the plasma membrane with actin filaments that is in turn facilitated by phosphorylation of the conserved threonine residue in the actin-binding domain. In this study, we describe a novel function of ezrin in regulating JNK activation that is mediated by phosphorylation of a tyrosine (Y353) residue that is unconserved with moesin and radixin. BCR, but not CD40, TLR4, or CXCR5 stimulation, induced phosphorylation of ezrin at Y353 in mouse splenic B cells. Ezrin existed in a preformed complex with Syk in unstimulated B cells and underwent Syk-dependent phosphorylation upon anti-IgM stimulation. Y353-phosphorylated ezrin colocalized with the BCR within minutes of stimulation and cotrafficked with the endocytosed BCRs through the early and late endosomes. The T567 residue of ezrin was rephosphorylated in late endosomes and at the plasma membrane at later times of BCR stimulation. Expression of a nonphosphorylatable Y353F mutant of ezrin specifically impaired JNK activation. BCR crosslinking induced the association of Y353-phosphorylated ezrin with JNK and its kinase MAPKK7, as well as spatial colocalization with phosphorylated JNK in the endosomes. The yellow fluorescent protein-tagged Y353F mutant displayed reduced colocalization with the endocytosed BCR as compared with wild-type ezrin-yellow fluorescent protein. Taken together, our data identify a novel role for ezrin as a spatial adaptor that couples JNK signaling components to the BCR signalosome, thus facilitating JNK activation.


Effects of higher order Jahn-Teller coupling on the nuclear dynamics.
In this paper effects of higher order Jahn-Teller coupling terms on the nonadiabatic dynamics are studied. Of particular interest is the case when the potential energy surfaces of the degenerate state show pronounced anharmonicity. In order to demonstrate the effects a two-dimensional E multiply sign in circle e Jahn-Teller model system is treated which is based on the e(') stretching vibration of the photoactive (2)E(') state of NO(3) as a realistic example. The sixth order E multiply sign in circle e Jahn-Teller Hamiltonian is derived in the diabatic representation which is valid for any system with a C(3) rotation axis. This diabatization scheme is compared to lower-order Jahn-Teller Hamiltonians and to symmetry adapted as well as ad hoc approximations. Lower-order potentials result in pronounced quantitative and qualitative differences in the dynamics, including differences in the evolution of mean values, the autocorrelation functions (and thus the corresponding spectra), and the electronic population evolution. In the particular example treated, the results of fourth and fifth order potentials are very similar to the sixth order reference system. In contrast, the approximate sixth order Hamiltonians, though the corresponding adiabatic surfaces seem to be nearly identical, results in pronounced differences. The possible consequences for the dynamics of realistic systems with higher dimensionality are briefly discussed.


Unusual human lymphoma phenotype defined by monoclonal antibody.
The phenotype of three large cell (histiocytic) lymphomas of man has been defined with convential lymphocyte surface marker techniques, a panel of monoclonal antisera of hybridoma derivation (Ortho Pharmaceutical Corp.), and the fluorescence microscope. Two tumors exhibited surface IgG of lambda light-chain type, whereas the third was negative for surface Ig but contained the same Ig in the cytoplasm. With the monoclonal antisera, all three were found to bear two surface antigens (OKT9 and OKT10) previously described on early thymocytes, and were devoid of the Ia antigen. The available knowledge suggests that these neoplasms represent the expansion of a clone of B lymphocytes along the pathway that leads to plasma cell differentiation rather than a clone with both B and T surface membrane markers.


Eye movements and visual encoding during scene perception.
The amount of time viewers could process a scene during eye fixations was varied by a mask that appeared at a certain point in each eye fixation. The scene did not reappear until the viewer made an eye movement. The main finding in the studies was that in order to normally process a scene, viewers needed to see the scene for at least 150 ms during each eye fixation. This result is surprising because viewers can extract the gist of a scene from a brief 40- to 100-ms exposure. It also stands in marked contrast to reading, as readers need only to view the words in the text for 50 to 60 ms to read normally. Thus, although the same neural mechanisms control eye movements in scene perception and reading, the cognitive processes associated with each task drive processing in different ways.


Mutations in the RSPO1 coding region are not the main cause of canine SRY-negative XX sex reversal in several breeds.
This report details a case of SRY-negative XX sex reversal in a mixed breed dog and surveys affected dogs of several breeds for mutations in RSPO1 coding regions. Genomic DNA from the mixed breed case was evaluated for mutations in candidate genes. Sequencing identified a homozygous G to A transition in RSPO1 exon 4 that changes a highly conserved amino acid codon in the thrombospondin domain. The possibility that this was a single nucleotide polymorphism (SNP) could not be excluded by genotyping family members. Therefore, the coding region of RSPO1 was sequenced in a survey of affected dogs, which identified a T to C transition (exon 3) in some, the above G to A transition (exon 4) in others, and no change in the remaining affected dogs. Genotypes at these base pair positions were not uniquely associated with the affected phenotype in any breed, indicating the identified transitions are most likely SNPs, not causative mutations for this canine disorder. However, the possibility that polymorphisms play a modifier role, such as changing threshold or severity of phenotypic expression in a mixed breed dog, cannot be excluded. This study emphasizes the importance of canine pedigree, breed, and population studies in evaluating candidate mutations.


Anti-inflammatory and antioxidant properties of jervine, a sterodial alkaloid from rhizomes of Veratrum album.
Veratrum, hellebore is an important plant species of the Liliaceae family and jervine is the characteristic steroidal alkaloid constituent of Veratrum album. In the current study, anti-inflammatory and antioxidant effects of jervine isolated from NH4OH-benzene extract of V. album rhizomes were investigated on CAR induced paw edema in rats. In inflammatory study, 50, 100, 200 and 400 mg/kg doses of jervine, 25 mg/kg doses of DIC and IND were orally administered, and the volume of the foots were measured up to their knee arthrosis by plethismometer. After one hour of the oral administration of the all treatments, 0.1 ml of CAR solution (1%) was injected into the foot of the all rat groups and the volume of the foots were measured during 5 h after CAR injection. GPx, SOD, GR, MPO, CAT enzymes activities and GSH, LPO levels of the supernatants of paw homogenates and inflammation biomarkers such as TNF-α and IL-1β in the rats serums were also estimated. According to the present results, jervine exerted 50.4-73.5% anti-inflammatory effects in carrageenan induced paw edema. Inflammation biomarkers such as TNF-α, IL-1β and MPO that increased by CAR injection were suppressed by the administrations of all doses of jervine, IND and DIC. In all paw tissues, LPO levels as indicator of oxidative tissue damage were found to be high in CAR-treated group and it was found to be decreased in all doses of jervine. Jervine, DIC and IND reduced the negative effects of CAR due to increasing effects on the SOD, CAT, GSH, GPx and GR antioxidants.


Flexibility in starting posture drives flexibility in kinematic behavior of the kinethmoid-mediated premaxillary protrusion mechanism in a cyprinid fish, Cyprinus carpio.
Premaxillary protrusion in cypriniform fishes involves rotation of the kinethmoid, an unpaired skeletal element in the dorsal midline of the rostrum. No muscles insert directly onto the kinethmoid, so its rotation must be caused by the movement of other bones. In turn, the kinethmoid is thought to push on the ascending processes of the premaxillae, effecting protrusion. To determine the causes and effects of kinethmoid motion, we used XROMM (x-ray reconstruction of moving morphology) to measure the kinematics of cranial bones in common carp, Cyprinus carpio. Mean kinethmoid rotation was 83 deg during premaxillary protrusion (18 events in 3 individuals). The kinethmoid rotates in a coordinated way with ventral translation of the maxillary bridge, and this ventral translation is likely driven primarily by the A1β muscle. Analyses of flexibility (variability between behaviors) and coordination (correlation between bones within a behavior) indicate that motion of the maxillary bridge, not the lower jaw, drives premaxillary protrusion. Thus, upper jaw protrusion is decoupled from lower jaw depression, allowing for two separate modes of protrusion, open mouth and closed mouth. These behaviors serve different functions: to procure food and to sort food, respectively. Variation in starting posture of the maxilla alone dictates which type of protrusion is performed; downstream motions are invariant. For closed mouth protrusion, a ventrally displaced maxillary starting posture causes kinethmoid rotation to produce more ventrally directed premaxillary protrusion. This flexibility, bestowed by the kinethmoid-maxillary bridge-A1β mechanism, one of several evolutionary novelties in the cypriniform feeding mechanism, may have contributed to the impressive trophic diversity that characterizes this speciose lineage.


Predictive factors for generalized seizures after deliberate citalopram overdose.
Seizures are a recognized complication of citalopram overdose. The present study sought to establish risk factors for seizures in this high-risk patient group, including stated dose ingested, co-ingested drugs or ethanol, and electrolyte disturbances. A retrospective casenote review was carried out of patients who attended the Emergency Department due to citalopram overdose between January 2000 and July 2007 inclusive. Stepwise logistic regression analysis considered age, gender, stated citalopram dose, acute ethanol consumption, co-ingested drugs, administration of activated charcoal, and hyponatraemia. There were 241 patients (177 women), and the median (interquartile range) stated citalopram dose was 300 mg (200 to 600 mg). Generalized seizures occurred in 18 patients (7.5%). Logistic regression analysis found co-ingested tricyclic antidepressants or venlafaxine predicted seizures with odds ratio = 15 (95% confidence interval 3, 75). In the absence of co-ingested drugs, the minimum citalopram dose associated with seizures was 400 mg. Odds ratio for seizures = 1.1 (95% confidence interval 1.0, 1.2) for every 100 mg increment in citalopram dose. Seizures were associated with a greater need for invasive ventilatory support, higher creatine kinase activity, and prolonged hospital stay. Generalized seizures are an important manifestation of citalopram toxicity, and cannot be explained solely by electrolyte disturbances or co-ingestion of other drugs or ethanol. The strongest predictors of seizures in this patient series were ingestion of high citalopram dosages and co-ingestion of drugs capable of lowering seizure threshold.


Developing an Intuitive Graph Representation of Knowledge for Nonpharmacological Treatment of Psychotic Symptoms in Dementia.
Applying person-centered, nonpharmacological interventions to manage psychotic symptoms of dementia is promoted for health care professionals, particularly gerontological nurses, who are responsible for care of older adults in nursing homes. A knowledge graph is a graph consisting of a set of concepts that are linked together by their interrelationship and has been widely used as a formal representation of domain knowledge in health. However, there is lack of a knowledge graph for nonpharmacological treatment of psychotic symptoms in dementia. Therefore, we developed a comprehensive, human- and machine-understandable knowledge graph for this domain, named Dementia-Related Psychotic Symptom Nonpharmacological Treatment Ontology (DRPSNPTO). This graph was built by adopting the established NeOn methodology, a knowledge graph engineering method, to meet the quality standards for biomedical knowledge graphs. This intuitive graph representation of the domain knowledge sets a new direction for visualizing and computerizing gerontological knowledge to facilitate human comprehension and build intelligent aged care information systems. [Journal of Gerontological Nursing, 48(4), 49-55.].


Addressing the Ethical Challenges of Providing Kidney Failure Care for Children: A Global Stance.
Children with kidney failure require kidney replacement therapy (KRT), namely maintenance dialysis and kidney transplant. Adequate kidney failure care consists of KRT or conservative treatment with palliative care. In the context of kidney failure, children depend on parents who are their surrogate decision-makers, and the pediatric nephrology team for taking decisions about KRT or conservative care. In this paper, we discuss the ethical challenges that arise relating to such decision-making, from a global perspective, using the framework of pediatric bioethics. While many ethical dilemmas in the care of children with KRT are universal, the most significant ethical dilemma is the inequitable access to KRT in low & middle income countries (LMICs) where rates of morbidity and mortality depend on the family's ability to pay. Children with kidney failure in LMICs have inadequate access to maintenance dialysis, timely kidney transplant and palliative care compared to their counterparts in high income countries. Using case vignettes, we highlight how these disparities place severe burdens on caregivers, resulting in difficult decision-making, and lead to moral distress among pediatric nephrologists. We conclude with key action points to change this status-quo, the most important being advocacy by the global pediatric nephrology community for better access to affordable kidney failure care for children.


Signatures of irreversibility in microscopic models of flocking.
Flocking in d=2 is a genuine nonequilibrium phenomenon for which irreversibility is an essential ingredient. We study a class of minimal flocking models whose only source of irreversibility is self-propulsion and use the entropy production rate (EPR) to quantify the departure from equilibrium across their phase diagrams. The EPR is maximal in the vicinity of the order-disorder transition, where reshuffling of the interaction network is fast. We show that signatures of irreversibility come in the form of asymmetries in the steady-state distribution of the flock's microstates. These asymmetries occur as consequences of the time-reversal symmetry breaking in the considered self-propelled systems, independently of the interaction details. In the case of metric pairwise forces, they reduce to local asymmetries in the distribution of pairs of particles. This study suggests a possible use of pair asymmetries both to quantify the departure from equilibrium and to learn relevant information about aligning interaction potentials from data.


Serine/threonine kinase of Mpox virus: computational modeling and structural analysis.
Kinases catalyze phosphoryl transfer from a nucleoside triphosphate (usually ATP) to an amino acid on a protein for activation purposes. Although kinases are well-appreciated drug targets in different viruses and cancers, these enzymes in poxviruses received limited attention from the research community. In poxvirus, the production of infectious particles in the infected cells depends on a serine/threonine protein kinase (STK) that activates proteins implicated in the assembly of new virions. This work aimed to elucidate the structure and dynamics of the major kinase STK from Mpox virus (Orthopoxvirus). A state-of-the-art computational approach was employed to decipher the structure and dynamics of the STK using AlphaFold2 and molecular dynamics (MD) simulations. Although the predicted structure showed an atypical kinase, the overall structural fold is conserved. Binding free energy calculations via Molecular Mechanics/Generalized Born and Surface Area (MM/GBSA) determined the hotspot residues contributing to binding of ATP. The structural analysis in this work provides insights into the structure and behavior of STK in Mpox virus and possibly its closest members of Poxviridae. These findings also set the basis for setting up a thorough experimental investigation to understand the enzymatic mechanism, peptide substrate binding, and the development of small-molecule inhibitors against this kinase.Communicated by Ramaswamy H. Sarma.


Age-specific changes in sex steroid biosynthesis and sex development.
Normal male sex development requires the SRY gene on the Y chromosome, the regression of Müllerian structures via anti-Müllerian hormone (AMH) signalling, the development of the Wolffian duct system into normal male internal genital structures consequent to testosterone secretion by the testicular Leydig cells, and finally, sufficient activation of testosterone to dihydrotestosterone by 5alpha-reductase. All these events take place during weeks 8-12 of gestation, a narrow window of sexual differentiation. Recent studies in human fetal development have demonstrated the early fetal expression of the adrenocorticotrophic hormone (ACTH) receptor and all steroidogenic components necessary for the biosynthesis of cortisol. These findings provide compelling evidence for the assumed pathogenesis of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, diminished feedback to the pituitary due to glucocorticoid deficiency, subsequent ACTH excess, and up-regulation of adrenal androgen production with subsequent virilization. Another CAH variant, P450 oxidoreductase deficiency, manifests with 46,XX disorder of sex development (DSD), i.e., virilized female genitalia, despite concurrently low circulating androgens. This CAH variant illustrates the existence of an alternative pathway toward the biosynthesis of active androgens in humans which is active in human fetal life only. Thus CAH teaches important lessons from nature, providing privileged insights into the window of human sexual differentiation, and particularly highlighting the importance of steroidogenesis in the process of human sexual differentiation.


External quality assessment of serum alpha-fetoprotein assays.
Adequate control of performance in immunoassays of maternal serum alpha-fetoprotein is an essential part of screening for neural tube defects. Information derived from external quality assessment schemes may be of limited value in monitoring individual laboratory performance and stresses the need for proper internal quality control.


Dissociative experiences and anger proneness in late adolescent females with different attachment styles.
The study examined the relationships among dissociative experiences, anger proneness, and attachment styles in late adolescent females. One hundred sixty-two college students (mean age = 17.5 years) were assessed using the Dissociative Experience Scale (DES), the State-Trait Anger Expression Inventory (STAXI), and the Adult Attachment Questionnaire (AAQ), a self-report tool for assessing attachment styles (avoidant, secure, and ambivalent-resistant) in close relationships of youths and adults. Significant correlations were obtained between DES scores (total and factorial) and STAXI scores (State Anger, Trait Anger, Anger/In, and Anger/Expression), confirming in a nonclinical sample the connection between anger proneness and dissociation described in patients with dissociative disorders. Insecure females, particularly ambivalent ones, scored higher on the DES, supporting van der Kolk's hypothesis of an inverse relationship between secure attachment and dissociative tendency. Moreover, insecurely attached females showed more anger proneness, with some differences between ambivalent and avoidant types. Further research should be conducted to examine these relationships in males, as well as to clarify the role of insecure attachment in anger management and the recourse to dissociation in late adolescence as a protective response to trauma and emotional distress.


A Carbazole-Derived Nitroxide That Is an Analogue of Cytidine: A Rigid Spin Label for DNA and RNA.
A variety of semirigid and rigid spin labels comprise a valuable arsenal for measurements of biomolecular structures and dynamics by electron paramagnetic resonance (EPR) spectroscopy. Here, we report the synthesis and characterization of rigid spin labels Ċ and Ċm for DNA and RNA, respectively, that are carbazole-derived nitroxides and analogues of cytidine. Ċ and Ċm were converted to their phosphoramidites and used for their incorporation into oligonucleotides by solid-phase synthesis. Analysis of Ċ and Ċm by single-crystal X-ray crystallography verified their identity and showed little deviation from planarity of the nucleobase. Analysis of the continuous-wave (CW) EPR spectra of the spin-labeled DNA and RNA duplexes confirmed their incorporation into the nucleic acids and the line-shape was characteristic of rigid spin labels. Circular dichroism (CD) and thermal denaturation studies of the Ċ-labeled DNAs and Ċm-labeled RNAs indicated that the labels are nonperturbing of duplex structure.


The progenitor state is maintained by lysine-specific demethylase 1-mediated epigenetic plasticity during Drosophila follicle cell development.
Progenitors are early lineage cells that proliferate before the onset of terminal differentiation. Although widespread, the epigenetic mechanisms that control the progenitor state and the onset of differentiation remain elusive. By studying Drosophila ovarian follicle cell progenitors, we identified lysine-specific demethylase 1 (lsd1) and CoRest as differentiation regulators using a GAL4∷GFP variegation assay. The follicle cell progenitors in lsd1 or CoRest heterozygotes prematurely lose epigenetic plasticity, undergo the Notch-dependent mitotic-endocycle transition, and stop dividing before a normal number of follicle cells can be produced. Simultaneously reducing the dosage of the histone H3K4 methyltransferase Trithorax reverses these effects, suggesting that an Lsd1/CoRest complex times progenitor differentiation by controlling the stability of H3K4 methylation levels. Individual cells or small clones initially respond to Notch; hence, a critical level of epigenetic stabilization is acquired cell-autonomously and initiates differentiation by making progenitors responsive to pre-existing external signals.


Measuring cancer care coordination: development and validation of a questionnaire for patients.
Improving the coordination of cancer care is a priority area for service improvement. However, quality improvement initiatives are hindered by the lack of accurate and reliable measures of this aspect of cancer care. This study was conducted to develop a questionnaire to measures patients' experience of cancer care coordination and to assess the psychometric properties of this instrument. Questionnaire items were developed on the basis of literature review and qualitative research involving focus groups and interviews with cancer patients, carers and clinicians. The draft instrument was completed 686 patients who had been recently treated for a newly diagnosed cancer, including patients from metropolitan, regional and rural areas of New South Wales, Australia. To assess test-retest reliability, 119 patients completed the questionnaire twice. Unreliable items those with limited variability or high levels of missing data were eliminated. Exploratory factor analysis was conducted to define the underlying factor structure of the remaining items and subscales were constructed. Correlations between these and global measures of the experience of care coordination and the quality of care were assessed. Of 40 items included in the draft questionnaire, 20 were eliminated due to poor test-retest reliability (n = 4), limited response distributions (n = 8), failure to load onto a factor (n = 7) or detrimental effect on the internal consistency of the scale (n = 1). The remaining 20 items loaded onto two factors named 'Communication' and 'Navigation', which explained 91% of the common variance. Internal consistency was with high for the instrument (Cronbach's alpha 0.88) and each subscale (Cronbach's alpha 0.87 and 0.73 respectively). There was no apparent 'floor' or 'ceiling' effect for the total score or the Communication subscale, but evidence of a ceiling effect for the Navigation subscale with 21% of respondents achieving the highest possible score. There were moderate positive associations between the total score and global measures of care coordination (r = 0.57) and quality of care (r = 0.53). The instrument developed in this study demonstrated consistency and robust psychometric properties. It may provide a useful tool to measure patients' experience of cancer care coordination in future surveys and intervention studies.


The Effectiveness of Compression Garments for Reducing Pain in Non-Vascular Ehlers-Danlos Syndromes: A Prospective Observational Cohort Study.
Patients with Ehlers-Danlos Syndrome (EDS) frequently suffer from severe chronic pain. We carried out an observational cohort study to assess the effectiveness of compression garments (CGs) for reducing this pain. Patients with non-vascular EDS were given custom-made Cerecare® CGs during a visit to a specialist clinic (visit V0). They were followed up over 2 years with visits every 6 months (V1-V4). At each visit, pain was assessed for the joints treated with CGs using a visual analogue scale (VAS; 0-100 mm). Additional measures were obtained to assess neuropathic pain (painDETECT questionnaire), proprioception/balance (Berg Balance Scale), and functional independence, amongst others. Data were analyzed for 67 patients with EDS (hypermobile: 91%; classical: 6%; kyphoscoliotic: 3%). For the most painful joint, the mean VAS rating was 71.5 ± 22.8 mm at V0; this decreased to 53.5 ± 25.5 mm at V1 and 45.7 ± 29 mm at V4 (t-tests: p < 0.0001). From V0 to V4, improvements were also seen for pain at the other joints, neuropathic pain, functional independence, proprioception/balance, and the incidence of sprains and dislocations/subluxations, although not all comparisons were statistically significant (p < 0.05 level). These results indicate that CGs may effectively reduce the pain and joint instability in non-vascular EDS patients.


EGFR protein overexpression and gene amplification in squamous cell carcinomas of the esophagus.
Overexpression of epidermal growth factor receptor (EGFR) is observed in many cancers, sometimes accompanied by gene amplification. Recently, several clinical therapies targeting EGFR were developed, but the eligibility criteria for these therapies is not fully established. To develop such eligibility criteria for esophageal squamous cell carcinoma (ESCC), we sought to clarify: (i) the exact frequency of EGFR overexpression, (ii) the relationship between protein overexpression and gene amplification, (iii) the relationship between gene amplification and specific gene mutations and (iv) the correlation between the status of EGFR and clinical or pathological features. Immunohistochemistry revealed that EGFR protein is overexpressed in 53 (50%) of the 106 ESCC examined. Fluorescence in situ hybridization (FISH) indicated clear EGFR gene amplification in 15 of the 53 tumors, somewhat higher EGFR copy in 32 cases, and no increase in 6 cases. Gene amplification was significantly associated with high level overexpression. Direct sequencing of exons 19 and 21 of EGFR revealed no mutations in 15 tumors exhibiting gene amplification, and no mutations in 25 tumors not exhibiting gene amplification. Overexpression of EGFR was significantly correlated with depth of invasion of the tumor. In conclusion, anti-EGFR therapies may be appropriate for patients with ESCC. We assume that combined analyses by immunohistochemistry/FISH would clarify aberrations in protein and gene function, and could help to identify those patients who may benefit from anti-EGFR therapy.


Bifunctional Enzyme JMJD6 Contributes to Multiple Disease Pathogenesis: New Twist on the Old Story.
Jumonji domain-containing protein 6 (JMJD6) is a non-heme Fe(II) 2-oxoglutarate (2OG)-dependent oxygenase with arginine demethylase and lysyl hydroxylase activities. Its initial discovery as a dispensable phosphatidylserine receptor (PSR) in the cell membrane of macrophages for phagocytosis was squashed by newer studies which revealed its nuclear localization and bifunctional enzymatic activity. Though its interaction with several nuclear and cytoplasmic target proteins has been demonstrated, the exact mechanisms and clinical significance of these various biologic interplays are not yet well established. Recent investigations have shed the light on the multiple pathways by which JMJD6 can regulate cell proliferation and cause tumorigenesis. Clinically, JMJD6 has been associated with more aggressive and metastatic disease, poorer prognosis, and lower overall survival rates-particularly in lung colon and oral cancers. JMJD6 is a novel biomarker for predicting future disease outcomes and is a target for new therapeutic treatments in future studies. Aberrant expression and dysregulation of JMJD6 are implicated in various other processes such as impaired T-cell proliferation and maturation, inoculation, and virulence of foot-and-mouth disease virus (FMDV), and impaired methylation of innate immunity factor. This article reviews the association of JMJD6 with various pathological processes-particularly, its role in tumorigenesis and virological interactions.


Straightforward access to α-thiocyanoketones and thiazoles from sulfoxonium ylides.
Efficient, versatile, and metal-free strategies for synthesizing α-thiocyanoketones and thiazoles from β-ketosulfoxonium ylides and ammonium thiocyanate have been described. Due to its simplicity, benign reaction conditions, excellent chemoselectivity, and high yield, this method represents a unique approach for divergent synthesis. Finally, the potential value of the developed methods is demonstrated via large-scale reactions and synthesis of Fanetizole, an anti-inflammatory drug.


Cigarette smoking and the treatment of angina with propranolol, atenolol, and nifedipine.
To determine whether cigarette smoking affects the results of drug treatment for angina, we studied 10 cigarette smokers with angina who were given placebo, nifedipine (60 mg per day), propranolol (240 mg per day), and atenolol (100 mg per day), each for one week. The four-week double-blind study was repeated with the same randomly determined order of drug sequences, after all 10 subjects had stopped smoking. Before and after the subjects stopped smoking, all three drugs significantly reduced the frequency of angina, as measured with angina diaries, and improved the results of maximal exercise testing and 48-hour ambulatory monitoring of ST segments (P less than 0.01). However, during the nonsmoking phase of the study, there was an overall decline in the frequency of angina and an improvement in performance on exercise testing (P less than 0.05) as compared with the smoking period, although the results of 48-hour ambulatory monitoring remained unchanged. The improvement after patients stopped smoking was greater during treatment with nifedipine than during administration of the other two drugs or placebo. Blood levels of propranolol were increased when patients stopped smoking; levels of nifedipine and atenolol were unchanged. Our data show that smoking had direct and adverse effects on the heart and interfered with the efficacy of all three anti-anginal drugs, but with nifedipine the most.


Broad-spectrum enhanced absorption of graphene-molybdenum disulfide photovoltaic cells in metal-mirror microcavity.
The optical absorption of graphene-molybdenum disulfide photovoltaic cells (GM-PVc) in wedge-shaped metal-mirror microcavities (w-MMCs) combined with a spectrum-splitting structure was studied. Results showed that the combination of spectrum-splitting structure and w-MMC can enable the light absorption of GM-PVcs to reach about 65% in the broad spectrum. The influence of processing errors on the absorption of GM-PVcs in w-MMCs was 3-14 times lower than that of GM-PVcs in wedge photonic crystal microcavities. The light absorption of GM-PVcs reached 60% in the broad spectrum, even with the processing errors. The proposed structure is easy to implement and may have potentially important applications in the development of ultra-thin and high-efficiency solar cells and optoelectronic devices.


[Development of a new delayed healing model of an open skin wound and effects of M-1011G (ointment gauze containing 5% lysozyme hydrochloride) on the model].
We tried to develop a new delayed healing model of an open wound made on the dorsal skin of a rat by inducing malnutrition with restriction of food intake. We determined the effects of a newly introduced ointment gauze containing 5% lysozyme hydrochloride (M-1011G) on this model. Malnutrition characterized by a decrease in body weight and serum protein was produced by restricting the daily intake of commercially available food to 6 g for 2 weeks without liver disturbance and thereafter maintained with food intake of 12 g/day. Under these conditions, healing of the open wound made on the dorsal skin was prolonged, as compared with that of the wound made on a well-nourished animal. In this model, statistical studies showed that M-1011G was the most effective in accelerating the reduction of the wound area and shortening of the time required for the complete healing, among the following treatments: sterilized gauze alone, ointment gauze alone and 5% lysozyme hydrochloride-containing emulsified ointment. Histological findings showed that M-1011G greatly accelerated the granulation of this tissue which is essential for wound healing, probably due to stimulation of epidermization and regenerated granulation in the wound.


New Rebek imide-type receptors for adenine featuring acetylene-linked pi-stacking platforms.
Rebek imide-type molecular clefts with pi-stacking platforms attached to the imide scaffold by an acetylene linker have been prepared by Sonogashira cross-coupling. In the solid state, a novel dimerisation mode for this class of imide receptors was found by crystal structure analysis, whereas efficient 1 : 1 complexation with 9-ethyladenine was observed in CDCl3 solution.


Fitness effects of a selfish gene (the Mus t complex) are revealed in an ecological context.
In wild house mice, genes linked to the t transmission distortion complex cause meiotic drive by sabotaging wild-type gametes. The t complex is consequently inherited at frequencies higher than 90%. Yet, for unclear reasons, in wild mouse populations this selfish DNA is found at frequencies much lower than expected. Here, we examine selection on the t complex in 10 seminatural populations of wild mice based on data from 234 founders and nearly 2000 progeny. Eight of the 10 populations decreased in t frequency over one generation, and the overall frequency of t haplotypes across all 10 populations was 48.5% below expectations based on transmission distortion and 34.3% below Mendelian (or Hardy-Weinberg) expectations. Behavioral and reproductive data were collected for 10 months for each population, and microsatellite genotyping was performed on seven of the populations to determine parentage. These combined data show t-associated fitness declines in both males and females. This is the first study to show evidence for a reduction in the ability of +/t males to maintain territories. Because females tend to mate with dominant males, impairment of territorial success can explain much of the selection against t observed in our populations. In nature, selection against heterozygote carriers of the t complex helps solve the puzzlingly low t frequencies found in wild populations. This ecological approach for determining fitness consequences of genetic variants has broad application for the discovery of gene function in general.


Structural Characterization of Mannoglucan Isolated from Ophiocordyceps sobolifera and Its Antioxidant Activities.
A novel polysaccharide structure (PS-T80) was collected from Ophiocordyceps sobolifera biomass and characterized via a combination of chemical and spectral analyses. Employing high-performance gel permeation chromatography (HPGPC), the average molecular weight is proven to be 7.4 × 104 Da. Furthermore, a sugar composition analysis of the obtained polysaccharide suggests two main sugars, β-d-glucose and α-d-mannose, at a molar ratio of 2:1, respectively, in the backbone. The structure analysis unveils that PS-T80 is a mannoglucan, possessing the repeating unit of [→3)-β-d-Glcp-(1 → 3)-α-d-Manp-(1 → 3)-β-d-Glcp-(1→] n . Such a configuration could be considered a novel polysaccharide. Impressively, in vitro antioxidant tests revealed that PS-T80 has a promising antioxidant activity. These results demonstrate that the obtained PS is a potential bioactive material for biomedical applications.


The management of recurrent inguinal hernias by muscle transposition--a preliminary communication.
Recurrent inguinal hernias occur almost exclusively in adult men. The rarity of both direct and recurrent hernias in women is due, among other factors, to the muscularity of an inguinal canal that has not been partially replaced by fibrous tissue to allow the passage of a large spermatic cord. Throughout the body, contractile dynamic muscular tissue resists strains and stresses better than do fascia and ligaments. With regard to the abdominal wall, herniation through this muscular corset is a rare event and herniations nearly always occur through areas in which fibrous tissue has replaced muscle. When the tissues of a recurrent hernia or the type of hernia preclude a satisfactory repair, transposition of a thigh muscle, preferably the gracilis, will provide a dynamic repair that is superior to the introduction of foreign material with all its disadvantages or to the other approaches when local conditions are unsatisfactory. Clinical experience with seven procedures in six patients is presented as a preliminary report.


Monitoring adherence and abstinence of cannabis use disorder patients: Profile identification and relationship with long-term treatment outcomes.
Patients with cannabis use disorder (CUD) show heterogeneous sociodemographic and consumption patterns. Although previous studies, focused on identifying subgroups of CUD patients using input variables, have yielded useful results for planning individualized treatments, no published research has analyzed the profiles of CUD patients according to their therapeutic progress. This study therefore aims to identify subgroups of patients using adherence and abstinence indicators and to explore whether these profiles are associated with sociodemographic characteristics, consumption variables, and long-term therapeutic outcomes. This was a retrospective observational study with a multisite sample of 2055 CUD outpatients who were beginning treatment. The study monitored patient data at two-year follow-up. We conducted latent profiles analysis on the appointment attendance ratio and percentage of negative cannabis tests. A three profile solution emerged: i) moderate abstinence/moderate adherence (n = 997); ii) high abstinence/moderate adherence (n = 613); and iii) high abstinence/high adherence (n = 445). The study found the most marked differences at the beginning of treatment for education level (chi2 (8) = 121.70, p < .001), source of referral (chi2 (12) = 203.55, p < .001), and frequency of cannabis use (chi2 (10) = 232.39, p < .001). Eighty percent of patients from the "high abstinence/high adherence" group were relapse-free at two year follow-up. This percentage decreased to 24.3 % in the "moderate abstinence/moderate adherence" group. Research has shown adherence and abstinence indicators to be useful for identifying subgroups of patients with different prognoses regarding long-term success. Recognizing the sociodemographic and consumption variables associated with these profiles at the beginning of treatment could help to inform the design of more individualized interventions.


Rh immune globulin: an interfering substance in compatibility testing.
Immunoglobulin therapy that interferes with pretransfusion testing may complicate the interpretation of test results and adversely affect patient management. Rh immune globulin (RhIG) should be considered an interfering immunoglobulin therapy when it is detected in an antibody detection test of a sample from a patient who has been treated with RhIG. Frequently, detection occurs in mother's or newborn's plasma. Because an antenatal injection of RhIG is indicated for pregnant Rh-negative women, anti-D is detected frequently by today's highly sensitive antibody screen methods when the mother's plasma is tested subsequently at delivery. Ascertaining the source of anti-D is complicated by the inability of routine clinical laboratory methods to distinguish anti-D due to RhIG from alloimmune anti-D. A combination of qualitative and quantitative test methods, as well as a complete clinical history, is necessary for accurate diagnosis and patient management.


Apoptotic pathways in ischemic acute renal failure.
The study of cell death has emerged as an important and exciting area of research in cell biology. Although two kinds of cell death, apoptosis and necrosis, are recognized, one of the major advances in our understanding of cell death has been the recognition that the pathways traditionally associated with apoptosis may be very critical in the form of cell injury associated with necrosis. Renal tubular epithelial cell injury from ischemia has been generally regarded as a result of necrotic form of cell death. We briefly describe recent evidence indicating that pathways generally associated with apoptosis, including endonuclease activation, role of mitochondria and caspases, are important in renal tubular injury. It is likely that the cascades that lead to apoptotic or necrotic mode of cell death are activated almost simultaneously and may share some common pathways.


Reply to the 'Comment on "Spectroscopic properties and location of the Ce3+ energy levels in Y3Al2Ga3O12 and Y3Ga5O12 at ambient and high hydrostatic pressure"' by Y. Wang, M. Głowacki, M. Berkowski, A. Kamińska and A. Suchocki, Phys. Chem. Chem. Phys., 2019, 21, DOI.
New results presented by Wang et al. showing the temperature dependence of the Y3Ga5O12:Ce3+ energy bandgap have been taken into account in the calculations of the changes of the energy distance between the lowest 5d state of Ce3+ and the edge of the conduction band. Our calculations show that the diminishing of the band gap energy with temperature has a negligible effect on the difference between the energy of the conduction band and the localized states of the 5d configuration of Ce3+, which means that the new experimental results do not undermine the validity of the conclusions of our previous paper.


Curdione inhibits proliferation of MCF-7 cells by inducing apoptosis.
Curdione, one of the major components of Curcuma zedoaria, has been reported to possess various biological activities. It thus might be a candidate anti-flammatory and cancer chemopreventive agent. However, the precise molecular mechanisms of action of curdione on cancer cells are still unclear. In this study, we investigated the effect of curdione on breast cancer. Xenograft nude mice were used to detect the effect of curdione on breast cancer in vivo; we also tested the effect of curdione on breast cancer in vitro by MTT, Flow cytometry, JC-I assay, and western blot. Firstly, we found that curdione significantly suppressed tumor growth in a xenograft nude mouse breast tumor model in a dose-dependent manner. In addition, curdione treatment inhibited cell proliferation and induced cell apoptosis. Moreover, after curdione treatment, increase of impaired mitochondrial membrane potential occurred in a concentration dependent manner. Furthermore, the expression of apoptosis-related proteins including cleaved caspase-3, caspase-9 and Bax was increased in curdione treatment groups, while the expression of the anti-apoptotic Bcl-2 was decreased. Inhibitors of caspase-3 were used to confirm that curdione induced apoptosis. Overall, our observations first suggested that curdione inhibited the proliferation of breast cancer cells by inducing apoptosis. These results might provide some molecular basis for the anti-cancer activity of curdione.


Modification of the Assessment of Life Habits (LIFE-Hm) to consider personalized satisfaction with participation in activities and roles: results from a construct validity study with older adults.
Participation, defined as a person's involvement in activities and roles, is a primary intervention goal in rehabilitation. To achieve client-centered practice, rehabilitation professionals need to go beyond objective accomplishment criteria and consider satisfaction with and the importance of participation in activities and roles. To our knowledge, no instrument considers accomplishment, satisfaction and importance of activities and roles, and allows numerical scoring and comparison. The objectives of this study were to modify the Assessment of Life Habits questionnaire (LIFE-Hm) to consider personalized satisfaction (satisfaction weighted by importance) with participation in activities and roles, and to: (1) examine its convergent validity with quality of life (QOL) and (2) compare the associations between QOL on the one hand and, satisfaction (LIFE-H) and personalized satisfaction (LIFE-Hm) with participation on the other. A descriptive cross-sectional study was conducted with 84 older adults, average age 76 years, with different functional autonomy levels. Quality of life was associated with personalized satisfaction for all categories of activities and roles (r = 0.45 to 0.75; p < 0.001). These associations differed significantly from the associations with satisfaction for the "housing", "mobility" and "responsibilities" categories (p = 0.04 to 0.0047). This study found good construct validity of the LIFE-Hm with QOL. Personalization can add value in achieving client-centered practice. Implications for Rehabilitation The LIFE-Hm becomes the first instrument available in English and French that allows comparison between individuals and informs rehabilitation professionals about the level of accomplishment, satisfaction and personalized satisfaction with participation in activities and roles. Personalized satisfaction can add value in achieving client-centered practice as it considers not only how satisfying activities and roles are for the person, but also the importance that these activities and roles have for her/him. The LIFE-Hm offers the advantage of systematically identifying activities and roles which are not satisfactory but are important for the client and have the potential to be improved (lower accomplishment level).


Antibiotic prophylaxis in neurosurgery. A randomized controlled trial.
A randomized trial was performed to support the contention that prophylactic antibiotics can reduce the incidence of postoperative neurosurgical wound infections. The regime outlined by Malis was followed. Vancomycin and gentamicin were administered systemically just prior to surgery and streptomycin was added to the irrigating solution. Patients were randomly assigned to two groups: control and treated. The infection rate in the control group was 3.5% and in the treated group 0.5%.


The biogenesis and function of eukaryotic porins.
Like most other mitochondrial proteins porin is synthesized in the cytosol and imported posttranslationally into the outer mitochondrial membrane. This transport follows the general rules for mitochondrial protein import with a few aberrations: a) porin contains an uncleaved NH2-terminal signal sequence, b) also its carboxyterminus might be involved in the import process, and c) this transport does not seem to require a membrane potential delta psi, although it is ATP-dependent. Most likely the actual import step occurs at contact sites between the outer and the inner mitochondrial membrane and involves at least one receptor protein. Although porin is known to be the major gate through the outer mitochondrial membrane, its absence only causes transient respiratory problems in yeast cells. This could mean a) that there is a bypass for some mitochondrial functions in the cytosol and/or b) that there are alternative channel proteins in the outer membrane. The first idea is supported by the overexpression of cytosolic virus-like particles in yeast cells lacking porin and the second by the occurrence of residual pore activity in mitochondrial outer membrane purified from porinless mutant cells.


Tsukamurella spumae sp. nov., a novel actinomycete associated with foaming in activated sludge plants.
A polyphasic taxonomic study was undertaken to establish the taxonomic position of six representative strains isolated from activated sewage sludge foam. The organisms were found to have chemical and morphological properties consistent with their assignment to the genus Tsukamurella. DNA:DNA relatedness studies showed that five out of the six isolates formed a distinct genomic species, the remaining strain was most closely associated with this taxon. The five isolates had a unique phenotypic profile that served to distinguish them from representatives of the validly described species of Tsukamurella. The combination of the genotypic and phenotypic data indicated that the five strains should be classified as a new species in the genus Tsukamurella. The name proposed for this taxon is Tsukamurella spumae, the type strain is N1171T (= DSM 44.113T = NCIMB 13947T). It was also shown that some of the reference strains were misclassified as Tsukamurella paurometabola.


Study of GePb photodetectors for shortwave infrared detection.
Ge0.998Pb0.002 photodetectors (PDs) with a GePb layer grown on n-type Ge (100) substrate by magnetron sputtering epitaxy were fabricated by complementary metal-oxide semiconductor (CMOS)-compatible technology. For Ge0.998Pb0.002 PDs, the room-temperature dark current density at -1 V was 3.3 A/cm2. At room temperature, the GePb PDs demonstrated a longwave cutoff of 2.5 μm and the optical responsivities of GePb PDs ranging from 1500 nm to 2000 nm were measured. A temperature dependence optical characterization of these detectors was conducted and temperature-dependent energy bandgaps of Ge0.998Pb0.002 were derived from the photocurrent spectra.


Controllable coordination-driven self-assembly: from discrete metallocages to infinite cage-based frameworks.
CONSPECTUS: Nanosized supramolecular metallocages have a unique self-assembly process that allows chemists to both understand and control it. In addition, well-defined cavities of such supramolecular aggregates have various attractive applications including storage, separation, catalysis, recognition, drug delivery, and many others. Coordination-driven self-assembly of nanosized supramolecular metallocages is a powerful methodology to construct supramolecular metallocages with considerable size and desirable shapes. In this Account, we summarize our recent research on controllable coordination-driven assembly of supramolecular metallocages and infinite cage-based frameworks. To this end, we have chosen flexible ligands that can adopt various conformations and metal ions with suitable coordination sites for the rational design and assembly of metal-organic supramolecular ensembles. This has resulted in various types of metallocages including M3L2, M6L8, M6L4, and M12L8 with different sizes and shapes. Because the kinds of metal geometries are limited, we have found that we can replace single metal ions with metal clusters to alternatively increase molecular diversity and complexity. There are two clear-cut merits of this strategy. First, metal clusters are much bigger than single metal ions, which helps in the construction and stabilization of large metallocages, especially nanosized cages. Second, metal clusters can generate diverse assembly modes that chemists could not synthesize with single metal ions. This allows us to obtain a series of unprecedented supramolecular metallocages. The large cavities and potential unsaturated coordination sites of these discrete supramolecular cages offer opportunities to construct infinite cage-based frameworks. This in turn can offer us a new avenue to understand self-assembly and realize certain various functionalities. We introduce two types of infinite cage-based frameworks here: cage-based coordination polymers and cage-based polycatenanes, which we can construct through coordination bonds and mechanical bonds, respectively. Through either directly linking the unsaturated coordination sites of metallocages or replacing the labile terminal ligands with bridging ligands, we can produce infinite cage-based frameworks based on coordination bonds. We introduce several interesting cage-based coordination polymers, including a single-crystal-to-single-crystal transformation from a M6L8 cage to an infinite cage-based chain. Compared with discrete metallocages, these kinds of materials can give us higher structural stability and complexity, favoring the applications of metallocages. In addition, we discuss how we can use mechanical bonds, such as interlocking and interpenetrating, to construct extended cage-based frameworks. So far, study in this field has focused on polycatenanes constructed from M6L4 and M12L8 cages, as well as a controllable and dynamic self-assembly based on M6L4 metallocages. We also discuss cage-based polycatenanes, which can give dynamic properties to discrete metallocages. We hope that our investigations will bring new insights to the world of the supramolecular metallocages by enlarging its breadth and encourage us to devote more effort to this blossoming field in the future.


Affinity mode of capillary isoelectric focusing for the characterization of the biotin-binding protein actinavidin.
Different modes of capillary isoelectric focusing (CIEF) with salt mobilization and zwitterionic additive to cathodic mobilizer were applied to characterize the biotin-binding protein actinavidin and its affinity properties. The analysis is performed in a neutral coated capillary with completely eliminated electroosmotic flow. Synthetic pI standards with absorption in the visible region were used in all runs and pI determinations were based on a fitted nonlinear calibration graph. CIEF of highly purified actinavidin in native conditions was revealed in about 12 peaks in pI range 6.2-7.5, with three major forms having pI 6.80, 6.86, 6.90. CIEF of a mixture of actinavidin and increasing concentrations of two affinity ligands (biotin and biotinylated oligonucleotide) demonstrated drastic changes in the number of protein isoforms. In the latter case it resulted in only one peak (pI 5.05) when the ligand was in excess. This method, which can be named affinity CIEF, was found to be well-suited for studying structural changes, occurring in receptor proteins upon binding with a ligand. CIEF of the protein, performed under denaturing conditions (6 M urea in a solution of carrier ampholytes) is also reported. It was revealed in three isoforms with a pI more acidic than that of native actinavidin. It is demonstrated that careful selection of denaturing conditions was necessary for the reproducible results.


Glutaminyl-peptide gamma-glutamyltransferase dependence of the uptake of trypsin-alpha-macroglobulin complexes by macrophages.
The canine alpha-macroglobulin 125I-trypsin complexes were prepared and exposed to canine alveolar macrophages. The binding of the complexes to cells was time- and dose-dependent. A rapid uptake and degradation of the bound complexes was evidenced by the finding of less than 20% cell-bound radioactivity after a 4 h incubation at 20 degrees C. The canine alveolar macrophages contain a glutaminyl-peptide gamma-glutamyltransferase which shows slightly retarded agarose gel electrophoretic mobility as compared to the respective enzymes from tissues of other species, such as guinea pig and man. Evidence is presented that the binding and degradation of trypsin alpha-macroglobulin complexes by macrophages is dependent on this gamma-glutamyltransferase. Monodansylthiacadaverine, a strong inhibitor of this enzyme, blocks the binding of trypsin-alpha-macroglobulin complexes to macrophages and (probably as a consequence of this) degradation of the complexes. Furthermore, this gamma-glutamyltransferase is a calcium-dependent enzyme and the process of binding trypsin-alpha-macroglobulin complexes to the macrophages was likewise found to be calcium-dependent.


Copy-Pasting in Patients' Electronic Medical Records (EMRs): Use Judiciously and With Caution.
An electronic medical record (EMR) is an electronic, comprehensive, and up-to-date compilation of a patient's medical history and information stored in a secure digital format. It provides real-time access to patient data, enabling healthcare providers to make informed decisions quickly and accurately. EMR systems streamline a patient's healthcare journey and enable shared care across the medical practice. By providing a comprehensive view of a patient's medical history, EMRs can be invaluable tools for physicians and healthcare providers, allowing them to collaborate more effectively and provide better care. Additionally, EMRs can help reduce paperwork, improve accuracy, and increase efficiency, ultimately leading to improved patient outcomes. The true potential of EMR systems can be realized when they are used in conjunction with evidence-based medicine methodologies, quality improvement initiatives, and team-based care. This combination of technologies and practices can revolutionize healthcare delivery, improving patient outcomes, greater efficiency, and cost savings. "Copy-pasting" is an essential feature of EMR systems, with physicians relying on it for up to 35.7% of their workflow. By leveraging the copy-pasting feature of their EMR system, physicians can ensure that their data capture is accurate and timely, leading to better patient care. Copy-pasting can be a valuable tool for physicians, saving time and allowing them to focus on practical clinical issues. However, it is essential to note that while most clinicians copy-paste, 25% of them believe it can lead to a high frequency of medical errors, with the potential for a significant number of errors being attributed to this practice. Therefore, physicians must exercise caution when copy-pasting and take the necessary steps to ensure accuracy and reduce the risk of errors. Copy-pasting can cause severe adverse patient events by introducing new inaccuracies, rapidly spreading inaccurate or outdated information, leading to discordant notes, and creating long notes that mask essential clinical information. Despite these risks, copy-pasting has become widely used in EMRs. Additionally, copy-pasting can reduce the time spent on documentation, allowing healthcare providers to focus more on patient care. Inappropriate copy-pasting can have serious consequences, such as compromising data integrity, endangering patient safety, increasing costs, and even leading to fraudulent malpractice claims. In conclusion, copy-pasting can be helpful for healthcare professionals, but it must be used cautiously. Proper education and safeguards should be implemented to ensure accuracy and up-to-date patient data. Additionally, healthcare professionals should be aware of the legal implications of copy-pasting, as it may be considered a form of medical malpractice. With the proper precautions, copy-pasting can be a safe and efficient way to save time and reduce errors in patient records.


Has translational genomics come of age in Africa?
The rapid increase in genomics research in Africa and the growing promise of precision public health (PPH) begs the question of whether African genomics has come of age and is being translated into improved healthcare for Africans. An assessment of the continent's readiness suggests that genetic service delivery remains limited and extremely fragile. The paucity of data on mutation profiles for monogenic disorders and lack of large genome-wide association cohorts for complex traits in African populations is a significant barrier, coupled with extreme genetic variation across different regions and ethnic groups. Data from many different populations are essential to developing appropriate genetic services. Of the proposed genetic service delivery models currently used in Africa-Uncharacterized, Limited, Disease-focused, Emerging and Established-the first three best describe the situation in most African countries. Implementation is fraught with difficulties related to the scarcity of an appropriately skilled medical genetic workforce, limited infrastructure and processes, insufficient health funding and lack of political support, and overstretched health systems. There is a strong nucleus of determined and optimistic clinicians and scientists with a clear vision, and there is a hope for innovative solutions and technological leapfrogging. However, a multi-dimensional approach with active interventions to stimulate genomic research, clinical genetics and overarching healthcare systems is needed to reduce genetic service inequalities and accelerate PPH on the continent. Human and infrastructure capacity development, dedicated funding, political will and supporting legislation, and public education and awareness, are critical elements for success. Africa-relevant genomic and related health economics research remains imperative with an overarching need to translate knowledge into improved healthcare. Given the limited data and genetic services across most of Africa, the continent has not yet come of 'genomics' age.


Effects of pancuronium and vecuronium on plasma levels of immunoglobulins, IgG, IgM and IgE, in patients undergoing minor gynaecological surgery.
1. The effects of two competitive neuromuscular blocking agents, pancuronium and vecuronium, on plasma levels of immunoglobulins, IgG, IgM and IgE, were studied and compared, using the ELISA assay, in patients undergoing minor gynaecological surgery. 2. The results showed that neither pancuronium (0.1 mg/kg) nor vecuronium (0.1 mg/kg) had any significant effect on IgG, IgM and IgE levels in these patients. However, the underlying trend was that both pancuronium and vecuronium slightly increased the IgG and IgM levels, (by 19.5%, 22.1%, of control IgG, and by 17.3%, 28.8% of control IgM, respectively), with vecuronium being more effective than pancuronium). In addition, pancuronium, but not vecuronium, also slightly increased the IgE levels (by 5.9% of control IgE). Vecuronium, on the other hand, slightly decreased the IgE level (by 4.9% of control IgE). However, these increases or decreases were not statistically significant. 3. The significance of the present results are discussed in relation to changes in immunoglobulins and adverse effects induced by drugs, such as muscle relaxants.


Therapeutic Potential of Exosomes Derived From circRNA_0002113 Lacking Mesenchymal Stem Cells in Myocardial Infarction.
Exosomes are participated in the pathogenesis of cardiovascular diseases and can be secreted by mesenchymal stem cells (MSCs). However, the effects of circRNA, delivered by exosomes derived from MSCs, on myocardial injury remain unclear. Hence, this study aims to explore the therapeutic potential of exosomes derived from circRNA_0002113 lacking MSCs in the treatment of myocardial injury in vitro and in vivo. Our results reveal that exosomes derived from circRNA_0002113 lacking MSCs decreased cell apoptosis in anoxia-reoxygenation (A/R) model cells, and reduced myocardial injury by inhibiting nuclear translocation of RUNX1 in vitro and in vivo. Moreover, miR-188-3p, which targets RUNX1 in cardiomyocytes was also found to interact with circRNA_0002113. In conclusion, exosomes derived from circRNA_0002113 lacking MSCs could suppress myocardial infarction by sponging miR-188-3p to regulate RUNX1 nuclear translocation. The circRNA_0002113/miR-188-3p/RUNX1 axis mediated alleviation of apoptosis serves as a novel strategy to treat myocardial I/R injury.


A neutralization epitope in the hepatitis C virus E2 glycoprotein interacts with host entry factor CD81.
The identification of a specific immunogenic candidate that will effectively activate the appropriate pathway for neutralizing antibody production is fundamental for vaccine design. By using a monoclonal antibody (1H8) that neutralizes HCV in vitro, we have demonstrated here that 1H8 recognized an epitope mapped between residues A524 and W529 of the E2 protein. We also found that the epitope residues A524, P525, Y527 and W529 were crucial for antibody binding, while the residues T526, Y527 and W529 within the same epitope engaged in the interaction with the host entry factor CD81. Furthermore, we detected "1H8-like" antibodies, defined as those with amino acid-specificity similar to 1H8, in the plasma of patients with chronic HCV infection. The time course study of plasma samples from Patient H, a well-characterized case of post-transfusion hepatitis C, showed that "1H8-like" antibodies could be detected in a sample collected almost two years after the initial infection, thus confirming the immunogenicity of this epitope in vivo. The characterization of this neutralization epitope with a function in host entry factor CD81 interaction should enhance our understanding of antibody-mediated neutralization of HCV infections.


Direction-sensitive detection of a spinning object using dual-frequency vortex light.
Rotational Doppler effect (RDE) has attracted much attention in recent years which opens new avenues to angular velocity measurement. However, most previous studies used single-frequency vortex light as the detection beam so that the rotational Doppler signal is in the low frequency domain where most of noise signals exist. In this article, we use the dual-frequency 2-fold multiplexed vortex light as the probe beam and transform the Doppler signals from the low frequency domain to the high frequency domain successfully. The results show hardly any noise compared with the measurement in the low frequency domain. More importantly, the direction of rotation can be obtained directly by comparing the modulated signal and the reference signal. Our work demonstrates a new detection method for the RDE and provides a reference for its practical application.


Directed evolution of the promiscuous esterase activity of carbonic anhydrase II.
A promiscuous activity of an existing enzyme can confer an evolutionary advantage by providing an immediate response to a new selection pressure and a starting point for the divergence of a new enzyme. This work seeks to examine how this process might take place. Human carbonic anhydrase II (hCAII) is an enzyme that evolved to catalyze the reversible hydration of CO(2) and performs this task at a remarkable rate (k(cat) approximately 10(6) s(-)(1)). hCAII also exhibits promiscuous activity toward highly activated esters such as 4-nitrophenyl acetate. We describe a much weaker esterase activity of hCAII toward the bulkier and much less activated ester substrate 2-naphthyl acetate (2NA). Directed evolution of hCAII produced a variant with 40-fold higher rates toward 2NA, owing to two mutations: one within the active site (Ala65Val) and one at its mouth (Thr200Ala). Structure-activity studies suggest that these mutations led to adaptation of the active site for bulkier substrates and for the catalysis of nonactivated esters. The mutations did not, however, significantly alter the native activity of hCAII. Our results support the notion that the evolution of a new function can be driven by mutations that increase a promiscuous function (which serves as the starting point for the evolutionary process) but do not harm the native function.


Transfer of Extracellular Vesicle-Associated-RNAs Induces Drug Resistance in ALK-Translocated Lung Adenocarcinoma.
Anaplastic lymphoma kinase (ALK) translocation is an actionable mutation in lung adenocarcinoma. Nonetheless tumour consists of heterogeneous cell subpopulations with diverse phenotypes and genotypes, and cancer cells can actively release extracellular vesicles (EVs) to modulate the phenotype of other cells in the tumour microenvironment. We hypothesized that EVs derived from a drug-resistant subpopulation of cells could induce drug resistance in recipient cells. We have established ALK-translocated lung adenocarcinoma cell lines and subclones. The subclones have been characterized and the expression of EV-RNAs determined by quantitative polymerase chain reaction. The effects of EV transfer on drug resistance were examined in vitro. Serum EV-RNA was assayed serially in two patients prescribed ALK-tyrosine kinase inhibitor (ALK-TKI) treatment. We demonstrated that the EVs from an ALK-TKI-resistant subclone could induce drug resistance in the originally sensitive subclone. EV-RNA profiling revealed that miRNAs miR-21-5p and miR-486-3p, and lncRNAs MEG3 and XIST were differentially expressed in the EVs secreted by the resistant subclones. These circulating EV-RNA levels have been found to correlate with disease progression of EML4-ALK-translocated lung adenocarcinoma in patients prescribed ALK-TKI treatment. The results from this study suggest that EVs released by a drug-resistant subpopulation can induce drug resistance in other subpopulations and may sustain intratumoural heterogeneity.


Evaluating intensive care unit medication charges in a teaching hospital in Jordan.
Background: Intensive Care Unit (ICU) medication costs contribute to a large portion of the total ICU costs. Evaluating ICU drug expenditures is essential for optimal resource use especially in countries with limited resources. Considering the dearth of data regarding ICU medication expenses in the Middle East, we sought to evaluate ICU medication charges at a large academic hospital in Jordan. Methods: ICU drug charges were extracted from the hospital administration database at King Abdullah University Hospital for 2014-2015 fiscal years (FYs). ICU drug charges were compared to non-ICU drug charges that were incurred during the same patient admissions. ICU medications with the most significant charges were identified. The most frequent diagnoses with the highest ICU medication charges were described. Results: Average ICU medication charges per day were approximately twice that of non-ICU medication charges ($121.5 versus $55.7 in 2014 and $100.2 versus $52.2 in 2015; p < 0.001 in both FYs). Meropenem and human albumin were the most expensive ICU medications. Drug charge allocation was most expensive for sepsis, motor vehicle accidents and respiratory failure. Conclusion: Drug charges in the ICU are considerably higher than non-ICU drug charges, thus requiring more vigilant cost containment approaches. Further research is needed to evaluate the appropriateness of expensive ICU medications.


A phenomenological study on older persons as a breadwinner of A skipped-generation family: day by day coping journey in Thai context.
Purpose: Many countries around the world are facing an ageing society in which older persons share the fate of carrying a burden in their families, especially in skipped-generation families. This increasing trend has noted over the past several years in Thailand. This is an interpretive phenomenological study that seeks to explore Thai older grandparents' life experience of raising grandchildren in skipped-generation families.Methods: The participants were purposively selected from older grandparents in skipped-generation families in the Northeast of Thailand in 2019. Data were collected by in-depth interviews with 29 participants. Data were analysed using Diekelmann & Allen method.Results: Three major themes emerged regarding the Thai older persons as a breadwinner of a skipped-generation family were as follows. 1) Sacrifice for the family is a value of life. 2) Day by day coping journey of individuals maintains mental well-being. 3) Being grandparents leads to spiritual pride.Conclusion: The older grandparents suffered from a variety of burden and vulnerability beyond their abilities. Social and governmental supporting systems are limited. Creating supporting system strategy is required to increase well-being of grandparents in skipped-generation families.


Toward carbon monoxide based therapeutics: carbon monoxide in a pill.
As one of the three known gasotransmitters, carbon monoxide (CO) has demonstrated therapeutic potential against a wide range of human diseases. However, development of CO as a therapeutic agent is severely impeded, primarily due to the lack of pharmaceutically acceptable delivery forms of CO. Gaseous CO may only have limited utility under carefully controlled clinical environment. As a result, there have been efforts in developing metal-based CO-releasing molecules and organic CO-releasing molecules that require light activation. We are interested in developing CO prodrugs, which are metal free and release CO spontaneously under physiological conditions without light irradiation. In this review, we summarize progress in this area with a focus on a recent patent and related publications.


Phylogenetic relationships among highly virulent Newcastle disease virus isolates obtained from exotic birds and poultry from 1989 to 1996.
Newcastle disease virus [NDV (avian paramyxovirus type 1 [APMV1])] isolates were recovered from imported exotic birds confiscated following importation into the United States, from waterbirds in the United States, and from poultry. The exotic birds probably originated from Central and South America, Asia, and Africa. The NDV isolates were initially characterized as highly virulent because of a short mean death time in embryonated chicken eggs. The isolates were typed as neurotropic or viscerotropic velogenic by intracloacal inoculation of adult chickens. Intracerebral pathogenicity index values for the virulent NDV isolates ranged from 1.54 to 1.90, compared to a possible maximum value of 2.0. These isolates had a dibasic amino acid motif in the fusion protein cleavage site sequence required for host systemic replication. Sequence differences were detected surrounding the fusion protein cleavage site and the matrix protein nuclear localization signal, indicating evolution of highly virulent NDV. Phylogenetically, these isolates were categorized with other highly virulent NDV strains that caused outbreaks in southern California poultry during 1972 and in cormorants in the north central United States and southern Canada during 1990 and 1992. These isolates are related to NDV that may have the APMV1 strain chicken/Australia/AV/32 or a related virus as a possible progenitor. Recent virulent NDV isolates and those recovered during disease outbreaks since the 1970s are phylogenetically distinct from current vaccine viruses and standard challenge strains.


Deleted in liver cancer 2 (DLC2) suppresses cell transformation by means of inhibition of RhoA activity.
The deleted in liver cancer 2 (DLC2) gene, located at chromosome 13q12.3, is a recently identified tumor suppressor gene. The gene is frequently underexpressed in human hepatocellular carcinoma, and its chromosomal region shows frequent deletion. DLC2 encodes a unique RhoGTPase-activating protein (RhoGAP) specific for small RhoGTPases, RhoA, and Cdc42. With bioinformatic analysis, we have identified four different isoforms of DLC2, which we named DLC2alpha, DLC2beta, DLC2gamma, and DLC2delta. Three of the isoforms contain the RhoGAP domain, namely, DLC2alpha, DLC2beta, and DLC2gamma. Ectopic expression of these three isoforms in mouse fibroblasts showed cytoplasmic localization. Of interest, overexpression of these isoforms suppressed the lysophosphatidic acid-induced stress fiber formation in mouse fibroblasts and changed the morphology of the transfected cells from angular and spindle to round. Furthermore, the RhoA pull-down assay demonstrated a remarkable reduction in RhoA activity in the DLC2 transiently transfected cells. In contrast, cells transfected with inactive DLC2 GAP-mutant remained unchanged in cell morphology, actin stress fiber formation, and RhoA activity. HepG2 hepatoma cells stably transfected with the DLC2gamma isoform also changed to a round morphology, as in mouse fibroblasts. Of significance, these DLC2gamma stable transfectants showed marked suppression in cell proliferation, motility, and transformation, and there was a remarkable reduction in in vivo RhoA activity in these cells. These results suggest that DLC2 exhibits its tumor suppressor functions in vivo as a GAP specific for RhoA, exerting its effects in suppression of cytoskeleton reorganization, cell growth, cell migration, and transformation.


Takayasu's arteritis occurring under TNF-α blockers: a new paradoxical effect?
Takayasu's arteritis (TA) is a rare granulomatous vasculitic disease. Recently, experimental studies and several case reports have supported the use of anti-tumour necrosis factor (TNF) therapy for severe forms of TA. We report a case of a 58-year-old woman who was followed for spondyloarthritis. Her disease was resistant to non-steroidal anti-inflammatory drugs, and TNF-α blockers were initiated. The patient developed asthaenia and severe back pain. The erythrocyte sedimentation rate was 82 mm and C reactive protein was 192 mg/L. Based on thickened walls of large vessel on MRI, a diagnosis of TA was established. Under corticosteroids and after discontinuation of TNF-α blockers, the patient remained free of symptoms at 8-month follow-up.


Long-Term Results of Hemiarthroplasty Compared With Arthrodesis for Osteoarthritis of the First Metatarsophalangeal Joint.
If operative treatment is opted for grade 3 and 4 osteoarthritis of the first metatarsophalangeal joint, arthrodesis is considered the standard of care. However, if preservation of joint mobility is preferred, implant arthroplasty could be favored. Previous studies have suggested hemiarthroplasty might result in less pain, better function, and greater patient satisfaction compared with arthrodesis. However, these studies only evaluated short-term results (range 2.2 to 6.6 years). The aim of our study was to determine whether patients treated with hemiarthroplasty would show better postoperative outcomes compared with those treated with arthrodesis after ≥5 years after surgery. The American Orthopaedic Foot and Ankle Society hallux metatarsophalangeal interphalangeal (AOFAS-HMI) scale score was used as the primary outcome measure. Secondary outcomes addressed satisfaction rates, patient procedure recommendation, and number of unplanned repeat surgical procedures. We also addressed the influence of the procedures on daily activities (work and sports), the influence of smoking on the postoperative results, and the costs for both procedures. A total of 47 primary arthrodeses and 31 hemiarthroplasties performed between January 2005 and December 2011 were evaluated. After a mean follow-up period of 8.3 (range 5 to 11.8) years, the mean AOFAS-HMI scale score after arthrodesis and hemiarthroplasty was 72.8 ± 14.5 and 89.7 ± 6.6, respectively (p = .001). The patients were significantly more pleased after hemiarthroplasty (p < .001), and this procedure was recommended more often (p < .001). The number of unplanned repeat surgical procedures did not differ between the 2 groups. Patients resumed sports activities significantly sooner after hemiarthroplasty (p = .002). The overall crude costs were similar for both procedures. Our results have shown more favorable postoperative outcomes for hemiarthroplasty compared with arthrodesis as operative treatment of osteoarthritis of the first metatarsophalangeal joint after a mean follow-up period of 8.3 years.


A mutation in the prion protein gene in Creutzfeldt-Jakob disease in Jewish patients of Libyan, Greek, and Tunisian origin.
A modified host protein encoded by the gene specifying the scrapie amyloid precursor is critically involved in the pathogenesis of transmissible spongiform encephalopathies such as Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker's syndrome, and Kuru. A mutation in the open reading frame of this gene was recently described in a cluster of patients with CJD in Slovakia. This mutation at codon 200 changes glutamic acid coded by GAG to lysine coded by AAG. We examined the prevalence of this mutation in the cluster of patients with CJD among Sephardic Jews of Libyan descent in Israel. A polymerase chain reaction was used to amplify the open reading frame of the prion protein gene from DNA extracted from frozen brain tissue of five Israeli residents (four of Libyan and one of Greek origin) and two familial cases in Jews born in Greece and Tunisia who later emigrated to France. The existence of the codon 200 mutation was detected by digestion of the open reading frame fragments with the BsmA1 restriction enzyme. All patients had the same codon 200 mutation. These findings implicate this mutation in the high prevalence of CJD among Libyan and Sephardic Jews from other Mediterranean countries.


DNA methylation 101: what is important to know about DNA methylation and its role in SLE risk and disease heterogeneity.
SLE is a complex autoimmune disease that results from the interplay of genetics, epigenetics and environmental exposures. DNA methylation is an epigenetic mechanism that regulates gene expression and tissue differentiation. Among all the epigenetic modifications, DNA methylation perturbations have been the most widely studied in SLE. It mediates processes relevant to SLE, including lymphocyte development, X-chromosome inactivation and the suppression of endogenous retroviruses. The establishment of most DNA methylation marks occurs in utero; however, a small percentage of epigenetic marks are dynamic and can change throughout a person's lifetime and in relation to exposures. In this review, we discuss the current understanding of the biology of DNA methylation and its regulators, the measurement and interpretation of methylation marks, the effects of genetics on DNA methylation and the role of environmental exposures with relevance to SLE. We also summarise research findings associated with SLE disease risk and heterogeneity. The robust finding of hypomethylation of interferon-responsive genes in patients with SLE and new associations beyond interferon-responsive genes such as cell-specific methylation abnormalities are described. We also discuss methylation changes associated with lupus nephritis, autoantibody status and disease activity. Lastly, we explore future research directions, emphasising the need for longitudinal studies, cell tissue and context-specific profiling, as well as integrative approaches. With new technologies, DNA methylation perturbations could be targeted and edited, offering novel therapeutic approaches.


Serological and physicochemical reactivity of bovine erythrocytes before and after trypsin treatment.
On partition in aqueous polymer two-phase systems containing dextran, poly(ethyleneglycol) (PEG), and PEG substituted with charged or hydrophobic groups "inagglutinable" ox erythrocytes showed more negative surface charge and less hydrophobicity than "agglutinable" ox erythrocytes. Tryspin treatment of the erythrocytes increased the agglutinability, reduced the negative charge, and seemed to increase the liability to hydrophobic interaction. Haemagglutination of highly negatively charged ox erythrocytes is almost impossible to accomplish by antibody against the ox erythrocytes alone or against IgG antigen linked to the erythrocytes in passive haemagglutination. Likewise, reverse passive (antiglobulin) haemagglutination cannot be accomplished with these cells when immunoglobulin antigens of moderate molecular size (less than or equal to 900,000) are used. However, these cells may be agglutinated when a non-charged carrier such as a bacterium coated with sensitizing antibody (immunoglobulin) is used to bridge the antiglobulin-coupled erythrocytes in a mixed latticer aggllutinate. Such a bridging can also be accomplished by heat aggregation of the immunoglobulin antigen.