Cautious application of pleural N-terminal pro-B-type natriuretic peptide in diagnosis of congestive heart failure pleural effusions among critically ill patients.
Several studies on diagnostic accuracy of pleural N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) for effusions from congestive heart failure (CHF) conclude that pleural NT-pro-BNP is a useful biomarker with high diagnostic accuracy for distinguishing CHF effusions. However, its applicability in critical care settings remains uncertain and requires further investigations. NT-proBNP was measured in pleural fluid samples of a prospective cohort of intensive care unit patients with pleural effusions. Receiver operating characteristic curve analysis was performed to determine diagnostic accuracy of pleural NT-proBNP for prediction of CHF effusions. One hundred forty-seven critically ill patients were evaluated, 38 (26%) with CHF effusions and 109 (74%) with non-CHF effusions of various causes. Pleural NT-proBNP levels were significantly elevated in patients with CHF effusions. Pleural NT-pro-BNP demonstrated the area under the curve of 0.87 for diagnosing effusions due to CHF. With a cutoff of 2200 pg/mL, pleural NT-proBNP displayed high sensitivity (89%) but moderate specificity (73%). Notably, 29 (27%) of 109 patients with non-CHF effusions had pleural NT-proBNP levels >2200 pg/mL and these patients were more likely to experience septic shock (18/29 vs. 10/80, P<0.001) or acute kidney injury (19/29 vs. 9/80, P<0.001). Among critically ill patients, pleural NT-proBNP measurements remain a useful diagnostic aid in evaluation of pleural effusions. However, patients with non-CHF effusions may exhibit high pleural NT-proBNP concentrations if they suffer from septic shock or acute kidney injury. Accordingly, it is suggested that clinical context should be taken into account when interpreting pleural NT-proBNP values in critical care settings.


Separator Decoration with Cobalt/Nitrogen Codoped Carbon for Highly Efficient Polysulfide Confinement in Lithium-Sulfur Batteries.
A macro-/mesoporous Co-N-C-decorated separator is proposed to confine and reutilize migrating polysulfides. Endowed with a desirable structure and synchronous lithio- and sulfiphilic chemistry, the macro-/mesoporous Co-N-C interface manipulates large polysulfide adsorption uptake, enabling good polysulfide adsorption kinetics, reversible electrocatalysis toward redox of anchored polysulfides, and facile charge transport. It significantly boosts the performance of a simple 70 wt % S/MWCNTs (MWCNTs=multi-walled carbon nanotubes) cathode, achieving high initial capacities (e.g., 1406 mAh g-1 at 0.2C, 1203 mAh g-1 at 1C), nearly 100 % Coulombic efficiencies, and high reversible capacities after cycle tests (e.g., 828.4 mAh g-1 at 1C after 100 cycles) at both low and high current rates. These results demonstrate that decorating separator with macro-/mesoporous Co-N-C paves a feasible way for developing advanced Li-S batteries.


Noncovalent functionalization of boron nitride nanotubes with poly(p-phenylene-ethynylene)s and polythiophene.
Boron nitride nanotubes (BNNTs) are functionalized and solubilized in organic solvents such as chloroform, methylene chloride, and tetrahydrofuran by using conjugated poly(p-phenylene ethynylene)s (PPEs) (polymers A and B) and polythiophene (polymer C) via a noncovalent functionalization approach through strong pi-pi stacking interactions between the conjugated polymers and BNNTs. The functionalization of BNNTs with PPEs enhanced planarization of PPEs with red shifts in both absorbance and emission of the composite materials with reference to free PPEs, whereas the functionalization of BNNTs with polythiophene disrupts the pi-conjugation, resulting in blue shifts in both the absorption and emission of the composite material.


Roger T. Kelleher, behavior analyst.
Roger T. Kelleher, rightly known as one of the foremost contributors to behavioral pharmacology, also made many important contributions to the experimental analysis of behavior. He participated significantly in the development of the discipline, through both his research and his editorial contributions to thisjournal. This article summarizes his contributions to the field of behavior analysis. His most significant empirical and conceptual contributions to behavior analysis came in two domains-conditioned reinforcement and the power of schedules of reinforcement. His accomplishments in these two domains still serve as principal foundations for modern research and theory.


A framework for integrated environmental health impact assessment of systemic risks.
Traditional methods of risk assessment have provided good service in support of policy, mainly in relation to standard setting and regulation of hazardous chemicals or practices. In recent years, however, it has become apparent that many of the risks facing society are systemic in nature - complex risks, set within wider social, economic and environmental contexts. Reflecting this, policy-making too has become more wide-ranging in scope, more collaborative and more precautionary in approach. In order to inform such policies, more integrated methods of assessment are needed. Based on work undertaken in two large EU-funded projects (INTARESE and HEIMTSA), this paper reviews the range of approaches to assessment now in used, proposes a framework for integrated environmental health impact assessment (both as a basis for bringing together and choosing between different methods of assessment, and extending these to more complex problems), and discusses some of the challenges involved in conducting integrated assessments to support policy. Integrated environmental health impact assessment is defined as a means of assessing health-related problems deriving from the environment, and health-related impacts of policies and other interventions that affect the environment, in ways that take account of the complexities, interdependencies and uncertainties of the real world. As such, it depends heavily on how issues are selected and framed, and implies the involvement of stakeholders both in issue-framing and design of the assessment, and to help interpret and evaluate the results. It is also a comparative process, which involves evaluating and comparing different scenarios. It consequently requires the ability to model the way in which the influences of exogenous factors, such as policies or other interventions, feed through the environment to affect health. Major challenges thus arise. Chief amongst these are the difficulties in ensuring effective stakeholder participation, in dealing with the multicausal and non-linear nature of many of the relationships between environment and health, and in taking account of adaptive and behavioural changes that characterise the systems concerned.


Significance of class 1 and class 2 major histocompatibility complex antigens: help to allogeneic K and D antigens does not involve I recognition.
The significance of the dichotomy of MHC antigens was investigated. It was determined that primed helpers directed against allogeneic class 1 antigens (K and D in the mouse) were not restricted to syngeneic class 2 antigens (I in the mouse). Furthermore, the generation of helper T cell-replacing factor by stimulation with K or D antigens was not blocked by Ia antibodies that were effective in blocking the same factors generated in response to I region MHC antigens. It is concluded that class 2 antigens are not recognized during the response of helpers to class 1 antigens, and it is suggested that class 1 and class 2 molecules can perform reciprocal functions.


Analytic evaluation of nonadiabatic coupling terms at the MR-CI level. I. Formalism.
An efficient and general method for the analytic computation of the nonandiabatic coupling vector at the multireference configuration interaction (MR-CI) level is presented. This method is based on a previously developed formalism for analytic MR-CI gradients adapted to the use for the computation of nonadiabatic coupling terms. As was the case for the analytic energy gradients, very general, separate choices of invariant orbital subspaces at the multiconfiguration self-consistent field and MR-CI levels are possible, allowing flexible selections of MR-CI wave functions. The computational cost for the calculation of the nonadiabatic coupling vector at the MR-CI level is far below the cost for the energy calculation. In this paper the formalism of the method is presented and in the following paper [Dallos et al., J. Chem. Phys. 120, 7330 (2004)] applications concerning the optimization of minima on the crossing seam are described.


Imaging Lysosomal pH Alteration in Stressed Cells with a Sensitive Ratiometric Fluorescence Sensor.
The organelle-specific pH is crucial for cell homeostasis. Aberrant pH of lysosomes has been manifested in myriad diseases. To probe lysosome responses to cell stress, we herein report the detection of lysosomal pH changes with a dual colored probe (CM-ROX), featuring a coumarin domain with "always-on" blue fluorescence and a rhodamine-lactam domain activatable to lysosomal acidity to give red fluorescence. With sensitive ratiometric signals upon subtle pH changes, CM-ROX enables discernment of lysosomal pH changes in cells undergoing autophagy, cell death, and viral infection.


Gender Differentials and Disease-Specific Cause of Infant Mortality: A Case Study in an Urban Hospital in Accra, Ghana.
Infant mortality is a major public health problem especially in developing countries. It is an indicator of quality of and accessibility to primary healthcare as well as the overall health status of a country. Understanding the risk factors for infant mortality is the first important step to reducing its incidence/prevalence. This study examined the prevalence and disease-specific causes of infant mortality in an urban hospital in Ghana and gender differences in the burden of infant mortality. Births and deaths data at the hospital were reviewed and analyzed. Results indicated infant mortality of 32/1000 live births and highlighted malaria, severe anemia, and neonatal sepsis as the leading causes of infant deaths. Gender differences in infant mortality was not statistically significant (X2; P-value=0.73). It is critical to strengthen existing malaria control programs for infants and develop targeted interventions to improve infant nutrition for high risk infants.


Oxidative stress and hypoxia: implications for plasminogen activator inhibitor-1 expression.
Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of urokinase-type and tissue-type plasminogen activators. It has gained special interest among clinicians because a number of pathological conditions, such as myocardial infarction, atherosclerosis, thrombosis, several types of cancer, and the metabolic syndrome, as well as type 2 diabetes mellitus, are associated with increased PAI-1 levels. Interestingly, a number of these diseases are also accompanied by oxidative stress and the enhanced production of reactive oxygen species or tissue hypoxia. This article tries to summarize some aspects leading to enhanced PAI-1 production under oxidative stress or hypoxia.


Violence among young men: the importance of a gender-specific developmental approach to adolescent male suicide and homicide.
Suicide and homicide are much more commonly committed by adolescent males than females. Herein, a proposal in favor of gender-specific understanding and approach to these violent behaviors is presented. Social and healthcare service system factors, including issues of male adolescents' access to care and help-seeking behaviors, are reviewed alongside the epidemiology of adolescent suicide and homicide as a transition into a detailed discussion of the putative biological factors at play. An emphasis upon the male androgen testosterone organizes the discussion. Behavioral manifestations of this brain-based organizational model are presented with a focus on impulsivity, aggression, and externalizing dysregulated emotionality. Treatment considerations and implications are developed.


SLC6A4 expression and anti-proliferative responses to serotonin transporter ligands chlomipramine and fluoxetine in primary B-cell malignancies.
B-cell lines of diverse neoplastic origin express the serotonin transporter (SERT/SLC6A4) and growth arrest in response to SERT-ligands, including the antidepressants chlomipramine and fluoxetine. Here we detail SLC6A4 transcript (Q-PCR) and protein (FACS) expression in primary cells from patients with: chronic lymphocytic leukaemia; mantle cell lymphoma; follicular lymphoma; Burkitt's lymphoma; and diffuse large B-cell lymphoma. The ability of the SERT-binding antidepressants to impact the growth of these cells when sustained on CD154-transfected fibroblasts was also determined. The results reveal a broad spectrum of primary B-cell malignancies expressing SLC6A4 with a proportion additionally displaying growth arrest on SERT-ligand exposure.


Stacking for nonaqueous capillary electrophoresis.
Nonaqueous capillary electrophoresis (NACE) is a useful mode in CE for separation and quantification of hydrophobic compounds. However, because of the low conductivity of most of the organic solutions, stacking is not used often in this technique and the sample volume is very limited. As a result of the small sample volume, the detection limits are poor. Furthermore, NACE is affected greatly by the presence of salts in the sample. Here, we show that transient isotachophoresis (t-ITP) can be used easily in this type of electrophoresis to enhance the detection limits and also to reverse the deleterious effects of salts in the sample. Several factors, which affect the stacking in this type of electrophoresis, are described. For example, the presence of salts in the organic solvent, type of sample introduction, and the solvent for the terminating ion were all found to have profound effects on the degree of concentration. Furthermore, the separation time can be shortened by t-ITP.


SUBRETINAL ENDOSCOPIC SURGERY TO TREAT LARGE SUBRETINAL HEMORRHAGES SECONDARY TO AGE-RELATED MACULAR DEGENERATION.
To evaluate the potential of subretinal endoscopic surgery as a novel treatment for large subretinal hemorrhage secondary to age-related macular degeneration. Five patients with large subretinal hemorrhage secondary to age-related macular degeneration underwent subretinal endoscopic surgery, with a minimum follow-up of 12 months. The large subretinal hemorrhage was completely removed by subretinal endoscopic surgery without a large retinotomy in all cases. The fibrovascular pigment epithelial detachment including choroidal neovascularization was completely removed in four cases. In three of these cases, the bleeding was confirmed to be originating from one point of rupture in the Bruch membrane, which was treated by coagulation using intraocular diathermy. Although visual acuity improved in three cases, it deteriorated and remained stable in one case each. Fibrovascular pigment epithelial detachment persisted in one patient after surgery; he needed anti-vascular endothelial growth factor therapy, whereas the other four did not because their fibrovascular pigment epithelial detachment was removed. At the final follow-up, no severe postoperative complications, such as retinal detachment or proliferative vitreoretinopathy, were noted. Subretinal endoscopic surgery can completely remove subretinal hemorrhage and fibrovascular pigment epithelial detachment including choroidal neovascularization without a large retinotomy. It also aids in the direct and detailed confirmation of subretinal lesions by ophthalmic endoscope.


Subcellular localization of alkaline phosphatase in Bacillus licheniformis 749/C by immunoelectron microscopy with colloidal gold.
Subcellular distribution of the alkaline phosphatase of Bacillus licheniformis 749/C was determined by an immunoelectron microscopy method. Anti-alkaline phosphatase antibody labeled with 15- to 18-nm colloidal gold particles (gold-immunoglobulin G [IgG] complex) were used for the study. Both the plasma membrane and cytoplasmic material were labeled with the gold-IgG particles. These particles formed clusters in association with the plasma membrane; in contrast, in the cytoplasm the particles were largely dispersed, and only a few clusters were found. The gold-IgG binding was quantitatively estimated by stereological analysis of labeled, frozen thin sections. This estimation of a variety of control samples showed that the labeling was specific for the alkaline phosphatase. Cluster formation of the gold-IgG particles in association with the plasma membrane suggests that existence of specific alkaline phosphatase binding sites (receptors) in the plasma membrane of B. licheniformis 749/C.


[Evolution of delta bilirubin/conjugated bilirubins ratio in serum after live transplantation].
Serum delta-bilirubin measured in relationship to total bilirubin could be a liver function test in hepatobiliary diseases and even a marker of early rejection after liver transplantation. Delta-bilirubin bound to albumin constitutes with mono and diglucuroconjugates, conjugated bilirubins. We determined the delta-bilirubin/conjugated bilirubins ratio and studied its value in various complications in 16 liver recipients. The results were compared with alanine aminotransferase activity and prothrombin index. Hyperbilirubinemia and a delta-bilirubin/conjugated bilirubins ratio lower than 40% were observed initially. After 15 days, the delta-bilirubin/conjugated bilirubins ratio evolved differently according to the functional state of the graft, which allowed to distinguish three patient groups: in patients with good graft function, the ratio increased regularly to reach 65% or more on the 30th day; in patients with dysfunctional episodes, the ratio was always less than or equal to 40% and did not increase after the 15th day; in other patients, the ratio was lower than 40% and dropped suddenly before death. After liver transplantation, the delta-bilirubin/conjugated bilirubins ratio may be a simple liver function marker. Alone, however, it cannot be used to assess acute rejection.


Splenectomy may not influence glutathione metabolism in children with beta-thalassaemia major.
The present study was undertaken to evaluate glutathione and its related enzymes in beta-thalassaemia major and to elucidate the effect of splenectomy on glutathione metabolism. The study includes three groups, those are: healthy individuals (n= 35) taken as control, a group of beta-thalassaemia major children with intact spleen (n= 29) and a group of splenectomized beta-thalassaemia major children (n= 11). Levels of reduced glutathione, glutathione peroxidase, glutathione reductase and glucose 6-phosphate dehydrogenases in erythrocytes were estimated in all groups. Levels of glutathione p< 0.001 and glutathione reductase p< 0.05 in thalassaemic groups significantly increased, whereas glutathione peroxidase levels p< 0.005 were significantly decreased when compared to control. Glutathione and enzymes levels followed the same pattern in splenectomized group when compared to nonsplenectomized one; however the difference between the various parameters was not significant. Glutathione and its redox enzymes were severely disturbed in thalassaemic patients. Splenectomy, however appears to have no role in influencing glutathione metabolism in betathalassaemia major children.


Cervical spine trauma associated with moderate and severe head injury: incidence, risk factors, and injury characteristics.
Diagnosing and managing cervical spine trauma in head-injured patients is problematic due to an altered level of consciousness in such individuals. The reported incidence of cervical spine trauma in head-injured patients has generally ranged from 4 to 8%. In this retrospective study the authors sought to define the incidence of cervical injury in association with moderate or severe brain injury, emphasizing the identification of high-risk patients. The study included 447 consecutive moderately (209 cases) or severely (238 cases) head injured patients who underwent evaluation at two Level 1 trauma centers over a 40-month period. Of the 447 patients, 24 (5.4%) suffered a cervical spine injury (17 men and seven women; mean age 39 years; median Glasgow Coma Scale [GCS] score of 6, range 3-14). Of these 24 patients, 14 (58.3%) sustained spinal cord injuries (SCIs), 14 sustained injuries in the occiput-C3 region, and 10 underwent a stabilization procedure. Of the 14 patients with SCIs, nine experienced an early hypotensive and/or hypoxic insult. Regarding the mechanism of injury, cervical injuries occurred in 21 (8.2%) of 256 patients involved in motor vehicle accidents (MVAs), either as passengers or pedestrians, compared with three (1.6%) of 191 patients with non-MVA-associated trauma (p < 0.01). In the subset of 131 MVA passengers, 13 (9.9%) sustained cervical injuries. Patients with an initial GCS score less than or equal to 8 were more likely to sustain a cervical injury than those with a score higher than 8 (odds ratio [OR] 2.77, 95% confidence interval [CI] = 1.11-7.73) and were more likely to sustain a cervical SCI (OR 5.5, 95% CI 1.22-24.85). At 6 months or more postinjury, functional neurological recovery had occurred in nine patients (37.5%) and eight (33.3%) had died. Head-injured patients sustaining MVA-related trauma and those with an initial GCS score less than or equal to 8 are at highest risk for concomitant cervical spine injury. A disproportionate number of these patients sustain high cervical injuries, the majority of which are mechanically unstable and involve an SCI. The development of safer and more rapid means of determining cervical spine integrity should remain a high priority in the care of head-injured patients.


Pain Informed Movement for people with knee osteoarthritis: Protocol for a pilot randomized controlled trial.
Conservative pain management strategies for knee osteoarthritis (KOA) have limited effectiveness and do not employ a pain-mechanism informed approach. Pain Informed Movement is a novel intervention combining mind-body techniques with neuromuscular exercise and pain neuroscience education (PNE), aimed at improving endogenous pain modulation. While the feasibility and acceptability of this program has been previously established, it now requires further evaluation in comparison to standard KOA care. This protocol describes the design of a pilot two-arm randomized controlled trial (RCT) with an embedded qualitative component. The primary outcome is complete follow-up rate. With an allocation ratio of 1:1, 66 participants (33/arm) (age ≥40 years, KOA diagnosis or meeting KOA NICE criteria, and pain intensity ≥3/10), will be randomly allocated to two groups that will both receive 8 weeks of twice weekly in-person exercise sessions. Those randomized to Pain Informed Movement will receive PNE and mind-body technique instruction provided initially as videos and integrated into exercise sessions. The control arm will receive neuromuscular exercise and standard OA education. Assessment will include clinical questionnaires, physical and psychophysical tests, and blood draws at baseline and program completion. Secondary outcomes are program acceptability, burden, rate of recruitment, compliance and adherence, and adverse events. Participants will be invited to an online focus group at program completion. The results of this pilot RCT will serve as the basis for a larger multi-site RCT aimed at determining the program's effectiveness with the primary outcome of assessing the mediating effects of descending modulation on changes in pain.


[Biochemical parameters in the blood in patients during open-heart surgery. II. Malondialdehyde, superoxide dismutase and catalase as indicators of formation and elimination of free oxygen radicals].
Investigation of cardiosurgical patients have provided evidence for the generation of free oxygen radicals during open heart surgery. The finding of increased plasma malondialdehyde concentrations, considered to be an indicator of lipid peroxidation in cell membranes, is suggestive of this process. Simultaneously, the antiradical capacity of tissue was found to exhibit a decreasing trend, as established by the levels of superoxide dismutase and catalase in erythrocytes of peripheral blood which tended to diminish. The funding that no changes in the studied parameters were observed in the blood from the coronary sinus taken before and after interruption of coronary blood flow demonstrates that the commonly applied protection of the myocardium by hypothermic cardioplegic solution and topical cooling of the heart is effective in suppressing radical formation. (Fig. 5, Ref. 36.)


Hfq C-terminal region forms a β-rich amyloid-like motif without perturbing the N-terminal Sm-like structure.
Hfq is a pleitropic actor that serves as stress response and virulence factor in the bacterial cell. To execute its multiple functions, Hfq assembles into symmetric torus-shaped hexamers. Extending outward from the hexameric core, Hfq presents a C-terminal region, described as intrinsically disordered in solution. Many aspects of the role and the structure of this region remain unclear. For instance, in its truncated form it can promote amyloid-like filament assembly. Here, we show that a minimal 11-residue motif at the C-terminal end of Hfq assembles into filaments with amyloid characteristics. Our data suggest that the full-length Hfq in its filamentous state contains a similar molecular fingerprint than that of the short β-strand peptide, and that the Sm-core structure is not affected by filament formation. Hfq proteins might thus co-exist in two forms in vivo, either as isolated, soluble hexamers or as self-assembled hexamers through amyloid-reminiscent interactions, modulating Hfq cellular functions.


Laparoscopic vs open approach for the treatment of gastroesophageal reflux in children.
The laparoscopic approach has become increasingly popular for fundoplication over the last few years; however many surgeons are skeptical about its real advantages. We conducted a prospective comparative study of children operated on for gastroesophageal reflux (GER). Exclusion criteria included age <1 YEAR AND >14 years, previous surgery on the esophagus or stomach, and neurologic impairment. We compared two groups of patients who met the same inclusion/exclusion criteria. One group was treated via a laparotomic approach between January 1993 and December 1997; the other was treated via a laparoscopic approach between September 1998 and December 2000. A 360 degrees wrap was performed in each group. Group 1 (laparotomic approach) included 17 patients; mean operative time was 100 min and postoperative time was 7 days. Group 2 comprised 49 children operated on via a laparoscopic approach; mean operative time was 78 min and postoperative time was 48 hours. No major complications were encountered in either group. In postoperative period, two patients in group 1 had complications. One had a prolonged bout of gastroplegia, which required nasogastric drainage, and then recovered spontaneously after 20 days; the other had stenosis of the wrap, which required dilation. No relapses occurred during a follow-up of 6 months. Long-term follow-up data are not presented. Comparative analysis of the short-term functional results indicated that there were no differences between the two groups. This study confirms that the minimally invasive approach is safe and effective for the treatment of primary gastroesophageal reflux disease in children.


Activation of adult human derived microglia by myelin phagocytosis in vitro.
The present study was designed to determine the extent to which cultured glial cells phagocytose normal central nervous system (CNS) myelin and CNS myelin opsonized with serum or purified antibody against myelin basic protein (MBP). Glial cells studied were mixed cultures (consisting of astrocytes, microglia, and oligodendrocytes) and enriched microglia established from adult human brain specimens and enriched astrocytes from fetal human brain. A human monocytic cell line, THP-1, was included as a control. Uptake of 125I-labelled myelin was followed over a 24 hr time period. An assay of oxidative burst (30 min) and cytokine bioassays measuring IL-1, IL-6, and tumor necrosis factor (TNF) production (6-48 hr) were used to investigate short- and long-term activation of phagocytosing cells. Maximum myelin uptake by phagocytosing glial cells occurred within 12-24 hr following myelin incubation. Opsonization of myelin prior to the phagocytosis assay resulted in greater myelin uptake by mixed glial cell cultures, microglia, and THP-1 cells over that of nontreated myelin. The magnitude of myelin phagocytosis by astrocytes was considerably lower than microglia and THP-1, and was not affected by myelin opsonization. Within 30 min of myelin phagocytosis, microglia and THP-1 cells underwent oxidative burst; opsonization of myelin by purified anti-MBP IgG and heat-inactivated serum enhanced the microglial oxidative burst activity. Production of IL-1, TNF, and most markedly IL-6 by microglia was increased following 12-24 hr of myelin ingestion. Our data demonstrate that myelin phagocytosis by adult human-derived microglia occurs in vitro, is augmented when myelin is opsonized, and results in the activation of microglia as assessed by oxidative burst and cytokine production.


Epidermoid tumor presenting as tension pneumocephalus. Case report.
The authors report a patient with an epidermoid tumor that eroded through the frontal sinus, causing an acute neurological deficit secondary to tension pneumocephalus. The historical perspective, radiographic features, and pathophysiological mechanisms are discussed.


[Histochemical studies on innervation of the distal ureter in primary vesico-ureteral reflux in children (author's transl)].
The purpose of the present investigation was to evaluate the distribution-pattern of the intramural vegetative nerve fibres in cases of vesico-ureteral reflux. Resected specimens of the vesico-ureteral junction of 14 children with primary vesico-ureteral reflux are investigated using histochemical technics for demonstrating acetylcholinesterase (El Badawi and Schenk, 1967). Additionally the catecholamines (Falck et al. 1962) were demonstrated in two of the cases. The results are compared with findings in normal ureters in literature. There was no evidence of a pathological pattern of distribution of the nerve fibres.


Sulfonium-Containing Glycopolypeptides Tethering Trehalose for Protein Stabilization.
Protection of proteins is of great significance since external stimuli can cause denaturation due to aggregation. Herein, a series of well-defined cationic trehalose-glycopolypeptides, poly(ethylene glycol)-b-(l-methionine-g-trehalose)s (PEG45-b-(Met-g-Tre)x), were synthesized for stabilization of a model protein, glucose oxidase (GOx), against lyophilization and heating. The isothermal titration calorimetry results revealed that polyionic complexes (PICs) were formed between the synthesized trehalose-glycopolypeptides and GOx via electrostatic interactions. These PICs allowed GOx to maintain an approximately 80% enzymatic activity compared with native GOx after 6× lyophilization. Meanwhile, PEG45-b-(Met-g-Tre)x also provided a positive effect on the protection of GOx upon heating at 60 °C. Results of transmission electron microscopy suggested that the trehalose-glycopolypeptides could prevent protein aggregation, thereby maintaining the bioactive function of GOx. In brief, it provided a synthesis strategy for the precise preparation of trehalose-glycopolypeptides, as well as a suitable method for stabilization of proteins.


Heterogeneity of human erythrocyte acetylcholinesterase. Individual variation revealed by DEAE-cellulose chromatography and polyacrylamide gel disc electrophoresis.
Acetylcholinesterase (EAChE; acetylcholine acetyl hydrolase, EC 126.96.36.199) was prepared from the erythrocyte membrane of Chinese adult males, and solubilised with 1% Triton X-100 in 20 mmol/l phosphate buffer, pH 7.4. Chromatography of the preparation on DEAE-cellulose, using a linear gradient of increasing NaCl concentration, yielded four reproducible elution patterns with differing peaks of enzyme activity. On the basis of the number and position of the enzymatically active peaks, the individuals could be grouped into four types: type I: with 4 peaks of activity, EAChe 1, EAChE 2, EAChE 3, EAChE 4; type II: with 3 peaks of activity, EAChE 1, EAChE 3, EAChE 4; type III: with 3 peaks of activity, EAChE 1, EAChE 2, EAChE 4; type IV: with 3 peaks of activity, EAChE 1, EAChE 2, EAChE 3. Each enzyme entity could be eluted in the similar position on rechromatography with loss of activity. When the same samples were subjected to disc electrophoresis on 5% polyacrylamide gel at pH 8.6, three different repeatable patterns were observed. A distinct band (Ch4) at the origin, containing a largest proportion of the enzyme activity, was present in all the samples. One group contained three additional bands of activity Ch3, Ch2, Ch1, while the other two groups had either Ch2 and Ch1 or Ch3 and Ch1 in addition to the Ch4 band. No correlation was apparent between individuals typed by DEAE-cellulose chromatography and those typed by disc electrophoresis; further no correlation between either of these types and blood group was apparent.


Dual role of insulin in transcriptional regulation of the acute phase reactant ceruloplasmin.
Insulin is a potent negative regulator of the response of hepatic cells to pro-inflammatory cytokines, particularly, interleukin (IL)-6. The action of insulin is target-selective because it inhibits transcription of most but not all acute phase genes. We here show that ceruloplasmin (Cp), an acute phase reactant with important functions in iron homeostasis, is subject to a unique dual regulation by insulin. IL-6 increased Cp mRNA expression in HepG2 cells by approximately 5-fold. Simultaneous treatment with insulin reduced this stimulation by half. Surprisingly, insulin by itself caused a 2-4-fold induction in Cp mRNA expression. The mechanism of induction by insulin was studied by transfecting into HepG2 cells chimeric constructs of the Cp 5'-flanking region driving luciferase. The activity of a 4800-bp segment of the Cp 5'-flanking region was increased 3-fold by insulin. Deletion and mutation analyses showed the requirement for a single hypoxia-responsive element in a 96-bp segment approximately 3600 bp upstream of the initiation site. The domains required for the two activities of insulin were distinct: The distal, hypoxia-responsive element-containing site was sufficient for Cp transactivation by insulin; in contrast, an 848-bp region adjacent to the initiation site was sufficient for IL-6 transactivation of Cp and for the inhibitory activity of insulin. The role of hypoxia-inducible factor-1 in the induction of Cp by insulin was shown by electrophoretic mobility shift assays and by the absence of insulin-stimulated Cp promoter activation in mouse Hepa c4 cells deficient in hypoxia-inducible factor-1 activity. Taken together these results show that insulin functions as a bidirectional, condition-dependent regulator of hepatic cell Cp expression. The unique regulation of Cp may reflect its dual roles in inflammation and iron homeostasis.


UV-patterned poly(ethylene glycol) matrix for microarray applications.
A versatile method to fabricate polymeric matrixes for microarray applications is demonstrated. Several different design strategies are presented where a variety of organic films, such as plastic polymers and self-assembled monolayers (SAMs) on planar silica and gold substrates, act as supports for the graft polymerization procedure. An ensemble of poly(ethylene glycol) methacrylate monomers are combined to obtain a matrix with desired properties: low nonspecific binding and easily accessible groups for postimmobilization of ligands. The free radical graft polymerization process occurs under irradiation with UV light in the 254-266 nm range, which offers the possibility to introduce patterns by means of a photomask. The arrays are created on inert and homogeneous coatings prepared either by graft polymerization of a methoxy-terminated PEG-methacrylate or self-assembly of a methoxy-terminated oligo(ethylene glycol) thiol. Carboxylic acid groups, introduced in the array spots either during graft polymerization or upon wet chemical conversion of hydroxyls, grant the capability to immobilize proteins and other molecules via free amine groups. Immobilization of fluorescent species as well as biotin followed by exposure to a fluorescently labeled antibody directed toward biotin display both excellent integrity of the spots and low nonspecific binding to the surrounding framework. Beside patterns of uniform height and size, an array of spots with varying thickness (a sort of gradient) is demonstrated. Such gradient samples enable us to address critical issues regarding the mechanism(s) behind spatially resolved free radical polymerization of methacrylates. It also offers a convenient route to optimize the matrix properties with respect to thickness, loading capacity, protein diffusion/penetration, and nonspecific binding.


Invasive house mice facing a changing environment on the Sub-Antarctic Guillou Island (Kerguelen Archipelago).
Adaptation to new environments is a key feature in evolution promoting divergence in morphological structures under selection. The house mouse (Mus musculus domesticus) introduced on the Sub-Antarctic Guillou Island (Kerguelen Archipelago) had and still has to face environmental conditions that likely shaped the pattern and pace of its insular evolution. Since mouse arrival on the island, probably not more than two centuries ago, ecological conditions dramatically differed from those available to their Western European commensal source populations. In addition, over the last two decades, the plant and animal communities of Guillou Island were considerably modified by the eradication of rabbits, the effects of climate change and the spread of invasive species detrimental to native communities. Under such a changing habitat, the mouse response was investigated using a morphometric quantification of mandible and molar tooth, two morphological structures related to food processing. A marked differentiation of the insular mice compared with their relatives from Western Europe was documented for both mandibles and molar shapes. Moreover, these shapes changed through the 16 years of the record, in agreement with expectations of drift for the molar, but more than expected by chance for the mandible. These results suggest that mice responded to the recent changes in food resources, possibly with a part of plastic variation for the mandible prone to bone remodelling. This pattern exemplifies the intricate interplay of evolution, ecology and plasticity that is a probable key of the success of such an invasive rodent facing pronounced shifts in food resources exploitation under a changing environment.


Reversible posterior leukoencephalopathy associated with chronic graft-versus-host disease: A case report.
The present study describes the clinical manifestations, magnetic resonance imaging (MRI) features and treatments of a 22-year-old male patient diagnosed with reversible posterior leukoencephalopathy syndrome (RPLS) associated with graft-versus-host disease (GVHD) 7 months after a haploid hematopoietic stem cell transplantation. The patient was admitted to hospital after falling unconscious. Head MRI demonstrated abnormal signals in the bilateral, frontal, parietal, temporal and occipital lobes, consistent with reversible posterior leukoencephalopathy syndrome (RPLS). Based on a detailed diagnosis, the response to treatment and follow-up, it was concluded that RPLS was closely associated with chronic graft-versus-host disease in the patient. The present case report is described in order to increase the awareness of RPLS.


Divergent consequences of success and failure in japan and north america: an investigation of self-improving motivations and malleable selves.
Self-enhancing and self-improving motivations were investigated across cultures. Replicating past research, North Americans who failed on a task persisted less on a follow-up task than those who succeeded. In contrast, Japanese who failed persisted more than those who succeeded. The Japanese pattern is evidence for a self-improving orientation: Failures highlight where corrective efforts are needed. Japanese who failed also enhanced the importance and the diagnosticity of the task compared with those who succeeded, whereas North Americans did the opposite. Study 2 revealed that self-improving motivations are specific to the tasks on which one receives feedback. Study 3 unpackaged the cultural differences by demonstrating that they are due, at least in part, to divergent lay theories regarding the utility of effort. Study 4 addressed the problem of comparing cultures on subjective Likert scales and replicated the findings with a different measure.


TIPSS in the treatment of ectopic variceal bleeding.
Bleeding from ectopic varices is a well recognized life-threatening complication of portal hypertension but the optimal treatment of this problem is yet to be established. We retrospectively reviewed patients with ectopic variceal bleeding who underwent transjugular intrahepatic portosystemic shunting for recurrent bleeding not responding to conservative management. Over an eleven-year period we identified ten patients who underwent TIPSS for ectopic variceal hemorrhage. Six patients bled from rectal varices and four from stomal varices. TIPSS was successful in nine patients. The Childs-Pugh grade of the patients was A=3, B=3 and C=4. The follow-up period ranged from 7 days to 1380 days. Rebleeding occurred in three patients, two of whom died. The remaining patient had a blocked TIPSS and successfully underwent repeat stenting which re-established patency. Four patients (Childs B=2, Childs C=2) died within 60 days. All three patients with Childs A liver disease were alive at one year. TIPSS can be used effectively to treat ectopic variceal bleeding. Patients with Childs grade A liver disease appear to do well with TIPSS. Those with advanced liver disease (Childs B & C) have a uniformly poor outcome. In these patients ectopic variceal hemorrhage is likely to represent a terminal event.


SIRT1 regulates Mxd1 during malignant melanoma progression.
In a murine melanoma model, malignant transformation promoted by a sustained stress condition was causally related to increased levels of reactive oxygen species resulting in DNA damage and massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, γH2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found downregulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to down-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, whose upregulation is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression.


Bio-Metal Dyshomeostasis-Associated Acceleration of Aging and Cognitive Decline in Down Syndrome.
Down syndrome (DS), which is caused by triplication of human chromosome 21 (Hsa21), exhibits some physical signs of accelerated aging, such as graying hair, wrinkles and menopause at an unusually young age. Development of early-onset Alzheimer's disease, which is frequently observed in adults with DS, is also suggested to occur due to accelerated aging of the brain. Several Hsa21 genes are suggested to be responsible for the accelerated aging in DS. In this review, we summarize these candidate genes and possible molecular mechanisms, and discuss the related key factors. In particular, we focus on copper, an essential trace element, as a key factor in the accelerated aging in DS. In addition, the physiological significance of brain copper accumulation in cognitive impairment is discussed. We herein provide our hypothesis on the copper dyshomeostasis-based pathophysiology of DS.


Novel organic dyes for efficient dye-sensitized solar cells.
Two novel metal-free organic dyes containing thienothiophene and thiophene segments have been synthesized. Nano-crystalline TiO2 dye-sensitized solar cells were fabricated using these dyes as light-harvesting sensitizers, and a high solar energy-to-electricity conversion efficiency of 6.23% was achieved.


The receptor for urokinase-type plasminogen activator of a human keratinocyte line (HaCaT).
It is assumed that plasmin participates in pericellular proteolysis in the epidermis. Plasmin is generated by keratinocyte-associated plasminogen activators from the proenzyme plasminogen; plasminogen activation can proceed at the keratinocyte surface. The resultant plasmin interferes with cell to matrix adhesion and does possibly contribute to keratinocyte migration during reepithelialization. Here we describe the receptor for urokinase-type plasminogen activator (uPA-R) in the human keratinocyte cell line HaCaT, which serves to direct plasminogen activation to the cell surface; we relate the receptor to the uPA-R previously described in human myelo-/monocytes. Binding of uPA to the receptor accelerated plasminogen activation by a factor of approximately 10, compared to uPA in solution. Receptor-bound uPA was susceptible to inhibition by the plasminogen activator inhibitors 1 and 2. uPA and uPA-R antigen, as well as uPA activity, were localized to the leading front of expanding sheets of HaCaT cells. Exposure of HaCaT cells to plasminogen was followed by detachment of the cells. Detachment was prevented by an anticatalytic anti-uPA antibody, by the plasmin-specific inhibitor aprotinin, and by the lysine analogue tranexamic acid, the latter of which prevents plasmin(ogen) binding to the cell surface. Our findings support the hypothesis that uPA-mediated plasminogen activation is characteristic of mobile rather than sessile keratinocytes. Moreover, the uPA-R seems to focalize plasminogen activation to the surface of cells at the site of keratinocyte migration.


Amisulpride-associated mania in a young adult with schizophrenia and cerebral disease.
A case of rapid-onset mania after initiating amisulpride in a patient with schizophrenia and cerebral disease is reported. A 19-year-old Taiwanese man had a 1-year history of schizophrenia, paranoid type, and cerebral palsy. His only medication was a 12-week course of risperidone 6 mg orally daily. His positive symptoms of auditory hallucinations and paranoid delusions improved markedly, but negative symptoms of inattention, avolition, and anhedonia continued. His motor disability and athetosis of the hand related to cerebral palsy also worsened during risperidone therapy. After a discussion with the patient's guardian, conversion of antipsychotic therapy from risperidone to amisulpride was commenced. On days 1-8 of the conversion, amisulpride 400 mg was given orally daily. The daily risperidone dose on days 1, 2, and 3 was 6, 4, and 2 mg, respectively; risperidone was discontinued after day 3. On day 4, the patient exhibited a euphoric mood, with persistent laughing, expansive self-esteem, extreme talkativeness, flight of ideas, distractibility, and psychomotor agitation. On day 8, the amisulpride dosage was increased to 800 mg orally daily and his manic symptoms worsened. On day 17, amisulpride was withheld and risperidone 4 mg daily was resumed. The manic symptoms subsided within three days after the cessation of amisulpride. The patient was maintained on risperidone 4 mg daily for six months without any further hypomanic or manic symptoms. A 19-year-old man with schizophrenia and underlying cerebral disease developed rapid-onset mania after risperidone was replaced with amisulpride. The reaction resolved soon after amisulpride was discontinued and treatment with risperidone was reinstituted.


Depletion of dopamine in Parkinson's disease and relevant therapeutic options: A review of the literature.
Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects motor and cognition functions. The etiology of Parkinson's disease remains largely unknown, but genetic and environmental factors are believed to play a role. The neurotransmitter dopamine is implicated in regulating movement, motivation, memory, and other physiological processes. In individuals with Parkinson's disease, the loss of dopaminergic neurons leads to a reduction in dopamine levels, which causes motor impairment and may also contribute to the cognitive deficits observed in some patients. Therefore, it is important to understand the pathophysiology that leads to the loss of dopaminergic neurons, along with reliable biomarkers that may help distinguish PD from other conditions, monitor its progression, or indicate a positive response to a therapeutic intervention. Important advances in the treatment, etiology, and pathogenesis of Parkinson's disease have been made in the past 50 years. Therefore, this review tries to explain the different possible mechanisms behind the depletion of dopamine in PD patients such as alpha-synuclein abnormalities, mitochondrial dysfunction, and 3,4-dihydroxyphenylacetaldehyde (DOPAL) toxicity, along with the current therapies we have and the ones that are in development. The clinical aspect of Parkinson's disease such as the manifestation of both motor and non-motor symptoms, and the differential diagnosis with similar neurodegenerative disease are also discussed.


[Identification of hydroxylate metabolites of daidzein and its sulfate conjugates in rat urine by LC-ESI/MS(n)].
To identify the hydroxylate metabolites and its sulfate conjugates of daidzein in rat urine. Urine samples from 0 - 24 h were collected after single ig dose of 500 mg x kg(-1) daidzein to each of six rats. The urine samples were purified by SPE column (SPE C18) and analyzed with liquid chromatographic-tandem electrospray ionization ion trap mass spectrometry (LC-ESI/MS(n)) for potential metabolites. Several new hydroxylate metabolites and its sulfate conjugates were found and identified in rat urine. LC-ESI/MS(n) is proved to be a simple, rapid, sensitive and specific technique for identification of the hydroxylate metabolites and its sulfate conjugates of daidzein in rat urine.


Propylene glycol in the treatment of tinea versicolor.
Twenty patients with tinea versicolor were treated with propylene glycol 50% in water twice daily for 2 weeks. All of these were cured when seen 2 weeks after the last day of treatment. The patients found the treatment cosmetically attractive and only 2 patients complained of a slight burning sensation in the skin after application of the solution.


Sirtuin 1 and Vascular Function in Healthy Women and Men: A Randomized Clinical Trial Comparing the Effects of Energy Restriction and Resveratrol.
Background: Sirtuin 1 (SIRT1) has been associated with longevity and protection against cardiometabolic diseases, but little is known about how it influences human vascular function. Therefore, this study evaluated the effects of SIRT1 activation by resveratrol and energy restriction on vascular reactivity in adults. Methods: A randomized trial allocated 48 healthy adults (24 women and 24 men), aged 55 to 65 years, to resveratrol supplementation or energy restriction for 30 days. Blood lipids, glucose, insulin, C-reactive protein, noradrenaline, SIRT1 (circulating and gene expression), and flow-mediated vasodilation (FMD) and nitrate-mediated vasodilation (NMD) were measured. Results: Both interventions increased circulating SIRT1 (p < 0.001). Pre- and post-tests changes of plasma noradrenaline were significant for both groups (resveratrol: p = 0.037; energy restriction: p = 0.008). Baseline circulating SIRT1 was inversely correlated with noradrenaline (r = -0.508; p < 0.01), and post-treatment circulating SIRT1 was correlated with NMD (r = 0.433; p < 0.01). Circulating SIRT1 was a predictor of FMD in men (p = 0.045), but not in women. SIRT1 was an independent predictor of NMD (p = 0.026) only in the energy restriction group. Conclusions: Energy restriction and resveratrol increased circulating SIRT1 and reduced sympathetic activity similarly in healthy adults. SIRT1 was independently associated with NMD only in the energy restriction group.


Recurrent varicose veins: causes and neovascularisation. A 17-year experience.
The aim of the paper was to determine the causes of varicose vein recurrence and, when neovascularisation is suspected, to confirm or exclude its presence and to establish its contribution to the recurrence of varicose veins. A retrospective analysis of a set of 217 legs reoperated in our department over a period of 17 years with a two-year prospective histological and histochemical (nestin) analysis of resected veins. Reflux as a cause of varicose vein recurrence was identified in 93% of the limbs. It was most commonly found in the area of the saphenofemoral junction, followed by the area of the saphenopopliteal junction. Reflux in the perforating veins was almost invariably linked to that in the saphenofemoral junction or saphenopopliteal junction; an isolated damage to the perforating veins was only present in three limbs. Histological and histochemical analysis was performed for the samples of eleven veins in which neovascularisation was suspected based on preoperative duplex ultrasonography evaluation. Neovascularisation was confirmed in none of these veins and none of them was the cause of recurrence. The major cause of varicose vein recurrence is a reflux left unresolved during the primary surgery, particularly in the area of the saphenofemoral junction. A less common cause is progression of the disease and the occurrence of a new reflux. Neovascularisation is of no importance for the recurrence of varicose veins.


High quality of an absolute phase reconstruction for coherent digital holography with an enhanced anti-speckle deep neural unwrapping network.
It is always a challenge how to overcome speckle noise interference in the phase reconstruction for coherent digital holography (CDH) and its application, as this issue has not been solved well so far. In this paper, we are proposing an enhanced anti-speckle deep neural unwrapping network (E-ASDNUN) approach to achieve high quality of absolute phase reconstruction for CDH. The method designs a special network-based noise filter and embeds it into a deep neural unwrapping network to enhance anti-noise capacity in the image feature recognition and extraction process. The numerical simulation and experimental test on the phase unwrapping reconstruction and the image quality evaluation under the noise circumstances show that the E-ASDNUN approach is very effective against the speckle noise in realizing the high quality of absolute phase reconstruction. Meanwhile, it also demonstrates much better robustness than the typical U-net neural network and the traditional phase unwrapping algorithms in reconstructing high wrapping densities and high noise levels of phase images. The E-ASDNUN approach is also examined and confirmed by measuring the same phase object using a commercial white light interferometry as a reference. The result is perfectly consistent with that obtained by the E-ASDNUN approach.


[Endoscopic removal of papillary tumors of upper urinary tract].
To assess the results of organ-sparing endoscopic treatment of patients with tumors of the upper urinary tract (UUT). Twenty four patients underwent percutaneous and ureteropyeloscopic interventions for tumors of the upper urinary tract and were followed up at the Urology Clinic, I.M. Sechenov First MSMU. Retrograde removal of benign tumors of the renal pelvis and ureter (tumors sized from 5 to 35 mm), percutaneous removal of papillary carcinoma of renal pelvis of a solitary kidney, percutaneous removal of papillary carcinoma of renal pelvis of only one functioning kidney and percutaneous removal of papillary carcinoma of the lower calyx of the L-shaped kidney were performed in 21, 1, 1 and 1 patients, respectively. The patients had stage T1 papillary cancer of the upper urinary tract. There were 7 (29.2%) men and 17 (70.8%) women with mean age 64+/-5 years. Electroresection/vaporization was carried out in 18 patients, and 6 patients were treated using Holmium laser. None of the endoscopic procedures required conversion to open surgery or a more extended surgical operation. There were no recurrences or impaired UUT urinary flow in patients with benign UUT tumors at different points of follow-up. In 3 cases of malignant UUT tumors no recurrences occurred during 12-20 months follow-up. and discussion. Nephroureterectomy with resection of the urinary bladder is the standard radical treatment of patients with tumors of the UUT. Technological advances in endoscopic and percutaneous surgery for UUT have allowed for organ-sparing procedures in patients with neoplasms of pelvicalyceal system and ureter. The absolute indications for such organ-sparing operations now include solitary kidney or only one functioning kidney and chronic renal failure. Endoscopic resection of the tumor and renal pelvic wall within healthy tissue, including by holmium laser, with tumor stage not exceeding T1 and followed by trans-fistula chemotherapy can be regarded as an effective treatment for patients with tumors of pelvicalyceal system.


A longitudinal study of joint pain in older people.
Joint pain is extremely common in older people, but its natural history has been little described in the UK literature. A UK general practice population was followed for 1 yr in 1998. There were 4804 subjects aged 75 yr and over who accepted the offer of health screening. Assessments by postal questionnaire using the Elderly At Risk Rating Scale, which includes one question specifically covering joint pain. Some degree of joint pain was reported by 83%. This was related to age and female gender. The presence of pain was strongly related to mobility, energy and sadness. Over 1 yr, 18% acquired or had increased frequency of pain, while 14% had reduced frequency of pain. Resolution was associated with preserved indoor mobility, and functional recovery. There was little relationship between joint pain and adverse outcomes. Joint pain is very common in older people, fluctuates in frequency over time, and is strongly linked to psychological factors as well as disability. A positive approach to active management of joint pain is justified, and will be rewarded by improved quality of life for older people.


Quantifying RNA-peptide interaction by single-quantum dot-based nanosensor: an approach for drug screening.
The sequence-specific RRE RNA-Rev binding is essential for HIV-1 replication and provides a useful in vitro system for real-time evaluating the inhibitory effect of drugs on the RRE-Rev interaction. The rapid and sensitive detection of RRE-Rev interaction in complex biological systems represents a fundamental challenge. Here we report the development of a single-quantum-dot (QD)-based nanosensor for sensitively quantifying Rev peptide-RRE interaction and characterizing the potential inhibitors by virtue of single-molecule detection and QD-based fluorescence resonance energy transfer (FRET). We demonstrate that the stoichiometry of Rev peptide binding to RRE can be accurately determined by using this single-QD-based nanosensor. Importantly, this single-QD-based nanosensor can sensitively quantify the inhibitory efficacy of proflavin on the Rev peptide-RRE binding, even in the presence of substantial levels of interference fluorescence from high-concentration proflavin, which usually prevents the discrimination of FRET signals in ensemble measurements. The application of this nanosensor in the screening of libraries of small-molecule drugs will facilitate the development of new drugs against various diseases, cancers, and HIV.


Molecular pathogenesis of Hodgkin's lymphoma.
According to the WHO classification, Hodgkin's lymphoma (HL) is subdivided into a classical variant and a nodular lymphocyte predominant variant which are characterized by the presence of Hodgkin's and Reed-Sternberg (H-RS) cells or lymphocytic and histiocytic (L&H) cells, respectively. This article reviews genetic characteristics and transcriptional changes of H-RS and L&H cells, including recent knowledge about transforming mechanisms and signaling pathways that contribute to the antiapoptotic phenotype displayed by H-RS and L&H cells. We also discuss major cellular and molecular mediators contributing to the establishment and maintenance of a reactive background in HL-affected tissues. We believe that an in-depth understanding of the pathogenesis of HL will eventually lead to the development of novel biologically based therapeutic strategies in the near future.


Importance of dynamic contrast enhanced magnetic resonance imaging for targeting biopsy and salvage treatments after prostate cancer recurrence.
Evaluate T2 weighted MRI (T2W), diffusion weighted imaging (DWI), and dynamic contrast enhanced MRI (DCE-MRI) for determining areas of prostate cancer recurrence to target biopsy or salvage treatment in patients previously treated with I-125 seed brachytherapy. MRI data from 15 patients, whose primary treatment was I-125 seed brachytherapy and who were subsequently treated with partial gland salvage high-dose-rate brachytherapy were retrospectively analyzed. Two radiologists independently reviewed imaging on two occasions blinded to clinical and biopsy information. At first review, the T2W and DWI sequences were assessed for likely presence of tumor and at second review, the additional DCE-MRI sequence was assessed. Results were recorded and compared on a prostate diagram divided into 12 sectors (quadrants at each of base, mid-gland, and apex) plus seminal vesicles (SV). Number of patients for whom recurrence was visible was 7/15 for T2W, 6.5/15 for DWI, and 15/15 for DCE-MRI (average of results for the two radiologists). Approximately, half of the sectors identified as showing recurrence were at the anterior base of the prostate. In prostate cancer patients previously treated with I-125 permanent seed implants, DCE-MRI is superior to T2W and DWI in defining areas of recurrence, and should be used to target biopsy and for treatment planning of focal salvage therapies.


Supersymmetric formulation of multiplicative white-noise stochastic processes.
We present a supersymmetric formulation of Markov processes, represented by a family of Langevin equations with multiplicative white noise. The hidden symmetry encodes equilibrium properties such as fluctuation-dissipation relations. The formulation does not depend on the particular prescription to define the Wiener integral. In this way, different equilibrium distributions, reached at long times for each prescription, can be formally treated on the same footing.


Entropy and information in neural spike trains: progress on the sampling problem.
The major problem in information theoretic analysis of neural responses and other biological data is the reliable estimation of entropy-like quantities from small samples. We apply a recently introduced Bayesian entropy estimator to synthetic data inspired by experiments, and to real experimental spike trains. The estimator performs admirably even very deep in the undersampled regime, where other techniques fail. This opens new possibilities for the information theoretic analysis of experiments, and may be of general interest as an example of learning from limited data.


A Case Report: Large Trichobezoar Causing Rapunzel Syndrome.
Rapunzel syndrome is very rare gastric foreign bodies that occur in children. It is a severe condition of a gastric trichobezoar with a long tail that passes into the small intestine. Here, we present the case of an 8-year-old girl with Rapunzel syndrome due to a very large (7 × 7 × 30 cm) gastric trichobezoar. The patient had trichotillomania and trichophagia for 1 year prior to presentation. Ideally, small bezoars are removed through a minimally invasive method, such as endoscopic fragmentation. However, large trichobezoars, including those in Rapunzel syndrome, can only be managed with open surgical extraction, despite the large scars that may result.We report a case of Rapunzel syndrome with a large bezoar that was surgically removed after it was endoscopically cauterized with argon plasma. Endoscopic precutting was used to effectively reduce the size of the bezoar.


Phosphatidylinositol 4-phosphate is required for translation initiation in Saccharomyces cerevisiae.
The small natural product wortmannin inhibits protein synthesis by modulating several phosphatidylinositol (PI) metabolic pathways. A primary target of wortmannin in yeast is the plasma membrane-associated PI 4-kinase (PI4K) Stt4p, which is required for actin cytoskeleton organization. Here we show that wortmannin treatment or inactivation of Stt4p, but not disorganization of the actin cytoskeleton per se, leads to a rapid attenuation of translation initiation. Interestingly, inactivation of Pik1p, a wortmannin-insensitive, functionally distinct PI4K, implicated in the regulation of Golgi functions and secretion, also results in severe translation initiation defects with a marked increase of the phosphorylation of the translation initiation factor eIF2alpha. Because wortmannin largely phenocopies the effects of rapamycin (e.g. it triggers nuclear accumulation of Gln3p), it likely also inhibits the PI kinase-related, target of rapamycin (TOR) kinases. Importantly, however, neither inactivation of Stt4p nor Pik1p significantly affects TOR-controlled readouts other than translation initiation, indicating that these PI4Ks do not simply function upstream of TOR. Together, our results reveal the existence of a novel translation initiation control mechanism in yeast that is tightly coupled to the synthesis of distinct PI4P pools.


[Percutaneous coronary intervention of patients with complex small coronary artery lesion unsuitable for coronary artery bypass graft].
To investigate the safety and efficacy of percutaneous coronary intervention (PCI) in patients with low left ventricular ejection fraction (LVEF) and complex small coronary artery lesions. Complete or partial post-PCI revascularization of coronary artery was employed in 16 patients with a low LVEF and complex small coronary artery lesions who were unsuitable for CABG (coronary artery bypass grafting). All cases were observed with regards to immediate success rate of operation, complication, hospitalization duration, improvement of cardiac function and LVEF and major adverse cardiac events (including cardiac death, myocardial infarction and target lesion revascularization) at 12 months post-operation. All cases were successfully treated without death and severe complications while the hospitalization duration was (11 +/- 5) days. The follow-up survey at 12 months post-operation showed that no major adverse cardiac event occurred, the post-operative improvement of cardiac function was from III - IV grade to I - II grade, the improvement of LVEF was from 25% - 45% [(29 +/- 8)%] to 32% - 48% [(37 +/- 7)%], left ventricular end diastolic diameter (LVDd) was shortened from 52 - 79 (66 +/- 11) mm to 49 - 68 (58 +/- 8) mm. The reexamination of 14 cases by coronary angiography at 12 months post-operation showed that there was no intra-stent thrombosis while 20% - 40% intra-stent restenosis occurred in 2 cases. For patients with a low LVEF and complex small coronary artery lesions, PCI is a safe and effective method to lower the mortality rate of CHD patients with heart failure and improve the long-term patient prognosis.


LGBTQ Women, Appearance Negotiations, and Workplace Dress Codes.
The purpose of this study was to explore LGBTQ women's experiences with unwritten or formal dress codes at work. I asked: What are LGBTQ women's experiences in the workplace with appearance management, and what are LGBTQ women's experiences navigating the written and unwritten dress codes in the workplace? To answer the research question, interviews were conducted with 24 self-identifying LGBTQ women. Six key themes emerged from the data. Themes included (1) expressed sexual identity in appearance, (2) unwritten dress codes in work environments did not always allow for expression of sexual identity in appearance, (3) motivations for pressure or desire to conceal expression of sexual identity in appearance at work, (4) negotiations of revealing or concealing sexual identity in appearance in the workplace impacted levels of comfort and confidence, (5) verbal and nonverbal negative experiences related to appearance at work, and (6) received compliments about appearance at work.


Comparison of international breast cancer guidelines: are we globally consistent? cancer guideline AGREEment.
Evidence-based guidelines are used in health care systems throughout the world to aid in treatment decisions and to ensure quality and consistency in patient care. In breast oncology, guidelines for care are published by several internationally recognized organizations, including those from the United States, Canada, and the United Kingdom. The present study compared clinical breast cancer guidelines from the American Society of Clinical Oncology (ASCO, United States), Cancer Care Ontario (CCO, Canada), and the National Institute for Health and Clinical Excellence (NICE, United Kingdom) to determine the quality and consistency of content across international organizations. We searched for breast cancer guidelines published by ASCO, CCO, and NICE. Guidelines on the same theme were identified across organizations and appraised by 4 independent reviewers using the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument. Content of each guideline was also scored for consistency in overall recommendations across organizations and for consistency in cited evidence. The quality of breast cancer guidelines produced by the targeted organizations was consistently good in the areas of Scope and Purpose, Rigor of Development, and Clarity and Presentation, but variable in the domains of Stakeholder Involvement, Applicability, and Editorial Independence. The content of the guidelines varied slightly in the strength of their recommendations. Our review demonstrated consistency in quality and content for breast cancer practice guidelines published by various organizations. Future guidelines developed by these organizations should focus on how to implement and measure uptake of a guideline.


Support vector machines for oil classification link with polyaromatic hydrocarbon contamination in the environment.
The main focus of this study is exploring the spatial distribution of polyaromatics hydrocarbon links between oil spills in the environment via Support Vector Machines based on Kernel-Radial Basis Function (RBF) approach for high precision classification of oil spill type from its sample fingerprinting in Peninsular Malaysia. The results show the highest concentrations of Σ Alkylated PAHs and Σ EPA PAHs in ΣTAH concentration in diesel from the oil samples PP3_liquid and GP6_Jetty achieving 100% classification output, corresponding to coherent decision boundary and projective subspace estimation. The high dimensional nature of this approach has led to the existence of a perfect separability of the oil type classification from four clustered oil type components; i.e diesel, bunker C, Mixture Oil (MO), lube oil and Waste Oil (WO) with the slack variables of ξ ≠ 0. Of the four clusters, only the SVs of two are correctly predicted, namely diesel and MO. The kernel-RBF approach provides efficient and reliable oil sample classification, enabling the oil classification to be optimally performed within a relatively short period of execution and a faster dataset classification where the slack variables ξ are non-zero.


Induction of inflammatory mediator release (12-hydroxyeicosatetraenoic acid) from human platelets by Pseudomonas aeruginosa.
The role of platelets in acute and chronic infection has been widely discussed in various disease processes. We studied the effects of two lipolytic enzymes (phospholipase C, lipase) secreted by Pseudomonas aeruginosa strains isolated from cystic fibrosis (CF) patients with regard to 12-hydroxyeicosatetraenoic acid (12-HETE) generation from human platelets. Both phospholipase C (PLC) and lipase were secreted into the culture supernatant at the end of the logarithmic growth phase. Indeed, only culture supernatants obtained from the late logarithmic/early stationary phase of CF strains induced the generation of 12-hydroxyeicosatetraenoic acid (12-HETE) (from 15 +/- 9 to 370 +/- 98 ng, n = 7). Purified P. aeruginosa lipase itself generated only small amounts of 12-HETE from human platelets with a maximum of 30 +/- 7 ng/10(8) platelets at the highest concentration tested (20 nkat). A partially purified culture supernatant from P. aeruginosa strain PAO1 containing phospholipase C and lipase, but lacking glycolipid and protease activities, induced time- and dose-dependently a significant 12-HETE generation from human platelets. Maximal 12-HETE generation was observed at the highest enzyme concentrations tested (PLC: 1.35 nkat, lipase: 3.7 nkat/10(8) platelets). To analyze whether lipase exhibits a modulatory role on PLC-induced 12-HETE generation from human platelets we inhibited lipase activity in the P. aeruginosa partially purified culture supernatant by treatment with the lipase-specific inhibitor hexadecylsulfonylfluoride (AMSF) leaving the activity of PLC unaffected (lipase-free culture supernatant). The capacity of lipase-free culture supernatant to induce 12-HETE generation was diminished by up to 100% depending on the PLC activity.(ABSTRACT TRUNCATED AT 250 WORDS)


Low EGFR/MET ratio is associated with resistance to EGFR inhibitors in non-small cell lung cancer.
Although activating mutations in the epidermal growth factor receptor (EGFR) gene are predictive markers for response to EGFR inhibitors, 30-40% of EGFR-mutant non-small cell lung cancer (NSCLC) patients are de novo non-responders. Hence, we sought to explore additional biomarkers of response. We conducted a prospective pilot study to characterize the expression and/or activation of key receptor tyrosine kinases (RTKs) in stage IIIB-IV NSCLC tumors. A total of 37 patients were enrolled and 34 underwent EGFR inhibitor treatment. As expected, patients bearing activating EGFR mutations showed increased progression free survival (PFS) compared to patients with wild-type EGFR status (9.3 vs 1.4 months, p = 0.0629). Analysis of baseline tumor RTK profiles revealed that, regardless of EGFR mutation status, higher levels of EGFR relative to MET correlated with longer PFS. At multiple EGFR/MET ratio cut-offs, including 1, 2 and 3, median PFS according to below vs. above cut-offs were 0.4 vs. 6.1 (p = 0.0001), 0.5 vs. 9.3 (p = 0.0006) and 1.0 vs. 11.2 months (p = 0.0008), respectively. The EGFR/MET ratio measured in tumors at baseline may help identify NSCLC patients most likely to benefit from prolonged PFS when treated with EGFR inhibitors.


Stretching Hookean ribbons part II: from buckling instability to far-from-threshold wrinkle pattern.
We address the fully developed wrinkle pattern formed upon stretching a Hookean, rectangular-shaped sheet, when the longitudinal tensile load induces transverse compression that far exceeds the stability threshold of a purely planar deformation. At this "far-from-threshold" parameter regime, which has been the subject of the celebrated Cerda-Mahadevan model (Cerda and Mahadevan in Phys Rev Lett 90:074302, 2003), the wrinkle pattern expands throughout the length of the sheet and the characteristic wavelength of undulations is much smaller than its width. Employing Surface Evolver simulations over a range of sheet thicknesses and tensile loads, we elucidate the theoretical underpinnings of the far-from-threshold framework in this setup. We show that the evolution of wrinkles comes in tandem with collapse of transverse compressive stress, rather than vanishing transverse strain (which was hypothesized by Cerda and Mahadevan in Phys Rev Lett 90:074302, 2003), such that the stress field approaches asymptotically a compression-free limit, describable by tension field theory. We compute the compression-free stress field by simulating a Hookean sheet that has finite stretching modulus but no bending rigidity, and show that this singular limit encapsulates the geometrical nonlinearity underlying the amplitude-wavelength ratio of wrinkle patterns in physical, highly bendable sheets, even though the actual strains may be so small that the local mechanics is perfectly Hookean. Finally, we revisit the balance of bending and stretching energies that gives rise to a favorable wrinkle wavelength, and study the consequent dependence of the wavelength on the tensile load as well as the thickness and length of the sheet.


[Immunologic studies in active rheumatic fever and infectious endocarditis].
We compared clinical and immunological characteristics of acute rheumatic fever (19 cases) and infectious endocarditis (7 cases), because these two diseases can be confused easily with each other and their differential diagnosis is not simple. In this small series we had cases of acute rheumatic fever with splenomegaly and/or vasculitis, as well as infectious endocarditis with subcutaneous nodules, which exemplifies the diagnostic problem. Using laboratory tests we were able to point out differences which are statistically significant, such as: rheumatoid factor by passive agglutination of IgG sensitized latex particles (X2 4.27 p less than 0M05), and tests which reflects the presence of circulating immune complexes, hemolytic capacity of antigammaglobulin antibodies (X2 3.79 p less than 0.05) and the presence of circulating C3 degradation products (X2 5.92 p less than 0.01), which occurs preferentially or exclusively in infectious endocarditis. Although in the standard patient the clinical assessment is usually sufficient to establish a diagnosis, when differentiation between acute rheumatic fever and infectious endocarditis is not clear, immunologic tests are helpful.


Effect of accurate heart delineation on cardiac dose during the CONVERT trial.
This study investigated the effect of deviation from protocol in heart delineation for the Concurrent Once-daily Versus twice-daily Radiotherapy (CONVERT) Trial ( ClinicalTrials.gov Identifier NCT00433563) quality assurance (QA) programme and the effect of that on mean cardiac dose and percentage of heart volume receiving ≥5 Gy (V5%) and percentage of heart volume receiving ≥30 Gy (V30%). Patients with limited-stage small-cell lung cancer in the CONVERT trial were randomized to receive 45 Gy in 30# twice daily or 66 Gy in 33# once daily radiotherapy, with concurrent chemotherapy in both arms. Of the 100 trial patient cases reviewed by the QA team [for patient selection, disease/organs at risk (OARs) outlining and treatment planning], 50 patient cases were selected, and the heart was reoutlined according to the "gold standard" trial protocol. Dose-volume histogram (DVH) data were extracted. The impact of change in heart volume on cardiac DVH is presented. For gold standard cardiac outlines, an increase in V5% and V30% was seen in 77.3% and 81.8% of cases, respectively, in the control arm (45 Gy) and in 78.6% and 82.1% of cases, respectively, in the experimental arm (66 Gy). The median increase in V5% was 1.4% and in V30%, it was 3.4%. The average of the mean cardiac dose for the control arm increased by 2.1 Gy (from 15.2 Gy for the centres outline to 17.3 Gy for the gold standard outline) and for the experimental arm by 2.4 Gy (from 16.2 to 18.6 Gy). This study demonstrates the importance of having a robust QA programme in place to ensure accuracy of cardiac delineation to facilitate future studies investigating the impact of cardiac dose on toxicity. Advances in knowledge: This study highlights the importance of ensuring accurate delineation of OARs in clinical trials, where conclusions about normal tissue toxicity are to be drawn.


Systemic simvastatin rescues retinal ganglion cells from optic nerve injury possibly through suppression of astroglial NF-κB activation.
Neuroinflammation is involved in the death of retinal ganglion cells (RGCs) after optic nerve injury. The purpose of this study was to determine whether systemic simvastatin can suppress neuroinflammation in the optic nerve and rescue RGCs after the optic nerve is crushed. Simvastatin or its vehicle was given through an osmotic minipump beginning one week prior to the crushing. Immunohistochemistry and real-time PCR were used to determine the degree of neuroinflammation on day 3 after the crushing. The density of RGCs was determined in Tuj-1 stained retinal flat mounts on day 7. The effect of simvastain on the TNF-α-induced NF-κB activation was determined in cultured optic nerve astrocytes. On day 3, CD68-positive cells, most likely microglia/macrophages, were accumulated at the crushed site. Phosphorylated NF-κB was detected in some astrocytes at the border of the lesion where the immunoreactivity to MCP-1 was intensified. There was an increase in the mRNA levels of the CD68 (11.4-fold), MCP-1 (22.6-fold), ET-1 (2.3-fold), GFAP (1.6-fold), TNF-α (7.0-fold), and iNOS (14.8-fold) genes on day 3. Systemic simvastatin significantly reduced these changes. The mean ± SD number of RGCs was 1816.3±232.6/mm(2) (n = 6) in the sham controls which was significantly reduced to 831.4±202.5/mm(2) (n = 9) on day 7 after the optic nerve was crushed. This reduction was significantly suppressed to 1169.2±201.3/mm(2) (P = 0.01, Scheffe; n = 9) after systemic simvastatin. Simvastatin (1.0 µM) significantly reduced the TNF-α-induced NF-κB activation in cultured optic nerve astrocytes. We conclude that systemic simvastatin can reduce the death of RGCs induced by crushing the optic nerve possibly by suppressing astroglial NF-κB activation.


Relationships among genotypes, virulence and clinical forms of Sporothrix schenckii infection.
This study explored the relationships among genotypes, virulence and clinical forms of Sporothrix schenckii. Genomic DNA from isolates of S. schenckii, collected from different clinical forms of sporotrichosis, was amplified by randomly amplified polymorphic DNA (RAPD). Suspensions of different isolates of S. schenckii were inoculated into healthy BALB/c mice to compare their virulence, and the numbers and distribution of spores were determined by histological analysis. RAPD analysis indicated that the isolates from different clinical forms of sporotrichosis belonged to different genotypes. The mice inoculated with isolates from disseminated sporotrichosis showed an earlier onset of illness and more severe lesions than those inoculated with isolates from lymphocutaneous sporotrichosis, which, in turn, showed an earlier onset of illness and more severe lesions than those inoculated with isolates from fixed cutaneous sporotrichosis. Healthy BALB/c mice injected with isolates from disseminated sporotrichosis died within 10 days, whereas isolates from lymphocutaneous sporotrichosis and fixed cutaneous sporotrichosis failed to cause death. Histologically, mice inoculated with isolates from disseminated sporotrichosis had more spores than those inoculated with isolates from lymphocutaneous sporotrichosis and fixed cutaneous sporotrichosis. Thus, different genotypes may be associated closely with the virulence of different clinical forms of S. schenckii infection.


Specification of fetal liver endothelial progenitors to functional zonated adult sinusoids requires c-Maf induction.
The liver vascular network is patterned by sinusoidal and hepatocyte co-zonation. How intra-liver vessels acquire their hierarchical specialized functions is unknown. We study heterogeneity of hepatic vascular cells during mouse development through functional and single-cell RNA-sequencing. The acquisition of sinusoidal endothelial cell identity is initiated during early development and completed postnatally, originating from a pool of undifferentiated vascular progenitors at E12. The peri-natal induction of the transcription factor c-Maf is a critical switch for the sinusoidal identity determination. Endothelium-restricted deletion of c-Maf disrupts liver sinusoidal development, aberrantly expands postnatal liver hematopoiesis, promotes excessive postnatal sinusoidal proliferation, and aggravates liver pro-fibrotic sensitivity to chemical insult. Enforced c-Maf overexpression in generic human endothelial cells switches on a liver sinusoidal transcriptional program that maintains hepatocyte function. c-Maf represents an inducible intra-organotypic and niche-responsive molecular determinant of hepatic sinusoidal cell identity and lays the foundation for the strategies for vasculature-driven liver repair.


Treatment and prophylaxis of Pneumocystis carinii pneumonia.
Trimethoprim-sulfamethoxazole and parenteral pentamidine isethionate are effective in 60 to 80 per cent of AIDS patients with pneumocystis pneumonia. Adverse reactions are frequent with both agents, but because the adverse reactions are less severe with trimethoprim-sulfamethoxazole, this agent is the drug of choice for patients who are not known to be intolerant of it. The recommended duration of therapy is 21 days. Aerosolized pentamidine and intravenous trimetrexate are investigational agents that show considerable promise, but their role in the therapy of pneumocystis pneumonia will have to be demonstrated in controlled trials. For patients who fail to respond to conventional agents after 5 to 10 days of therapy, therapeutic alternatives to consider would be trimetrexate, DFMO, or high-dose corticosteroids, the latter given with conventional agents. Prophylaxis against pneumocystis pneumonia is appropriate for HIV-infected patients with fewer than 300 T4 lymphocytes per cu mm, even if they are receiving zidovudine (Retrovir). It also should be considered in patients with a prior history of this infection, irrespective of the T4 count. The efficacy of trimethoprim-sulfamethoxazole, pyrimethamine-sulfadoxine, or aerosolized pentamidine has not yet been substantiated. Many patients cannot tolerate the first two combinations chronically.


A Structurally-Tunable 3-Hydroxyflavone Motif for Visible Light-Induced Carbon Monoxide-Releasing Molecules (CORMs).
Molecules that can be used to deliver a controlled amount of carbon monoxide (CO) have the potential to facilitate investigations into the roles of this gaseous molecule in biology and advance therapeutic treatments. This has led to the development of light-induced CO-releasing molecules (photoCORMs). A goal in this field of research is the development of molecules that exhibit a combination of controlled CO release, favorable biological properties (e.g., low toxicity and trackability in cells), and structural tunability to affect CO release. Herein, we report a new biologically-inspired organic photoCORM motif that exhibits several features that are desirable in a next-generation photoCORM. We show that 3-hydroxyflavone-based compounds are easily synthesized and modified to impart changes in absorption features and quantum yield for CO release, exhibit low toxicity, are trackable in cells, and can exhibit both O2-dependent and -independent CO release reactivity.


HPV16/18 vaccination to prevent cervical cancer in The Netherlands: model-based cost-effectiveness.
We evaluated the cost-effectiveness of HPV16/18 vaccination for girls aged 12 years in The Netherlands in addition to cervical cancer screening. For this purpose, we developed a simulation model that describes the relation between each of the high-risk human papillomavirus (hrHPV) types and cervical disease, allowing the occurrence of multiple type-specific infections. Model parameters were derived from Dutch cohort studies, including a large population-based screening trial, and from the national cervical cancer registry. The model satisfactorily reproduced Dutch data on HPV infection and the presence of cervical lesions. For our base-case scenario in which 85% of the girls aged 12 years were vaccinated against types 16/18 (95% efficacy, lifelong protection), the model predicted a decrease of 60% in the number of cervical cancer cases and cervical cancer deaths indicating that substantial health benefits can be achieved. Health savings were robust against changes in the vaccine efficacy (varied from 85% to 98%) but savings showed a substantial reduction when the efficacy started waning 10 years after vaccination. The discounted costs per quality-adjusted life year (QALY) were euro 19,500/QALY (range euro 11,000 to euro 25,000/QALY) and lied near the cost-effectiveness threshold of euro 20,000/QALY used in The Netherlands. The simulations further showed that vaccination cannot replace screening because vaccination without screening was less effective than screening in preventing cancer in women over 40 years of age. In conclusion, our model results support the implementation of HPV16/18 vaccination in young women in addition to cervical cancer screening.


Reactive oxygen species mediate cyclooxygenase-2 induction during monocyte to macrophage differentiation: critical role of NADPH oxidase.
The objective of this study was to explore the relationship between monocyte differentiation into macrophages and cyclooxygenase-2 (Cox-2) expression, based upon the observation that high amounts of this enzyme, colocalizing mainly with macrophages, have been found in human atherosclerotic lesions. Moreover, the hypothesis that reactive oxygen species (ROS) could be important as mediators of Cox-2 expression during monocyte differentiation was verified. Although ROS are known as modulators of gene expression profile, their involvement in monocyte differentiation has not been explored previously. Human adherent monocytes and the promonocytic cell line U937 were differentiated into macrophages by phorbol ester (PMA). Cox-2 was evaluated in terms of protein, mRNA and activity. Intracellular ROS formation was measured by the oxidant sensitive dye 2',7'-dichlorofluorescein diacetate. NADPH oxidase subunit p47(phox) was evaluated by Western blot analysis. Functionally active Cox-2 is expressed during PMA-induced monocyte transition into macrophages and ROS driven by the NADPH oxidase play a critical role in this event. Monocyte differentiation into macrophages, possibly triggered by unquenched ROS, may contribute to the increased inflammatory response within atheromata.


Sequential [6+2], [2+2], and [3+2] annulations for rapid assembly of multiple fragments.
Assembly of four components through sequential [6+2], [2+2], and [3+2] annulations on an azulenone manifold allows for five-step access to a natural product-inspired scaffold with exquisite control of the ten consecutive stereocenters. X-ray analysis was used to define the spatial arrangement of the three fragments and functional groups on this rigid scaffold.


Dyslipidemia and Obesity in Ischemic Stroke.
Background Dyslipidemia and obesity are both important risk factors for the first and recurrent ischemic strokes. Dyslipidemia is highly prevalent among Asian populations, and the prevalence of obesity is also noted to be progressively increasing in this population. This study was carried out to determine the prevalence of dyslipidemia and central obesity and their association with each other and various cardiovascular risk factors among patients who presented with an acute ischemic stroke to a tertiary care university hospital in Nepal. Methods This study is a secondary analysis done on data from a prospective observational study that was carried out on patients who were either acutely admitted to or visited the outpatient department of the hospital with a diagnosis of ischemic stroke. Dyslipidemia was defined according to the third report of the National Cholesterol Education Program expert panel on detection, evaluation, and treatment of high blood cholesterol in adults. Obesity was defined as central obesity by measuring waist circumference. Data were collected by convenience sampling and analyzed by IBM Corp. Released 2019. IBM SPSS Statistics for Windows, Version 26.0. Armonk, NY: IBM Corp. Significant variables were compared with logistic regression analysis. Other data were expressed as frequencies and percentages. Results Out of 145 patients, 77 were male (53.1%). The mean age of the patients was 60.15 years. Dyslipidemia and central obesity were present in 96.6% and 57.9% of the patients, respectively. The most common lipid abnormality was low-density lipoprotein cholesterol, present in 82.8% of the patients, followed by high triglycerides, present in 21.4% of them. Dyslipidemia was not associated with any vascular risk factors. Central obesity was significantly associated with female gender, diabetes, and low-density lipoprotein cholesterol in univariate analysis. However, in multivariate logistic regression analysis, it was significantly associated with only female gender (p=0.003) and diabetes (p=0.012). Conclusion Dyslipidemia and central obesity are very common in patients with ischemic stroke. Dyslipidemia is not associated with any vascular risk factors. However, central obesity is significantly associated with the female gender and diabetes.


[Importance of structural examination methods in the follow-up of patients with ocular hypertension].
To evaluate the contribution of Heidelberg Retina Tomograph (HRT) and blue-on-yellow perimetry (B-Y) for the follow-up and early diagnosis of glaucoma in patients with ocular hypertension (OHT). We also dealed with the comparison of visual field (VF) examination by means of the B-Y and white-on-white perimetry, correlation between VF indexes and HRT parameters, importance of the central corneal thickness (CCT) and the comparison of other characteristics of the study and control groups during the 3-year-study-period. Both eyes of 28 patients with OHT (study group, SG) and 15 control subjects (control group, CG) were included in the study. Subjects in both groups were examined annually. At each visit complete ophthalmological examination was carried out, including the biomicroscopic evaluation of the optic disc, aplanation tonometry, HRT II analysis of the optic nerve head (ONH) and B-Y perimetry. Pachymetry was performed only once at the beginning of the study. During the 3-year-follow-up structural changes of the ONH developed in 2 patients with OHT only. They were not accompanied by VF defects on B-Y perimetry. Intraocular pressure and CCT were higher in the SG (p < 0.01). CCT significantly and positively correlated with the level of intraocular pressure in both groups. Mean sensitivity (MS) of the B-Y VF was repeatedly smaller in the SG compared to the CG (p < 0.01). Difference between MS a mean defect (MD) of the B-Y and white-on-white VF in the SG was significant (p < 0.01). The B-Y perimetry test lasted much longer than standard perimetry. A marked learning effect was found with B-Y perimetry. Despite significant correlations of follow-up B-Y perimetry examinations, high test-retest variability was found. No significant change in topographic parameters of the ONH occurred during the follow-up period. HRT displayed low variability of follow-up examinations. No significant correlation between topographic parameters of the ONH and VF indexes on B-Y perimetry was found. In 2 cases of OHT the HRT preceded VF changes on B-Y perimetry. HRT showed high reproducibility, on the contrary, B-Y perimetry was accompanied by high variability making the distinction of fluctuation and progression more difficult. Pachymetry is a very useful tool in patients with OHT.


Effect of severe isolated unilateral and bilateral diaphragm weakness on exercise performance.
Patients with isolated diaphragm paralysis depend on recruitment of extradiaphragmatic respiratory muscles to increase ventilation, but little is known about exercise performance or the response of the inspiratory muscles to loaded breathing. By convention, unilateral diaphragm paralysis is regarded as a trivial condition whereas bilateral paralysis is considered to be potentially life-threatening. In fact, no data exist concerning exercise performance under these conditions. We studied incremental treadmill exercise performed by eight patients with bilateral diaphragm paralysis, eight patients with unilateral diaphragm paralysis, and eight age-matched control subjects. Respiratory muscle endurance (RME) was also measured by an inspiratory threshold loading method. Exercise time, compared with control subjects (671 seconds), was moderately reduced in unilateral diaphragm paralysis (512 seconds, p = 0.07) and further reduced in bilateral diaphragm paralysis (456 seconds, p = 0.02). Similarly, peak minute ventilation was lower in patients with unilateral diaphragm paralysis (84 L x min(-1), p = 0.01) and in patients with bilateral diaphragm paralysis (69 L x min(-1), p = 0.001) compared with control subjects (114 L x min(-1)). However, patients with unilateral diaphragm paralysis and patients with bilateral diaphragm paralysis had increased ratios of peak oxygen consumption to peak minute ventilation compared with control subjects (p = 0.0007 and p < 0.0001, respectively). Nine patients had normal RME; exercise time was moderately increased in these patients (502 seconds) compared with seven patients with reduced RME (461 seconds). In conclusion, although exercise performance is impaired in bilateral diaphragm paralysis, these patients can sustain a reasonable exercise load, particularly if RME is preserved and compensatory mechanisms have developed. In addition, exercise tolerance is diminished in patients with unilateral diaphragm paralysis.