Longterm timolol therapy.
Of 145 patients registered for an investigation of timolol, 27 patients were dropped for unrelated reasons. Among the remaining 118 patients (212 eyes), a significant reduction in intraocular pressure resulted from twice-a-day topical instillation of 0.25 or 0.5% timolol to ocular hypertensives, primary open-angle glaucoma or aphakic glaucoma patients. Outflow facility improved only slightly, but remained improved throughout the course of this study. A significant reduction in aqueous secretion, however, was the predominant cause of intraocular pressure reduction. Timolol alone controlled intraocular pressure in 87% of ocular hypertensives, in 68% of patients with chronic open-angle glaucoma and in 68% of patients with angle-unobstructed aphakic glaucomas. The addition of epinephrine brought the intraocular pressure to less than 22 mm Hg in 85% of the total group of patients.


Pancreatic abscess: results of prolonged irrigation of the pancreatic bed after surgery.
The mortality from pancreatic abscess may approach 70 per cent and the survivors often require repeated operations to debride the pancreas and to drain recurrent abscesses. We report the results of prolonged irrigation of the pancreatic bed after surgical débridement in 11 patients. Surgery was performed at an average of 17 days (range 8-25 days) after the onset of symptoms. The pancreatic slough was thoroughly debrided and 2-6 large drains were placed in the pancreatic bed. Irrigation with saline or Diaflex solution (2-6 l/day) was started after 2 days and continued for a mean of 25 days (range 5-54 days). There were three deaths (27.3 per cent) after surgery: one of these patients required reoperation and packing for massive postoperative haemorrhage and all three had some evidence of persisting sepsis at autopsy. Prolonged irrigation of the pancreatic bed after surgical débridement may reduce mortality and the need for repeated drainage procedures in patients with pancreatic abscess, but the detection and treatment of persisting sepsis remains the major problem.


Maternal deprivation disrupts mitochondrial energy homeostasis in the brain of rats subjected to ketamine-induced schizophrenia.
Maternal deprivation (MD) appears to be one of the environmental factors involved in the pathophysiology of schizophrenia. A widely used animal model of the schizophrenia involves the administration of ketamine, a dissociative anesthetic, NMDA receptors noncompetitive antagonist, that induce symptoms such as schizophrenia. To clarify the molecular mechanism of schizophrenia induced by MD, we investigated alterations in energetic metabolism, oxidative stress and neurotrophic factor levels in the brain of rats following MD and/or a single administration of ketamine during adulthood. Male Wistar rats were subjected to MD for 10 days. Additionally, these animals received acute ketamine (5, 15 or 25 mg/kg by intraperitoneal route, i.p.) during adulthood, and 30 min later, they were killed and the prefrontal cortex (PFC), the hippocampus and the striatum were removed for molecular analyses. Ketamine 25 mg/kg and/or MD and Ketamine 15 and 5 mg/kg with MD decreased the creatine kinase (CK) activity in the hippocampus. The enzyme activity of succinate dehydrogenase (SDH) in the Krebs cycle had increased in the striatum following the administration of ketamine 25 mg/kg, MD per se or MD plus ketamine 5 and 15 mg/kg. MD per se or MD combined with ketamine in different doses increased the activity of mitochondrial complexes. The PFC of animals subjected to MD and administered with ketamine 5 mg/kg exhibited increased protein carbonyl content. In the hippocampus, ketamine 15 mg/kg, ketamine 25 mg/kg and MD each increased the carbonyl content. In the striatum, the TBARS levels were increased by the administration of ketamine 25 mg/kg. Finally, in the hippocampus, MD alone or in combination with ketamine reduced the Nerve Growth Factor (NGF) levels; however, the Brain-derived Neurotrophic Factor (BDNF) levels were unaltered. In the present study, we suggest that MD increased the risk of psychotic symptoms in adulthood, altering different parameters of energy and oxidative stress. Our results suggest that adverse experiences occurring early in life may sensitize specific neurocircuits to subsequent stressors, inducing vulnerability, and may help us understand the pathophysiological mechanisms involved in this disorder.


[Bacteriospermia in Assisted Reproductive Techniques: effects of bacteria on spermatozoa and seminal plasma, diagnosis and treatment].
The presence of bacteria in semen could induce impairment of sperm morphology, alteration of sperm function and mechanical or functional obstruction of the seminal tract. The term of bacteriospermia does not signify infection. Bacteriospermia and male accessory gland infection (MAGI) have indeed to be distinguished. They may lead both to male infertility but their diagnosis and treatment options differ. This review summarizes effects of bacteria and leucocytospermia on sperm parameters and functions. Then, indications, benefits and risks of treatment of bacteriospermia and MAGI, in assisted reproductive techniques (ART) will be discussed. For bacteria commonly observed in semen, this review aims at defining some thresholds above which a treatment is required. These thresholds were established according to literature, according to French microbiology society and in function of our usual practice. This review should help practitioners of reproductive medicine to take care of bacteriospermia in semen.


Who's included? The role of the Clinical Research Nurse in enabling research participation for under-represented and under-served groups.
There is a global call for more inclusive clinical research that is representative of all populations, particularly those historically under-represented or under-served. A lack of broad representation results in disproportionate health outcomes and limits the applicability and translation of research findings. Identify and describe barriers to participation across the research lifecycle and consider the role of the Clinical Research Nurse (CRN) in promoting inclusivity, including for Aboriginal and Torres Strait Islander Peoples within Australia. Review of recent literature and best practice identified barriers to research participation across the research process; at system, participant and practitioner levels. This discussion paper explores the role of the CRN; acting as enablers, facilitators and navigators, to mitigate participation barriers. With their comprehensive understanding of the research process, clinical care pathways, reflective practices and participant-centred approaches, CRNs are uniquely positioned to advocate for greater equity in access to clinical research and to motivate stakeholders across the research enterprise to embed inclusive approaches in the design, conduct and dissemination of research. An in-depth understanding of the research process, self, and cultural norms of the populations they serve is essential for CRNs to effectively advocate for equity in access to research.


Disruption of model-based behavior and learning by cocaine self-administration in rats.
Addiction is characterized by maladaptive decision-making, in which individuals seem unable to use adverse outcomes to modify their behavior. Adverse outcomes are often infrequent, delayed, and even rare events, especially when compared to the reliable rewarding drug-associated outcomes. As a result, recognizing and using information about their occurrence put a premium on the operation of so-called model-based systems of behavioral control, which allow one to mentally simulate outcomes of different courses of action based on knowledge of the underlying associative structure of the environment. This suggests that addiction may reflect, in part, drug-induced dysfunction in these systems. Here, we tested this hypothesis. This study aimed to test whether cocaine causes deficits in model-based behavior and learning independent of requirements for response inhibition or perception of costs or punishment. We trained rats to self-administer sucrose or cocaine for 2 weeks. Four weeks later, the rats began training on a sensory preconditioning and inferred value blocking task. Like devaluation, normal performance on this task requires representations of the underlying task structure; however, unlike devaluation, it does not require either response inhibition or adapting behavior to reflect aversive outcomes. Rats trained to self-administer cocaine failed to show conditioned responding or blocking to the preconditioned cue. These deficits were not observed in sucrose-trained rats nor did they reflect any changes in responding to cues paired directly with reward. These results imply that cocaine disrupts the operation of neural circuits that mediate model-based behavioral control.


Hybridoma antibodies reactive with human bladder carcinoma cell surface antigens.
Hybridoma antibodies to the human bladder cancer cell line RT4 were prepared by fusing spleen cells from RT4-immunized BALB/c mice with the murine plasmacytoma line NS-1. When antibodies were characterized by direct serological testing, antibody A2 exhibited highly restricted specificity for an antigen found only on RT4. However, further analysis with absorption, a standard serologic technique that has not been widely applied to hybridoma antibodies because of their monoclonal nature, revealed that the antigen could also be found on 1 other bladder cancer cell line, 5637, and on the human cervical carcinoma line ME-180. Quantitative absorption assays suggest that this phenomenon of absorption-positive, direct test-negative cells may be related to the amount of antigen present on the cell surface. Another antibody, A80, detected an antigen with broader distribution. Both antibodies described heat-labile, trypsin-resistant antigens present on a restricted range of cells. The role of these antibodies in identifying subsets of malignant urothelial cells is being investigated.


Transmission of Legionnaires' Disease through Toilet Flushing.
We describe 2 cases of healthcare-associated Legionnaires' disease in patients in France hospitalized 5 months apart in the same room. Whole-genome sequencing analyses showed that clinical isolates from the patients and isolates from the room's toilet clustered together. Toilet contamination by Legionella pneumophila could lead to a risk for exposure through flushing.


Histological analysis of spermatogenesis and the germ cell development strategy within the testis of the male Western Cottonmouth Snake, Agkistrodon piscivorus leucostoma.
Cottonmouth (Agkistrodon piscivorus leucostoma) testes were examined histologically to determine the germ cell development strategy employed during spermatogenesis. Testicular tissues from Cottonmouths were collected monthly from swamps around Hammond, Louisiana. Pieces of testis were fixed in Trump's fixative, dehydrated in ethanol, embedded in Spurr's plastic, sectioned with an ultramicrotome, and stained with toluidine blue and basic fuchsin. Spermatogenesis within Cottonmouths occurs in two independent events within a single calendar year. The testes are active during the months of March-June and August-October with spermiation most heavily observed during April-May and October. To our knowledge, this is the first study that describes bimodal spermatogenesis occurring in the same year within the subfamily Crotalinae. During spermatogenesis, no consistent spatial relationships are observed between germ cell generations. Typically, either certain cell types were missing (spermatocytes) or the layering of 3-5 spermatids and/or spermatocytes within the same cross-section of seminiferous tubule prevented consistent spatial stages from occurring. This temporal pattern of sperm development is different from the spatial development found within birds and mammals, being more reminiscent of that seen in amphibians, and has now been documented within every major clade of reptile (Chelonia, Serpentes, Sauria, Crocodylia). This primitive-like sperm development, within a testis structurally similar to mammals and birds, may represent an intermediate testicular model within the basally positioned (phylogenetically) reptiles that may be evolutionarily significant.


Benign retroperitoneal schwannoma.
A case of benign retroperitoneal Schwannoma is presented, with special attention to clarification of often confused pathologic nomenclature. The radiologic diagnosis and the literature on this rare tumor are reviewed.


Anode-Free Lithium Metal Batteries Based on an Ultrathin and Respirable Interphase Layer.
Anode-free lithium (Li) metal batteries are desirable candidates in pursuit of high-energy-density batteries. However, their poor cycling performances originated from the unsatisfactory reversibility of Li plating/stripping remains a grand challenge. Here we show a facile and scalable approach to produce high-performing anode-free Li metal batteries using a bioinspired and ultrathin (250 nm) interphase layer comprised of triethylamine germanate. The derived tertiary amine and Lix Ge alloy showed enhanced adsorption energy that significantly promoted Li-ion adsorption, nucleation and deposition, contributing to a reversible expansion/shrinkage process upon Li plating/stripping. Impressive Li plating/stripping Coulombic efficiencies (CEs) of ≈99.3 % were achieved for 250 cycles in Li/Cu cells. In addition, the anode-free LiFePO4 full batteries demonstrated maximal energy and power densities of 527 Wh kg-1 and 1554 W kg-1 , respectively, and remarkable cycling stability (over 250 cycles with an average CE of 99.4 %) at a practical areal capacity of ≈3 mAh cm-2 , the highest among state-of-the-art anode-free LiFePO4 batteries. Our ultrathin and respirable interphase layer presents a promising way to fully unlock large-scale production of anode-free batteries.


The role of air pollution and climate on the growth of urban trees.
The urban environment features poor air quality and harsher climate conditions that affect the life in the cities. Citizens are especially vulnerable to climate change, because heat island and impervious exacerbates extreme climate events. Urban trees are important tools for mitigation and adaptation of cities to climate change because they provide ecosystem services that increase while trees grow. Nonetheless, the growth of trees may be affected by the harsher conditions found in the urban environment. We assessed the impact of air pollution and climate on the spatial/temporal variability of tree growth in São Paulo, Brazil, one of the largest urban conglomerates in the world. For this purpose, we sampled 41 trees of the Tipuana tipu species in a region that includes industrial areas. We built a tree-ring chronology using standard dendrochronological methods. Spatial analyses show that trees grow faster in the warmer parts of the city and under higher concentrations of airborne P, whereas growth is reduced under higher concentrations of Al, Ba, Zn. Particulate matter (PM10) from the industrial cluster also reduce average growth rate of trees, up to 37% in all diameter classes. Similar results were obtained via temporal analyses, suggesting that the annual growth rate is positively associated with temperature, which explain 16% of interannual growth variability. Precipitation, on the other hand, has no association with tree growth. The average concentration of PM10 explains 41% of interannual growth variability, and higher concentrations during the driest months reduce growth rate. Despite heat island effect and water limitation in the soil of the city, this species takes advantage of warmer conditions and it is not limited by water availability as measured by precipitation. On the other hand, air pollution directly impacts the growth of these trees being a major limiting growth factor.


The effect of label affinity on the sensitivity and specificity of a hapten radioimmunoassay: a comparison of three [125I]diphenylhydantoin radioligands with the 14C-labelled drug.
The effect on the sensitivity and specificity of a radioimmunoassay for diphenylhydantoin (DPH)has been investigated using three 125I-labelled tyrosine ester derivatives of DPH having different bridge lengths between the tyrosine moiety and the DPH moiety and 14C-labelled DPH. The results demonstrate that for a hapten which does not completely fill the antibody-binding sites, greatest sensitivity is achieved when the bridge of the iodine label is most dissimilar to that present in the original immunogen, when the hapten and label affinities are nearly equivalent. Greatest specificity is achieved with the label which most resembles the original immunogen. These results illustrate the difficulty of designing satisfactory labels for assays of both high specificity and sensitivity since minimal changes in label structure may produce greatly amplified changes in the subsequent affinity of the label for the antiserum.


The unique biology and treatment of primary mediastinal B-cell lymphoma.
The unique biological features of primary mediastinal large B-cell lymphoma are offering suggestions for the development and application of innovative drugs in patients who do not respond to first-line regimens or relapse. This lymphoma, in fact, is characterised by high rates of curability with standard anthracycline-containing chemoimmunotherapy regimens, but still displays a severe prognosis if adequate responses are not rapidly achieved or if the disease recurs. Radiotherapy has proved to be effective to consolidate responses after induction, but it may be safely avoided in certain cases, especially when a metabolic complete response is obtained, as to reduce the incidence of radiation-induced long-term sequelae. The current management of this lymphoma, both at diagnosis and at relapse, is reviewed in this paper, along with the description of its peculiar biological panorama.


5-year interval change in voiding function of orthotopic ileal neobladder.
We report the 5-year interval change in voiding function of orthotopic ileal neobladder. Voiding function was evaluated at two points with an interval of 5 years in 49 patients with orthotopic ileal neobladder. The first and second surveys were performed in May, 1998 (1998 survey) and in April 2003 (2003 survey), respectively. Median age at operation was 67 years, ranging 47-77. Median follow-up times at the first and the second surveys were 19.5 months (range, 3-87) and 67.5 months (range, 62-145), respectively. There was no significant change in daytime continence status between the 1998 and 2003 surveys. More than 95% never or only occasionally suffered daytime incontinence in the two surveys. On the other hand, 15 (34.1%) and 14 (31.8%), respectively, experienced night-time incontinence, despite regular voiding during the night. When voiding patterns were analysed, 11 patients (23.4%) sometimes or often performed catheterization because of difficulty in urinating or incomplete emptying of the neobladder in the 1998 survey. Three patients (6.4%) were unable to void and required regular catheterization. In the 2003 survey, however, such poor voiders increased to nine (19.1%), although the difference was not significant. During the study period of 5 years, there was no change in renal function. Continence status, either at daytime or at nighttime, was stable during the study period. The number of the patients who needed regular catheterization tended to increase, suggesting deterioration of voiding function with time. Careful long-term follow up is warranted.


Individual and socio-demographic determinants of suicide: An examination on WHO countries.
Suicide cases have psychological, socio-economic and cultural aspects, and such cases may have catastrophic impacts in societies due to their outcomes. This study was aimed to reflect the effect of psychological, behavioral, socio-demographic and economic determinants on suicide. The Ordinary Least Square (OLS) Regression Analysis was utilized for the purposes of this study. Five models were established. In this contex, the first model includes the variables on psychological determinants; the second model with the variables on behavioral determinants; the third model with the variables on socio-demographic determinants; the fourth model with the variables on economic determinants and finally the fifth model with all of the independent variables. According to the results, the variables of depression prevalence, alcohol consumption and unemployment rates had statistically significant effect on the suicide cases (p < .05). The study's outcomes are considered to contribute on the evidence-based policy development process.


RA in 2011: Advances in diagnosis, treatment and definition of remission.
Evidence presented in 2011 suggests that rheumatoid arthritis might comprise two separate diseases—each with different etiological underpinnings—and that kinase inhibitors could soon be added to the therapeutic armamentarium. Together with new definitions of remission, these advances could aid the development of personalized, treat-to-target strategies.


Seasonal variation of dissolved bioaccessibility for potentially toxic elements in size-resolved PM: Impacts of bioaccessibility on inhalable risk and uncertainty.
The health effects of potentially toxic elements (PTEs) in airborne particulate matter (PM) are strongly dependent on their size distribution and dissolution. This study examined PTEs within nine distinct sizes of PM in a Chinese megacity, with a focus on their deposited and dissolved bioaccessibility in the human pulmonary region. A Multiple Path Particle Dosimetry (MPPD) model was used to estimate the deposited bioaccessibility, and an in-vitro experiment with simulated lung fluid was conducted for dissolved bioaccessibility. During the non-heating season, the dissolved bioaccessible fraction (DBF) of As, Cd, Co, Cr, Mn, Pb and V were greater in fine PM (aerodynamics less than 2.1 μm) than in coarse PM (aerodynamics between 2.1 and 10 μm), and vice versa for Ni. With the increased demand of heating, the DBF of Pb and As decreased in fine particle sizes, probably due to the presence of oxide/silicate compounds from coal combustion. Inhalation health risks based on the bioaccessible concentrations of PTEs displayed the peaks in <0.43 μm and 2.1-3.3 μm particulate sizes. The non-cancer risk was at an acceptable level (95th percentiles of hazard index (HI) was 0.49), but the cancer risk exceeded the threshold value (95th percentiles of total incremental lifetime cancer risk (TCR) was 8.91 × 10-5). Based on the results of uncertainty analysis, except for the exposure frequency, the total concentrations and DBF of As and Cr in <0.43 μm particle size segment have a greater influence on the uncertainty of probabilistic risk.


Carpenter's nails, phonograph needles, piano wires, and safety pins: the history of operative fixation of metacarpal and phalangeal fractures.
This century has witnessed advances in basic sciences that have led to and resulted from advances in operative fixation of fractures. In addition to the sweeping changes in medicine and surgery, the development of corrosion-resistant alloys underpins all current concepts of fracture surgery. Most of the techniques were originally borrowed from work on large bones and most of the materials came from workshops or sewing boxes. Today, as improved understanding of bone healing and appropriate application of mechanical principles to skeletal injuries have become indispensable for appreciating the relative value of these techniques, operative fixation of hand fractures has emerged as a science in its own right.


Combatting the Rising Tide of Antimicrobial Resistance: Pharmacokinetic/Pharmacodynamic Dosing Strategies for Maximal Precision.
Antimicrobial pharmacokinetics/pharmacodynamics (PK/PD) principles and PK/PD models have been essential in characterizing the mechanism of antibiotic bacterial killing and determining the most optimal dosing regimen that maximizes clinical outcomes. This review summarized the fundamentals of antimicrobial PK/PD and the various types of PK/PD experiments that shaped the utilization and dosing strategies of antibiotics today. Multiple databases - including PubMed, Scopus, and EMBASE - were searched for published articles that involved PK/PD modelling and precision dosing. Data from in vitro, in vivo and mechanistic PK/PD models were reviewed as a basis for compiling studies that guide dosing regimens used in clinical trials. Literature regarding the utilization of exposure-response analyses, mathematical modelling and simulations that were summarized are able to provide a better understanding of antibiotic pharmacodynamics that influence translational drug development. Optimal pharmacokinetic sampling of antibiotics from patients can lead to personalized dosing regimens that attain target concentrations while minimizing toxicity. Thus the development of a fully integrated mechanistic model based on systems pharmacology can continually adapt to data generated from clinical responses, which can provide the framework for individualized dosing regimens. The promise of what PK/PD can provide through precision dosing for antibiotics has not been fully realized in the clinical setting. Antimicrobial resistance, which has emerged as a significant public health threat, has forced clinicians to empirically utilize therapies. Future research focused on implementation and translation of PK/PD-based approaches integrating novel approaches that combine knowledge of combination therapies, systems pharmacology and resistance mechanisms are necessary. To fully realize maximally precise therapeutics, optimal PK/PD strategies are critical to maximize antimicrobial efficacy against extremely-drug-resistant organisms, while minimizing toxicity.


Surgical site infection after central venous catheter-related infection in cardiac surgery. Analysis of a cohort of 7557 patients.
The aim of this study was to establish the relationship between the occurrence of a surgical site infection (SSI) and the presence of a central venous catheter-related infection (CVCRI). The Department of Thoracic and Cardiovascular Surgery, University Hospital, Rouen, has carried out a prospective epidemiological survey of all nosocomial infections (pneumonia, SSI and CVCRI) since 1997. The study group included all consecutive patients who underwent cardiac surgery over a 10-year period from 1997 to 2007. A nested case-control study was conducted to identify the risk factors for SSI after CVCRI. Cases were patients with SSI after CVCRI and controls were randomized from patients who presented with CVCRI not followed by SSI. In total, 7557 patients were included and 133 SSIs (1.7%) were identified. The rate of superficial SSI was 0.7% [95% confidence interval (CI): 0.5-0.9] and of mediastinitis was 1.0% (95% CI: 0.8-1.2). Among the 133 cases of SSI, 12 (9.0%; 95% CI: 5.0-14.8) occurred after a CVCRI with identical micro-organisms. CVCRI [adjusted odds ratio (aOR): 5.2; 95% CI: 3.2-8.5], coronary artery bypass grafting (aOR: 2.9; 95% CI: 1.6-5.2), and obesity (aOR: 11.4; 95% CI: 1.0-130.1) were independent factors associated with SSI. The new finding of this study is that patients with CVCRI were 5.2 times more likely to develop SSI compared to patients without CVCRI.


The role of L-arginine in ameliorating reperfusion injury after myocardial ischemia in the cat.
Myocardial ischemia followed by reperfusion results in endothelial dysfunction characterized by a reduced release of endothelium-derived relaxing factor (EDRF). Because EDRF has been characterized as nitric oxide, we examined the ability of L-arginine, the substrate for nitric oxide synthesis, to protect in a feline model of myocardial ischemia plus reperfusion. The effects of L-arginine were investigated in a 6-hour model of myocardial ischemia and reperfusion in pentobarbital-anesthetized cats. A bolus administration (30 mg/kg) of L-arginine, or its enantiomer D-arginine, was given followed by a continuous infusion of 10 mg/kg/min for 1 hour starting 10 minutes before reperfusion. Myocardial ischemia plus reperfusion in cats receiving D-arginine resulted in severe myocardial injury and endothelial dysfunction characterized by marked myocardial necrosis, high cardiac myeloperoxidase activity in ischemic cardiac tissue, and loss of acetylcholine- and A-23187-induced endothelium-dependent relaxation in coronary artery rings. In contrast, myocardial ischemia plus reperfusion cats treated with L-arginine exhibited a reduced area of cardiac necrosis (16 +/- 2% versus 41 +/- 5% of area at risk, p less than 0.01), lower myeloperoxidase activity in the ischemic region (0.3 +/- 0.08 versus 0.8 +/- 0.10 units/100 mg tissue, p less than 0.05), and significant preservation of acetylcholine- (p less than 0.01) and A-23187- (p less than 0.01) induced endothelial-dependent relaxation. These results demonstrate the ability of L-arginine to reduce necrotic injury in a cat model of myocardial ischemia plus reperfusion, and this reduction in infarct size is associated with the preservation of endothelial function and attenuation of neutrophil accumulation in ischemic cardiac tissue.


Estimation of animal transfer factors for radioactive isotopes of iodine, technetium, selenium and uranium.
In post-closure radiological safety assessments of repositories for solid radioactive wastes, transfers of radionuclides to animal products are typically characterised using Transfer Factors (TFs), defined as the ratio of the concentration of the radionuclide in the animal product of interest to the rate of intake in diet. Such transfer factors can be measured directly in experimental studies, but they can also be estimated by use of biokinetic models for uptake and retention of radionuclides in animals. Based on a review of the literature, biokinetic models have been developed for the uptake and retention of iodine, technetium, selenium and uranium. These biokinetic models allow TF values to be estimated for different types of animals and for different animal lifetimes. For each radionuclide considered, reference values and ranges of TF values are estimated. These are summarised in Table 1.


Isolated light chain of tetanus toxin inhibits exocytosis: studies in digitonin-permeabilized cells.
Previous work indicates that the heavy chain of tetanus toxin is responsible for the binding of the toxin to the neuronal membrane and its subsequent internalization. In the present study, the light chain of tetanus toxin mimicked the holotoxin in inhibiting Ca2+-dependent secretion of [3H]norepinephrine from digitonin-permeabilized adrenal chromaffin cells. Preincubation of tetanus toxin with monoclonal antibodies to the light chain prevented the inhibition by tetanus toxin. Preincubation of tetanus toxin with nonimmune ascites fluid or with monoclonal antibodies directed against the C fragment (the C-terminal of the heavy chain) or the heavy-chain portion of the B fragment did not prevent inhibition by tetanus toxin. The data indicate that the light chain is responsible for the intracellular blockade of exocytosis.


Frequently missed diagnoses in adolescent psychiatry.
Symptom overlap, comorbidity, disagreement among informants, and the impact of development complicate psychiatric diagnoses in the adolescent patient. This review of frequently missed diagnoses includes anxiety disorders, ADD without hyperactivity, early-onset bipolar disorder, syndromes associated with trauma, and substance abuse.


Mitogenic signals are not required to circumvent the cyclosporin-induced inhibition of TNP-specific B memory cell expression.
Previous studies have shown that TNP-LPS-induced B memory cells can be recalled by either TNP-LPS or DNP-Ficoll and that cyclosporin A (CsA) prevents the expression of these B memory cells when DNP-Ficoll and not TNP-LPS is the challenging antigen. The possibility that the mitogenic signal delivered by TNP-LPS circumvents the inhibition exerted by CsA was investigated. It is demonstrated here that TNP-LPS, in its non-mitogenic (polymyxin-B-treated) as well as in its mitogenic form, is capable of driving TNP-specific B memory cells into the antibody-secreting stage, regardless of the presence or absence of CsA. It is suggested that both forms of TNP-LPS activate the same CsA-resistant subpopulation of B memory cells. The lack of DNP-Ficoll-induced memory expression in the presence of CsA is related to an intrinsic sensitivity to CsA inhibition of a subpopulation of B memory cells.


Factors associated with postoperative requirement of renal replacement therapy following off-pump coronary bypass surgery.
Cardiopulmonary bypass usage provokes a systemic inflammatory response resulting in deterioration of renal function. However, risk factors for requiring renal replacement therapy (RRT) following off-pump coronary artery bypass graft surgery (CABG) have not yet been fully elucidated. We reviewed 718 consecutive patients undergoing elective off-pump CABG at our institution, excluding patients on chronic hemodialysis preoperatively. Sub-analysis of patients with preserved renal function, defined as a creatinine level below a cut-off value of 1.12 mg/dL (obtained by receiver operating characteristic curve), was also performed. Of the 718 patients, 41 (5.7 %) required RRT. There were 556 patients (77.4 %) with preserved renal function preoperatively, and 13 (2.4 %) of these required postoperative RRT. Multivariate analysis revealed that age (years) and preoperative serum creatinine (mg/dL) and brain natriuretic peptide (BNP) levels (pg/dL) were associated with RRT [odds ratios (OR) 1.052, 95 % confidence interval (CI) 9.064 and 1.001, respectively, all p < 0.05] in the total population, whereas low albumin concentration was the only independent predictor for RRT in patients with preserved renal function (OR 0.062, p < 0.0001). When creatinine levels were below 1.5 mg/dL, the predictive power of hypoalbuminemia for RRT requirement overwhelmed that of creatinine or BNP levels. Older age, preoperative elevated creatinine and BNP levels were associated with a requirement for RRT following off-pump CABG. In patients with preserved renal function, hypoalbuminemia was most significantly related to the RRT requirement.


Contrast-enhanced colour-Doppler sonography versus pH-metry in the diagnosis of gastro-oesophageal reflux in children.
The aim of this study was to evaluate the accuracy of contrast-enhanced colour-Doppler ultrasound (CDUS) in the diagnosis of gastro-oesophageal reflux in children. One hundred and twenty children (68 boys and 52 girls aged between 1 month and two years) with a clinical suspicion of gastro-oesophageal reflux (postprandial vomiting, weight loss, failure to thrive, anaemia, night-time coughing and crying, regurgitation, etc.) were studied by contrast-enhanced CDUS and subsequently by 24-hour pH-metry. Results of the two techniques were compared using the McNemar test. Gastro-oesophageal reflux was detected on CDUS in 84 patients and with 24-h pH-metry in 86. In all cases of reflux, CDUS visualised the passage of contrast material from the stomach into the abdominal and middle and distal third of the thoracic oesophagus, enabling assessment of the segment of oesophagus involved by the reflux. Compared with pH-metry, CDUS had a sensitivity of 98% (p<0.0001 with McNemar's test). In consideration of the results obtained and particularly of the low level of invasiveness, contrast-enhanced CDUS could be used to monitor children undergoing medical or surgical treatment for the complications of gastro-oesophageal reflux disease.


Hypoxia, angiogenesis and apoptosis markers in locally advanced rectal cancer.
Hypoxia-inducible factor 1alpha (HIF-1alpha) is a critical regulatory protein of cellular response to hypoxia. HIF-1alpha triggers the angiogenic process through activation of the vascular endothelial factor (VEGF) gene. The bcl-2 anti-apoptotic and the death promoting p53 genes, regulate the apoptotic cell death. We investigated the relationship between hypoxia, angiogenesis and apoptosis and their prognostic impact in patients with advanced rectal cancer. The immunohistochemical expression of HIF-1alpha, VEGF, p53 and bcl-2 and the determination of microvessel density (MVD), apoptotic index (AI) were carried out in tumour tissue samples obtained from 92 patients with locally advanced rectal cancer (LARC) (T3,4/N+/-). HIF-1alpha high reactivity and VEGF overexpression were noted in 47.8 and 44.6% of the examined cases, respectively. They significantly correlated with lymph node metastasis (P<0.001) and low rectal location (P=0.016). HIF-1alpha expression was directly correlated with VEGF up-regulation (P<0.001) and MVD (P<0.001). VEGF expression was closely interrelated with MVD (P<0.001). In univariate analysis advanced grade, infiltrative pattern of tumour growth, vascular invasion, positive lymph node status, HIF-1alpha expression and VEGF upregulation were related to decreased disease-free and overall survival. In multivariate analysis, only high HIF-1alpha reactivity and positive lymph node status emerged as independent variables of adverse prognostic significance. HIF-1alpha and VEGF may play an important predictive and prognostic role in patients with LARC.


Accessing the Influence of Community Experience on Brand Loyalty Toward Virtual Brand Community: Developing Country Perspective.
With the development of information technology, more and more companies have taken the initiative to build virtual brand communities to strengthen the connection between brands and customers and create brand loyalty, but existing research lacks a clear explanation of how the customer community experience of virtual brand communities affects brand loyalty. In response to this question, this paper investigates the role and mechanism of different types of community experiences, namely information experience, entertainment experience and interactive experience, generated by customers' participation in community activities on brand loyalty based on the customer experience perspective. The findings show that different types of community experiences have a significant impact on brand loyalty, and which community identity is partially mediated in all of them. Further analysis for segmented populations in virtual communities revealed significant differences in the above mechanisms for members of different genders. The findings of this paper are important guidance for companies to manage virtual brand communities and create brand loyalty.


The effects of adrenocorticotrophic hormone and an equivalent dose of cortisol on the serum concentrations of lipids, lipoproteins, and apolipoproteins.
Previous studies have shown a strong lipid-lowering effect of adrenocorticotrophic hormone (ACTH) in healthy individuals and in patients with different kinds of dyslipoproteinemia. The mechanism behind this effect has not been established and its direct ACTH-specific nature has been questioned. Therefore, the present study was performed. Thirty healthy young males were randomized into 3 groups of equal size: one group received ACTH1-24 1 mg IM, daily for 4 days, another group was treated with cortisol 150 mg ID (50 mg tid) daily for 4 days, whereas a control group was observed for 4 days. Fasting blood samples were collected before and after treatment or observation. The serum concentrations of cholesterol (12%, P < .05), low-density lipoprotein cholesterol (24%, P < .01), and apolipoprotein (apo) B (31%, P < .01) decreased significantly in the ACTH group but not in the cortisol and control groups. The statistical workup confirmed that only ACTH had a lowering effect on the apo B-containing lipoproteins. In contrast, the results indicated conformity between the treatment groups with respect to increases in the serum apo E concentrations. There were inconsistent changes in the serum concentrations of the triglycerides, high-density lipoprotein cholesterol, apo A, and lipoprotein(a). The main results were clear: the lowering effect of ACTH on the serum concentration of apo B-containing lipoproteins could not be ascribed to cortisol. These, in combination with previous in vitro results, indicated an ACTH-specific effect.


A hydrophilic and hydrophobic organic solvent mixture enhances enzyme stability in organic media.
Binary mixtures of hydrophilic and hydrophobic solvents were assessed for their ability to balance enzyme activity with the conservation of enzyme stability in organic media. Acetone, dioxane and dodecane were chosen as model organic solvents, and subtilisin Carlsberg and horseradish peroxidase (HRP) were chosen as model enzymes. Residual enzyme activities were measured to monitor enzyme stability, and the fluorescence intensity of HRP was monitored to investigate structural changes due to the presence of an organic solvent. Enzyme stability increased with the increasing hydrophobicity of the solvent mixture used, and a solvent mixture with a high log P value (~ >4) was capable of conserving enzyme stability. Enzyme stability in organic media can be conserved therefore with a mixture of hydrophilic and hydrophobic solvents: this approach might be used as a general and practical strategy for optimizing enzyme activity and stability for industrial applications.


Trends in caries experience and associated contextual factors among indigenous children.
To assess dental caries trends in indigenous children in South Australia, 2001-2010; and contribution by area-level socioeconomic status (SES), remoteness and water fluoridation status. This study is a part of the Child Dental Health Survey (CDHS) is an ongoing national surveillance survey in Australia including children enrolled in the School Dental Services (SDS). Postcode-level adjusted mean deciduous and permanent caries experience was estimated at each year. Time trend of dental caries experience was estimated using mixed effect models. Area-level socioeconomic status, remoteness, water fluoridation status were independent variables in the models. There was a significant upward trend of dental caries experience over the 10 years. Dental caries experience of indigenous children living in low SES areas had nearly one more deciduous tooth and a half permanent tooth with caries than indigenous children living in higher SES areas. The remote postcodes showed higher levels of decay in deciduous dentition (+1.25 teeth) compared with others regions. The dental caries trend increased in South Australian indigenous children over the study period, and was associated with area-level SES and remoteness. The increasing trend in dental caries in indigenous children is important evidence to inform policies to improve oral health.


Epidemiological transition and distribution of stroke incidence in Tianjin, China, 1988-2010.
To examine the trends in epidemiological transition of stroke over the last two decades in Tianjin, and investigate the subtypes of stroke. A population-based epidemiological study using data from the Stroke Incidence Surveillance System of the Tianjin Centres for Disease Control and Prevention from 1988 to 2010. Almost 500,000 cases were analysed to examine changes in the incidence of stroke between 1988 and 2010 by age, sex, subtype, year and urban/rural status. The incidence of stroke amongst males increased from 136.8/100,000 in 1988 to 387.0/100,000 in 2010, and the incidence amongst females increased from 65.9/100,000 in 1988 to 249.7/100,000 in 2010. Over the study period, the proportion of haemorrhagic strokes decreased and the proportion of ischaemic strokes increased sharply in both men and woman; the differences were significant. The distribution of stroke subtypes changed dramatically over the study period. Changes in trend and subtypes of stroke have raised new challenges and there is a need for adjustment for stroke prevention in Tianjin.


Healthy-Weight Kindergarten Children with Autism Spectrum Disorder May Become Overweight and Obese during the First Few Years of Elementary School.
Analysis of a population-based, nationally-representative longitudinal sample from the Early Childhood Longitudinal Study, Kindergarten Class of 2010-11 identified an increase in healthy-weight children with autism spectrum disorder becoming overweight and obese between first and second grade, thus identifying a critical period for early prevention and treatment.


Synthesis, characterization and DFT study of methoxybenzylidene containing chromophores for DSSC materials.
Novel tricyanovinyl derived from hydrazones have been prepared by the reaction of tetracyanoethylene and phenylethylidene hydrazone, and these dyes showed absorption in the region of 539-650 nm. The dyes showed pronounced solvatochromic effects as the polarity of the solvents changed. The torsion in E isomer is smaller than Z and azo isomers of MBD1 and MBD2. The HOMOs are delocalized on whole of the molecule while LUMOs are distributed on the tricarbonitrile. The LUMO energies are above the conduction band of TiO(2) and HOMOs of the dyes are below the redox couple of MBD1 and MBD2. The HOMO energies, LUMO energies and HOMO-LUMO energy gap of MBD1 and MBD2 are almost same. The absorption spectra of both the dyes in different solvents are approximately same except in cyclohexane.


New contribution to the ethnopharmacological study of the Canary Islands.
We present in this paper a report of 155 species used for medicinal purpose in the Canary Islands. These species have been compiled in 13 tables in accordance with their main medicinal use, indicating also other possible popular uses. We have made a short inventory of the rates of the most important medicinal applications. This new compilation shows once more the traditional use of the phytotherapeutic resources by the Canary population and also the wide possibilities of the phytochemical and pharmacological investigations of the Canary Islands Flora.


Children with Narcolepsy type 1 have increased T-cell responses to orexins.
Narcolepsy type 1 (NT1) is caused by severe loss of the orexin neurons, and is highly associated with HLA DQB1*06:02. Using intracellular cytokine staining, we observed a higher frequency of IFN-γ- and TNF-α-producing CD4+ and CD8+ T-cells in response to orexins in 27 children with NT1 compared to 15 healthy control children. Conversely, no such difference was observed between 14 NT1 and 16 HC adults. In addition, priming with flu peptides amplified the T-cell response to orexins in children with NT1. Our data suggests that NT1 may be caused by an autoimmune T-cell response to orexins, possibly triggered by flu antigens.


Prior knowledge for time domain quantification of in vivo brain or liver 31P MR spectra.
Prior knowledge is required when quantifying in vivo (31)P magnetic resonance spectra from the brain or liver. The prior knowledge system we have used models both the phosphomonoester and phosphodiester resonances as two peaks of equal linewidth and fixed relative chemical shift. The analysis of the data is carried out in the time domain, which allows the broad component of the spectra to be modelled. This prior knowledge method has been tested for analysis of in vivo (31)P MR spectra from the liver and brain and gives results consistent with other methods that are also used to analyse the spectra, but with reduced variability. This technique may be utilized for studies requiring serial MR spectroscopy examinations, before and after patient treatment.


Analysis of glycosaminoglycan substitution in decorin by site-directed mutagenesis.
Posttranslational glycosaminoglycan attachment to decorin, a chondroitin/dermatan sulfate proteoglycan, was studied by expression of a wild-type decorin cDNA and several mutagenized forms in two types of mammalian cells. Transfection of the wild-type cDNA resulted in the synthesis of an authentic chondroitin/dermatan sulfate proteoglycan similar to the decorin molecule synthesized by cultured human fibroblasts. Conversion of the serine residue that serves as the attachment site for the sole glycosaminoglycan chain in decorin to a threonine residue greatly reduced the efficiency of the glycosaminoglycan substitution. Less than 10% of the threonine-mutated core protein acquired a glycosaminoglycan chain, whereas most of the core protein was secreted without such substitution. Expression of cDNA in which an alanine residue had been introduced into the substituted serine position resulted in the secretion of core protein with no detectable glycosaminoglycan. Conversion to alanine of either one of the glycine residues that are adjacent to the substituted serine yielded the proteoglycan form of decorin. These results show that the xylosyltransferase responsible for the initiation of the glycosaminoglycan chain on the core protein can use a threonine residue for this substitution instead of a serine residue, but that such substitution is only partial, creating a "part-time" proteoglycan. Moreover, variations are possible in the sequence context of a glycosaminoglycan-substituted serine residue without loss of glycosaminoglycan substitution. The conformation of the substitution site may therefore be important for xylosyltransferase recognition.


Two temperature-sensitive polA mutants: an approach to the role in vivo of DNA polymerase I.
DNA polymerase I (Pol I) purified from a strain carrying polA12 demonstrates a defect primarily in the polymerase portion of the molecule. The mutant enzyme is altered in its structure and template specificity. Pol I isolated from strains carrying polAexl are primarily defective in 5' in equilibrium 3' exonuclease. The polAexl lesion renders strains conditonally lethal.


The effectiveness of complete decongestive physiotherapy for the treatment of lymphedema following groin dissection for melanoma.
Groin dissection is performed for the treatment of melanoma and other malignancies. Lymphedema rates as high as 47% have been reported. In 1996, we began using complete decongestive physiotherapy (CDP) in selected patients with lymphedema following groin dissection. Here, we review our results in a small cohort of patients. A retrospective review of the medical records of 14 patients, treated with CDP for lymphedema secondary to groin dissection for melanoma was conducted. All patients were treated with CDP at Roswell Park Cancer Institute (RPCI), between 1996 and 2002. Of the 14 patients, 12 underwent groin dissection at RPCI. Response to therapy was measured by limb volume determinations. Patient gender, age, body mass index (BMI), type of operation, type of adjuvant therapy, time to treatment, patient compliance, lymphedema stage, and initial edema were analyzed for association with response to treatment. Incidence was estimated by a review of the operative logs. Fourteen patients were treated with CDP for lymphedema secondary to groin dissection for melanoma, with a median decrease in lymphedema of 60% (range: 35-145%; P = 0.0003). Increased BMI was associated with a decreased response to treatment (P = 0.02). Response to CDP was not effected by time to treatment, patient compliance, lymphedema stage, and initial edema. During this time, 39 groin dissections were done at RPCI. The incidence of lymphedema treated with CDP at RPCI was 31% (12/39; standard error 7.4%). With a decrease in lymphedema of 60%, CDP may provide relief for patients with lymphedema following groin dissection. Elevated BMI was associated with a decreased response to CDP.


Evaluation of the Effects of Gamma Radiation Sterilization on Rhein-Loaded Biodegradable Microparticles for the Treatment of Osteoarthritis.
In previous work, we reported on the design of biodegradable rhein-loaded PLGA microparticles for the treatment of osteoarthritis. Considering that a formulation designed for intra-articular administration must meet sterility requirements to guarantee its safety, in this study the effect of gamma radiation sterilization on these microparticles was evaluated. The size, morphology, and surface characteristics of the microparticles and the encapsulation efficiency of rhein were not affected by the sterilization process. Although DSC and PXRD analyses suggested otherwise, rhein release profiles were not altered by gamma radiation. The release of rhein from the microparticles was fitted to a Gompertz model. In conclusion, the results of this study suggest that gamma radiation is a suitable method for the sterilization of rhein-loaded PLGA microparticles to enable their intra-articular administration in order to provide a therapeutic solution to patients suffering from chronic joint diseases.


Novel macromolecular synthetic phenolic antioxidants in sludge on a national scale in China: Their distribution, potential transformation products, and ecological risk.
To fulfill the growing demand for retarding the oxidation of polymers and minimizing their migration from various products, new macromolecular synthetic phenolic antioxidants (SPAs) have emerged in the market. There is a concern that these SPAs may be released into wastewater streams during their manufacturing and use, eventually ending up in wastewater treatment plants (WWTPs). Nevertheless, information regarding the occurrence of these SPAs in sludge, particularly on a national scale, is scarce. In this study, several macromolecular SPAs and their transformation products (TPs) were investigated in sludge samples from 45 Chinese municipal WWTPs. All 14 analytes were detected in the sludge samples, among which, 12 analytes were first reported in sludge. 2,4,6-tri-tert-butylphenol (AO246) and 2 macromolecular SPAs, pentaerythritol tetrakis[3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate] (AO1010) and octadecyl-3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionate (AO1076), were the most dominant SPAs, with geometric mean (GM) concentrations of 547, 212, and 35.2 ng/g dw, respectively. Two TPs, 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propanoic acid (fenozan) and 3,5-di-tert-butyl-4-hydroxybenzoic acid (BHT-COOH), were found in some sludge samples (48.9-71.1 %) with GM of 45.5 and 12.8 ng/g dw, respectively. By using LC-Q-TOF-MS/MS analysis, we tentatively identified previously unknown TPs of 10 macromolecular SPAs in sludge. This suggests that there are still unclear mechanisms modulating the transformation of these SPAs, which underscores the complexity of their fate. Additionally, using the freshwater photobacteria Vibrio qinghaiensis sp.-Q67 (Q67) as model organism, the acute and chronic EC50 of the 14 analytes were assessed for ecological risk assessment. By considering toxicity data obtained from algae, daphnia, and fish collected or predicted from various databases, we found that these analytes, including their mixture at low detected concentrations, pose risks to aquatic systems that should not be disregarded. Overall, the current study provides a comprehensive overview of novel SPAs and their TPs in sludge, offering valuable insights for investigating their environmental behavior, fate, and risks.


Protein Structure Prediction with Mass Spectrometry Data.
Knowledge of protein structure is crucial to our understanding of biological function and is routinely used in drug discovery. High-resolution techniques to determine the three-dimensional atomic coordinates of proteins are available. However, such methods are frequently limited by experimental challenges such as sample quantity, target size, and efficiency. Structural mass spectrometry (MS) is a technique in which structural features of proteins are elucidated quickly and relatively easily. Computational techniques that convert sparse MS data into protein models that demonstrate agreement with the data are needed. This review features cutting-edge computational methods that predict protein structure from MS data such as chemical cross-linking, hydrogen-deuterium exchange, hydroxyl radical protein footprinting, limited proteolysis, ion mobility, and surface-induced dissociation. Additionally, we address future directions for protein structure prediction with sparse MS data.


p38β MAPK upregulates atrogin1/MAFbx by specific phosphorylation of C/EBPβ.
The p38 mitogen-activated protein kinases (MAPK) family plays pivotal roles in skeletal muscle metabolism. Recent evidence revealed that p38α and p38β exert paradoxical effects on muscle protein homeostasis. However, it is unknown why p38β, but not p38α, is capable of mediating muscle catabolism via selective activation of the C/EBPβ that upregulates atrogin1/MAFbx. Tryptic phosphopeptide mapping was carried out to identify p38α- and p38β-mediated phosphorylation sites in C/EBPβ. Chromosome immunoprecipitation (ChIP) assay was used to evaluate p38α and p38β effect on C/EBPβ binding to the atrogin1/MAFbx promoter. Overexpression or siRNA-mediated gene knockdown of p38α and p38β, and site-directed mutagenesis or knockout of C/EBPβ, were used to analyze the roles of these kinases in muscle catabolism in C2C12 myotubes and mice. Cellular expression of constitutively active p38α or p38β resulted in phosphorylation of C/EBPβ at multiple serine and threonine residues; however, only p38β phosphorylated Thr-188, which had been known to be critical to the DNA-binding activity of C/EBPβ. Only p38β, but not p38α, activated C/EBPβ-binding to the atrogin1/MAFbx promoter. A C/EBPβ mutant in which Thr-188 was replaced by alanine acted as a dominant-negative inhibitor of atrogin1/MAFbx upregulation induced by either p38β or Lewis lung carcinoma (LLC) cell-conditioned medium (LCM). In addition, knockdown of p38β specifically inhibited C/EBPβ activation and atrogin1/MAFbx upregulation induced by LCM. Finally, expression of active p38β in mouse tibialis anterior specifically induced C/EBPβ phosphorylation at Thr-188, atrogin1/MAFbx upregulation and muscle mass loss, which were blocked in C/EBPβ-null mice. The α and β isoforms of p38 MAPK are capable of recognizing distinct phosphorylation sites in a substrate. The unique capacity of p38β in mediating muscle catabolism is due to its capability in phosphorylating Thr-188 of C/EBPβ.


Triglyceride-rich lipoproteins of subjects heterozygous for apolipoprotein E2(Lys146-->Gln) are inefficiently converted to cholesterol-rich lipoproteins.
The APOE*2(Lys146-->Gln) allele behaves like a dominant trait in the expression of familial dysbetalipoproteinemia (FD) (Smit et al., J. Lipid Res. 1990; 31: 45-53). FD patients carrying the APOE*2(Lys146-->Gln) allele exhibit less elevated cholesterol to triglyceride ratios in the d < 1.019 g/ml lipoprotein density fraction as compared to classical FD patients displaying homozygosity for the APOE*2(Arg158-->Cys) allele (0.8 vs. 1.4). Upon treatment of complete serum with lipoprotein lipase (LPL), the mean cholesterol to triglyceride molar ratio of the d < 1.019 g/ml lipoprotein fraction in these FD patients increased only marginally (from 0.8 to 1.1), as compared with that of classical FD subjects (from 1.4 to 2.6) and non-FD control subjects (from 0.7 to 1.5). In order to obtain further evidence for an inefficient lipolysis of the d < 1.019 g/ml lipoprotein fraction in APOE*2(Lys146-->Gln) carriers, possibly in combination with a less efficient cholesteryl ester transfer protein (CETP) activity, blood samples of APOE*2(Lys146-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys149-->Gln) allele carrying FD patients were analysed and compared with classical FD patients and controls. In the APOE*2(Lys146-->Gln) FD patients, the increase in plasma cholesterol was mainly confined to the very low density lipoprotein (VLDL) fraction, whereas in classical FD patients, the levels of cholesterol in the intermediate density lipoprotein (IDL) fraction was also dramatically increased (ratios of VLDL to IDL cholesterol are 4.7 and 2.6, respectively). Family analyses of the APOE*2(Lys146-->Gln) FD subjects showed that the apo E to apo B ratio in the d < 1.019 g/ml lipoprotein fraction of allele carriers is 3.5 times as high as that found in non-carriers (2.8 vs. 0.8, by wt.). Also, in the APOE*2(Lys146-->Gln) allele carrying family members, the ratio of cholesterol to triglyceride of the d < 1.019 g/ml lipoprotein fraction is less markedly elevated upon addition of LPL when compared to that in non-carrying controls (from 1.1 to 1.8 vs 0.7 to 1.6). The efficiency of the d < 1.019 g/ml lipoprotein fraction of APOE*2(Lys146-->Gln) FD patients to compete with low density lipoprotein (LDL) for binding to the LDL receptor is intermediate to that of controls and classical APOE*2(Arg158-->Cys) homozygous FD patients. These findings suggest that in APOE*2(Lys146-->Gln) allele carriers, the conversion of VLDL into IDL is impaired due to an inefficient lipolysis, possibly in combination with a retarded CETP activity.(ABSTRACT TRUNCATED AT 250 WORDS)


KDM5B protein expressed in viable and fertile ΔARID mice exhibit no demethylase activity.
Post‑translational modification of histones serve a crucial role in the control of gene transcription. Trimethylation of lysine 4 on histone 3 is associated with transcription activation. There are currently six known methylases and six known demethylases that can control the methylation status of this site. Lysine demethylase 5B (KDM5B) is one such demethylase, which can repress gene expression. In particular KDM5B has been found to be overexpressed in a number of cancer types, and small‑molecular weight inhibitors of its demethylase activity have been identified. Previous characterisation of Kdm5b knock‑out mice has revealed that this genotype leads to either embryonic or neonatal lethality. However, the ΔA‑T rich interaction domain (ΔARID)‑KDM5B strain of mice, which have the ARID domain and five amino acids within the Jumonji (Jmj)N domain spliced out from KDM5B, remain viable and fertile. In the present study, ΔARID‑KDM5B was found to have no demethylase activity as determined by in vitro demethylase assays and by immunofluorescence in transfected Cos‑1 cells. Furthermore, molecular dynamic simulations revealed conformational changes within the ΔARID‑KDM5B structure compared with that in WT‑KDM5B, particularly in the JmjC domain, which is responsible for the catalytic activity of WT‑KDM5B. This supports the experimental data that shows the loss of demethylase activity. Since Kdm5b knock‑out mice show varying degrees of lethality, these data suggest that KDM5B serves a crucial function in development in a manner that is independent of its demethylase activity.


Further evidence for sensitivity to energy density and a two-component model of meal size: Analysis of meal calorie intakes in Argentina and Malaysia.
Previously, we demonstrated a non-linear association between meal caloric intake and meal energy density (ED, kcal/g) in data from a controlled trial in the US and from free-living participants in the UK [1]. In both datasets, meal caloric intake increased with ED in lower energy-dense meals (below ∼1.75 kcal/g) and decreased in higher energy-dense meals (above ∼1.75 kcal/g). In the current study, we sought to explore whether this pattern extends to data from free-living participants in Argentina (N = 2738 meals) and Malaysia (N = 4658 meals). Again, a significant breakpoint was found in both the Argentinean (2.04 kcal/g (SE = 0.06)) and Malaysian (2.17 kcal/g (SE = 0.06)) datasets with mean centered meal caloric intake increasing with ED below the breakpoint and decreasing above the breakpoint. These results lend further support for our two-component theoretical model of meal size (g) in which a volume signal is dominant in lower energy-dense meals and a calorie-content signal is dominant in higher energy-dense meals. Together, our research adds to evidence supporting human sensitivity to calories and exposes a complexity in the correspondence between meal energy content and meal size in everyday (non-manipulated) meals. Further research is needed to provide causal evidence for this sensitivity and whether individual variation impacts meal size and energy balance.


Adventitious agents, new technology, and risk assessment, 19-20 May 2011, Baltimore, MD.
In May 2011, the International Alliance for Biological Standardization, with the cooperation of WHO, FDA, and NIAID, organized a conference on adventitious agents that might be found in biological products using new technology (http://www.iabs.org/index.php/past-conference-reports/116-baltimore-2011-slides). The implications of such findings on risk assessment also were considered. Topics that were addressed included: a) current routine testing--what are we doing now?; b) recent advances in testing--what tests are being explored/applied?; c) examples of finding agents with "new" techniques; and d) risk assessment, including recent WHO activities. A draft algorithm for risk assessment was discussed in terms of its applicability to a variety of potential new agents and the possibilities for improving it.


Metabolite profile based on 1H NMR of broiler chicken breasts affected by wooden breast myodegeneration.
The objective was to characterize the effect of wooden breast (WB) myodegeneration on the metabolite profile of chicken meat by 1H NMR and multivariate data analysis. The results displayed that the metabonome of chicken breast consisted predominantly of 30 metabolites, including amino acids, organic acids, carbohydrates, alkaloids, nucleosides and their derivatives. WB-affected samples showed higher leucine, valine, alanine, glutamate, lysine, lactate, succinate, taurine, glucose, and 5'-IMP levels, but lower histidine, β-alanine, acetate, creatine, creatinine, anserine and nicotinamide adenine dinucleotide levels compared to normal fillets (p < 0.05). In conclusion, results indicated that WB-affected fillets possessed a unique biochemical signature. This unique profile could identify candidate biomarkers for diagnostic utilization and provide mechanistic insight into biochemical processes leading to WB myopathy in commercial broiler chickens.


Large-scale rotational motions of proteins detected by electron paramagnetic resonance and fluorescence.
Direct spectroscopic measurements of rotational motions of proteins and large protein segments are crucial to understanding the molecular dynamics of protein function. Fluorescent probes and spin labels attached to proteins have proved to be powerful tools in the study of large-scale protein motions. Fluorescence depolarization and conventional electron paramagnetic resonance (EPR) are applicable to the study of rotational motions in the nanosecond-to-microsecond time range, and have been used to demonstrate segmental flexibility in an antibody and in myosin. Very slow rotational motions, occurring in the microsecond-to-millisecond time range, are particularly important in supramolecular assemblies, where protein motions are restricted by association with other molecules. Saturation transfer spectroscopy (ST-EPR), a recently developed electron paramagnetic resonance (EPR) technique that permits the detection of rotational correlation times as long as 1 ms, has been used to detect large-scale rotational motions of spin-labeled proteins in muscle filaments and in membranes, providing valuable insights into energy transduction mechanisms in these assemblies.


P2Y2 and P2Y4 receptors regulate pancreatic Ca(2+)-activated K+ channels differently.
Extracellular ATP is an important regulator of transepithelial transport in a number of tissues. In pancreatic ducts, we have shown that ATP modulates epithelial K+ channels via purinergic receptors, most likely the P2Y2 and P2Y4 receptors, but the identity of the involved K+ channels was not clear. In this study, we show by RT-PCR analysis that rat pancreatic ducts express Ca(2+)-activated K+ channels of intermediate conductance (IK) and big conductance (BK), but not small conductance (SK). Possible interactions between P2Y receptors and these Ca(2+)-activated K+ channels were examined in co-expression experiments in Xenopus laevis oocytes. K+ channel activity was measured electrophysiologically in oocytes stimulated with UTP (0.1 mM). UTP stimulation of oocytes expressing P2Y4 receptors and BK channels resulted in a 30% increase in the current through the expressed channels. In contrast, stimulation of P2Y2 receptors led to a 20% inhibition of co-expressed BK channel activity, a response that was sensitive to TEA. Furthermore, co-expression of IK channels with P2Y4 and P2Y2 receptors resulted in a large hyperpolarization and 22-fold and 5-fold activation of currents by UTP, respectively. Taken together, this study shows that there are different interactions between the subtypes of P2Y purinergic receptors and different Ca(2+)-activated K+ channels.


A comprehensive procedure for antiviral inhibitor discovery using EV71 as an example.
The prevalence of chronic viral infectious diseases, the emergence and re-emergence of new viral infections, and in particular, resistance to currently used antiviral drugs have led to increased demand for new antiviral strategies and reagents. Increased understanding of the molecular mechanisms of viral infection has provided great potential for the discovery of new antiviral agents that target viral proteins or host factors. In this work, we introduce a comprehensive system using enteroviruses 71 (EV71) as an example for leading compound discovery to develop new antiviral.


5-(Adamantan-1-yl)-N-methyl-1,3,4-thia-diazol-2-amine.
In the title compound, C13H19N3S, the methyl-amine substituent is coplanar with the thia-diazole ring to which it is attached [C-N-C-S torsion angle = 175.9 (2)°] and the amine H atom is syn to the thia-diazole S atom. Supra-molecular chains along [101], sustained by N-H⋯N hydrogen bonding, feature in the crystal packing.


Urinary and serum zinc levels in chronic pancreatitis.
Urinary and serum zinc levels were determined in 51 patients with chronic pancreatitis. Urinary zinc excretion in patients with chronic calcified pancreatitis (832 +/- 111 micrograms/day) (mean +/- SE) but not in noncalcified pancreatitis (684 +/- 65 micrograms/day) was significantly higher than in normal controls (418 +/- 46 micrograms/day). The urinary zinc excretion increased with deterioration of exocrine pancreatic function. Serum zinc levels in advanced pancreatitis (105.9 +/- 4.5 micrograms/100 ml) were significantly higher when compared to the pancreatitis with normal exocrine pancreatic function (91.6 +/- 3.0 micrograms/100 ml), but the difference was less pronounced than for urinary zinc excretion. This may be due to complicating diabetes, which usually lowers serum zinc. Serum zinc and urinary zinc excretion were low in a patient with chronic calcified pancreatitis complicated with a pulmonary abscess and hypoalbuminemia. In conclusion, urinary and serum zinc levels in chronic pancreatitis were increased as a result of exocrine pancreatic dysfunction. Association of diabetes may lower serum zinc, and associated malnutrition depresses both urinary and serum zinc levels.


What can topology changes in the oddball N2 reveal about underlying processes?
A prominent theory of the N2 event-related potential component holds that the 'oddball' N2 is generated in the anterior cingulate cortex. However, observations of oddball N2s with posterior scalp distributions are inconsistent with this hypothesis. We suggest that variability in the topology of the oddball N2 is a key characteristic of the component that can inform theories of its neural basis. We propose that the oddball N2 reflects cortex-wide noradrenergic modulation of the ongoing cortical activity and thus should have a topology that varies systematically according to task specifics. Participants engaged in an oddball task with male and female faces tinted either yellow or blue, counting targets according to color or sex. Between blocks, targets were frequent or infrequent, counterbalanced across task (attend color, attend sex), and category (blue male, yellow male, blue female, yellow female). We created difference waves by subtracting frequent from infrequent category trials to isolate the oddball N2. When participants attended to color the oddball N2 was maximal over frontal-central areas and when they attended to sex it was maximal over lateral-occipital areas. Thus, the oddball N2 has a variable scalp distribution that depends on the relative engagement of cortical areas, consistent with noradrenergic modulation having the greatest impact in those areas mostly engaged by the task at hand.


The mouse C-reactive protein (CRP) gene is expressed in response to IL-1 but not IL-6.
C-Reactive protein (CRP) is a minor acute phase reactant (APR) in the mouse, whereas CRP is the prototypical and one of the major positive APRs in all other mammals. MoCRP gene expression was tissue specific for the liver and induced by culture supernatants of LPS-activated macrophages. MoCRP gene expression by isolated hepatocytes in culture increased c, 3-fold in response to interleukin (IL)-1, but not IL-6. IL-6 is the most potent inflammatory cytokine for the induction of human CRP and many other APRs. By contrast, gene expression of the major APR of the mouse, serum amyloid P-component (SAP), a structural homologue of CRP, increased in response to either IL-1 or IL-6 under the same conditions. The region containing two potentially IL-1 responsive C/EBP elements in the moCRP gene failed to respond to IL-1 when a pCAT construct containing the elements was transfected into Hep 3B2 hepatoma cells. Therefore, IL-1 may influence the expression of the moCRP gene at the post-transcriptional rather than at the transcriptional level. The findings suggest that moCRP may be a minor APR because of the limited response of the gene to inflammatory cytokine signals.


The Gamma-glutamyltransferase gene of Helicobacter pylori can promote gastric carcinogenesis by activating Wnt signal pathway through up-regulating TET1.
Helicobacter pylori (Hp) infection plays an important role in the development of gastric cancer. Hp can secrete gamma-glutamyltransferase (GGT), however, the impact of GGT of Hp on the human gastric cells is not clear. Although it has been demonstrated that ten-eleven translocation 1 (TET1) is overexpressed in gastric cancer, the relationship between the GGT of Hp and TET1 has not been studied. The aim of this study was to explore the relationship between GGT and TET1, and the role of TET1 in the development of gastric cancer induced by Hp was also explored. The correlation between TET1 and prognosis of gastric adenoma cancer was analyzed by bioinformatics. The GGT gene of Hp26695 was knocked out by electroporation with plasmid to construct the GGT knockout strain of Hp (Hp-KS-1). The shTET1 lentivirus transfected GES-1, MGC-803 and SGC-7901 cell lines were constructed. The biological characteristics of the three kind of cells were detected. TET1 was overexpressed in gastric tissues of Hp infected patients and mice. Bioinformatics analysis showed that in patients with gastric cancer, higher TET1 expression would result in poorer prognosis. The GGT gene of Hp can lead to overexpression of TET1 in GES-1, MGC-803 and SGC-7901 cells, along with the activation of Wnt/β-catenin signaling pathway, and then promoting tumorigenesis. After silencing TET1, the Wnt/β-catenin signaling pathway which was activated by GGT of Hp was inhibited. GGT of Helicobacter pylori can promote gastric carcinogenesis by activating Wnt/β-catenin signaling pathway trough up-regulating TET1.


Acute Response of Neurons: An Early Event of Neuronal Cell Death After Facial Nerve Injury.
To research the early acute response events of facial nerve injury. Sixty male Sprague-Dawley rats were randomly divided into 2 groups. Facial nerve anastomosis was performed for rats in study group. Rats in control group underwent the same surgical procedure, but without cutting off the facial nerve. Before nerve anastomosis and at days 1, 3, 7, 14, and 28 after nerve anastomosis, 5 rats of each group were selected and right side brainstem tissue samples containing the facial nerve nucleus were obtained. Hematoxylin and eosin (H&E) staining and TUNEL detection was performed to observe facial neurons changes. Facial neurons mortality and apoptosis were studied. Expression of caspase-3, LC3, and Beclin1 was detected with Western blot assay. In study group on day 7 day after nerve anastomosis, Nissl body dissolution and apoptotic facial neurons were significantly increased, the typical polygonal shape and swollen cells disappeared, the number of facial neurons was significantly lower, and the number of apoptotic facial neurons was significantly higher (P < 0.01). In addition, facial neuron mortality rate was significantly increased at day 7, reaching the peak at day 14. Expression of caspase-3, LC3, and Beclin1 was also significantly up-regulated after nerve anastomosis. Nissl body dissolution, typical polygonal shape disappearing, cell swelling, facial neuron mortality and apoptosis, and up-regulated expression of caspase-3, LC3, and Beclin1 are the early events of cell death after facial nerve injury, which are the important precursors to facial nerve injury.


ECOG performance score 0 versus 1: impact on efficacy and safety of first-line 5-FU-based chemotherapy among patients with metastatic colorectal cancer included in five randomized trials.
Within the context of metastatic colorectal cancer, patients with Eastern Cooperative Oncology Group (ECOG) performance score 0-1 are usually pooled together in clinical practice guidelines and clinical trials' reports. The current study aims to delineate potential differences in outcomes between metastatic colorectal cancer patients with ECOG score 0 versus 1 who are treated with currently accepted first-line fluorouracil (5FU)-based chemotherapy. The current study is based on a pooled dataset from five clinical trials of 5FU-based treatment for metastatic colorectal cancer (NCT00272051; NCT00115765; NCT00305188; NCT00364013; and NCT00384176). Patients with metastatic colorectal cancer and ECOG score of 0-1 were eligible for the current study. Multivariable logistic regression analysis was used to assess the relationship between ECOG performance status and the development of different toxicities. Kaplan-Meier survival estimates were used to clarify the impact of the ECOG score on overall and progression-free survivals. Multivariable Cox regression analysis was then used to evaluate the impact of ECOG score on overall and progression-free survivals. A total of 3143 patients were included in the current analysis. Within multivariable logistic regression analysis, patients with an ECOG score of 0 have a lower probability of serious adverse events (OR 0.678; 95% CI 0.583-0.788; P < 0.001), fatal adverse events (OR 0.552; 95% CI 0.397-0.766; P < 0.001), high-grade anemia (OR 0.426; 95% CI 0.252-0.721; P = 0.001), and high-grade nausea/vomiting (OR 0.697; 95% CI 0.509-0.955; P = 0.024). Through Kaplan-Meier survival analysis, patients with an ECOG score of 0 have better overall and progression-free survivals (P < 0.001 for both endpoints). Median overall survival was 27.63 months among patients with an ECOG score of 0 versus 20.00 months among patients with an ECOG score of 1. Within multivariable Cox regression analysis, patients with ECOG score of 0 were associated with better overall and progression-free survivals (HR for overall survival 0.613; 95% CI 0.556-0.676; P < 0.001); (HR for progression-free survival 0.765; 95% CI 0.705-0.829; P < 0.001). Compared with patients with ECOG score of 1, patients with ECOG score of 0 have better overall and progression-free survival, and less probability of serious and fatal adverse events. This distinction in outcomes should be noted when choosing appropriate therapeutic strategies and when designing/reporting the results of clinical trials.


"Devi Mangiare!" [You have to eat!]: Experiences of disordered eating among Italian-Australian women.
In this article, the researchers report findings on how food meanings, culture and gender intersect in the experiences of Italian-Australian women. In-depth narrative interviews were thematically analyzed using a feminist social constructionist framework informed by anthropological theories about "foodways" and culture. Three core themes were identified in the women's narratives: "il cibo e' tutto, il cibo e amore" - "food is everything, food is love"; "fare la bella figura" - "to make a good impression"; and "il mio piatto" - "it's my plate". The researchers demonstrate how gendered expectations of women in Italian-Australian culture intersect with food meanings, cultural ideals and practices to produce distinct experiences of disordered eating and restricted access to formal support. The relevance of the findings are likely to be applicable to other migrant communities across the world. Particularly where ethnic communities retain distinctive food related meanings and practices post migration, that may intersect with cultural ideals venerating female thinness and the psycho-medical models and practices that pathologize disordered eating.


Frequency tuning of a distributed feedback dye laser with two transmission gratings.
Distributed feedback dye lasers, which use a holographic grating, present a very simple and reliable way to generate ultrashort pulses. We have developed a new technique for wavelength tuning of this type of laser by projecting the image of a second grating into the dye cell. Single-line operating and tuning was demonstrated with transform-limited output pulses on a picosecond time scale.


Prediction of bacterial functional diversity in clay microcosms.
Microorganisms in clay barriers could affect the long-term performance of waste containers in future deep geological repositories (DGR) for used nuclear fuel through production of corrosive metabolites (e.g., sulfide), which is why clay materials are highly compacted: to reduce both physical space and access to water for microorganisms to grow. However, the highly compacted nature of clays and the resulting low activity or dormancy of microorganisms complicate the extraction of biomarkers (i.e., PLFA, DNA etc.) from such barriers for predictive analysis of microbial risks. In order to overcome these challenges, we have combined culture- and 16S rRNA gene amplicon sequencing-based approaches to describe the functional diversity of microorganisms in several commercial clay products, including two different samples of Wyoming type MX-80 bentonite (Batch 1 and Batch 2), the reference clay for a future Canadian DGR, and Avonlea type Canaprill, a clay sample for comparison. Microorganisms from as-received bentonites were enriched in anoxic 10% w/v clay microcosms for three months at ambient temperature with addition of 10% hydrogen along with presumable indigenous organics and sulfate in the clay. High-throughput sequencing of 16S rRNA gene fragments indicated a high abundance of Gram-positive bacteria of the phylum Firmicutes (82%) in MX-80 Batch 1 incubations. Bacterial libraries from microcosms with MX-80 Batch 2 were enriched with Firmicutes (53%) and Chloroflexi (43%). Firmicutes also significantly contributed (<15%) to the bacterial community in Canaprill clay microcosm, which was dominated by Gram-negative Proteobacteria (>70%). Sequence analysis revealed presence of the bacterial families Peptostreptococcaceae, Clostridiaceae, Peptococcaceae, Bacillaceae, Enterobacteriaceae, Veillonellaceae, Tissierellaceae and Planococcaceae in MX-80 Batch 1 incubations; Bacillaceae, along with unidentified bacteria of the phylum Chloroflexi, in MX-80 Batch 2 clay microcosms, and Pseudomonadaceae, Hydrogenophilaceae, Bacillaceae, Desulfobacteraceae, Desulfobulbaceae, Peptococcaceae, Pelobacteraceae, Alcaligenaceae, Rhodospirillaceae in Canaprill microcosms. Exploration of potential metabolic pathways in the bacterial communities from the clay microcosms suggested variable patterns of sulfur cycling in the different clays with the possible prevalence of bacterial sulfate-reduction in MX-80 bentonite, and probably successive sulfate-reduction/sulfur-oxidation reactions in Canaprill microcosms. Furthermore, analysis of potential metabolic pathways in the bentonite enrichments suggested that bacteria with acid-producing capabilities (i.e., fermenters and acetogens) together with sulfide-producing prokaryotes might perhaps contribute to corrosion risks in clay systems. However, the low activity or dormancy of microorganisms in highly compacted bentonites as a result of severe environmental constraints (e.g., low water activity and high swelling pressure in the confined bentonite) in situ would be expected to largely inhibit bacterial activity in highly compacted clay-based barriers in a future DGR.


Preoperative CT study of lymph nodes in cervical cancer--its correlation with histological findings.
A study was conducted to retrospectively evaluate the accuracy of abdominopelvic computed tomography (CT) in the diagnosis of paraaortic and pelvic lymph node metastases from carcinoma of the uterine cervix. Seventy patients with a diagnosis of invasive carcinoma of the cervix had preoperative CT of abdomen and pelvis and subsequently underwent a radical hysterectomy with pelvic lymph node dissection and paraaortic lymph node biopsy or an exploratory laparotomy with paraaortic lymph node biopsy. Five of six patients with metastatic paraaortic lymph nodes larger than 15 mm in diameter on the histologic slides were diagnosed by CT scan to have enlarged nodes. CT diagnosis was true-positive in five of seven patients with paraaortic lymph node metastases (71.4%). Two patients with false-positive paraaortic lymph nodes had clusters of small lymph nodes less than 10 mm in diameter on the histologic slides. In contrast, only a small number of the metastatic pelvic nodes were diagnosed by CT as enlarged nodes. CT diagnosis was true-positive in 5 of 11 sites with pelvic lymph node metastases (45.5%).


Sand aspiration in drowning and near drowning.
Aspiration of sand and other foreign material is often discovered at autopsy in victims of drowning, but is not commonly seen radiographically. Two such cases are described, one of drowning and one of near drowning. In each case, the sand was radiopaque because of its calcium carbonate content and created a "sand bronchogram", i.e., sand in the tracheobronchial tree. With early recognition, successful bronchoscopic removal of the aspirated sand is possible.


Clinical impact of long-term change in air trapping on pulmonary function and computed tomography parameters in chronic obstructive pulmonary disease.
Air trapping is associated with unfavorable outcomes in chronic obstructive pulmonary disease (COPD). The present study evaluated the association between longitudinal changes in air trapping with pulmonary function, computed tomography (CT) parameters and exacerbation. Patients enrolled in the Korean Obstructive Lung Disease (KOLD) study cohort from June 2005 to October 2015 were included. The study patients were categorized into four groups according to the change in residual volume to total lung capacity ratio (RV/TLC) over 3 years. The RV/TLC was considered abnormal when it was ≥ 40% and normal when it was < 40%. A total of 279 patients were categorized into four groups: 76 in the "normal to normal" (N→N) group, 34 in the "abnormal to normal" (A→N) group, 33 in the "normal to abnormal" (N→A) group, and 136 in the "abnormal to abnormal" (A→A) group. For forced expiratory volume in 1 second and forced vital capacity (FVC), respectively, group A→N showed a large increase of 266 mL (p < 0.001) and 381 mL (p < 0.001), group N→A showed a marked decrease of 216 mL (p < 0.001) and 332 mL(p = 0.029), and group A→A showed a decrease of 16 mL (p = 0.426) and 6 mL (p = 0.011) compared to group N→N. Group A→N showed a significant decrease of -0.013 in expiratory to inspiratory ratio of the mean lung density (p < 0.001), while group A→N showed an increase of 0.005 (p < 0.001). Patients with COPD whose RV/TLC changed from normal to abnormal showed deterioration of pulmonary function and worsening of CT parameters simultaneously.


An adaptive response to uncertainty generates positive and negative contrast effects.
Successive contrast effects, in which behavior is dependent on whether conditions are currently better or worse than they were before, are a striking illustration of the fact that animals evaluate the world in relative terms. Existing explanations for these effects are based on descriptive models of psychological and physiological processes, but little attention has been paid to the factors promoting their evolution. Using a simple and general optimality model, we show that contrast effects can result from an adaptive response to uncertainty in a changing, unpredictable world. A wide range of patterns of environmental change will select for sensitivity to past conditions, generating positive and negative contrast effects. Our analysis reveals the importance of incorporating uncertainty and environmental stochasticity into models of adaptive behavior.


Evaluation of outcomes in community-acquired pneumonia: a guide for patients, physicians, and policy-makers.
Community-acquired pneumonia (CAP) is a key target for research and quality improvement in acute medicine. However, many of the outcome measures used in prognostic and antibiotic studies are not validated and do not capture features of outcome that are important to patients. Substitutes for traditional outcome measures include a recently validated patient-based symptom questionnaire (the CAP-Sym) and process-of-care measures. The interpretation of outcomes also depends on the quality of the study design and methods used. This paper discusses the advantages and disadvantages of outcome, process-of-care, and economic measures in CAP and the interpretation of these measures in randomised and observational studies. A core set of measures for use in clinical CAP research and performance measurement is proposed.


The influence of coupling transferrin to liposomes or minibeads on its uptake and fate in leukemic L2C cells.
Coupling transferrin to liposomes or minibeads did not affect its uptake by L2C lymphocytes via the Tf specific receptors. The uptake kinetics of Tf conjugated with particles about 50 nm in diameter was as rapid as in the case of native Tf, and the receptors were recycled with a similar turnover time (about 15 min). Contrary to the generally accepted scheme, we found some Tf degradation provoked by cellular uptake. The degradation represented about 10% of the amount of ligand taken up by the cells. It occurred when transferrin was coupled to liposomes, but not when coupled to minibeads.


Treatment of resistant chronic migraine with anti-CGRP monoclonal antibodies: a systematic review.
Resistant chronic migraine is a highly disabling condition which is very difficult to treat. The majority of the treatments for migraine prophylaxis are nonspecific and present weak safety profiles, leading to low adherence and discontinuation. Currently, monoclonal antibodies (mAb) targeting the trigeminal sensory neuropeptide, calcitonin gene-related peptide (CGRP), are available for migraine prophylaxis being the first drugs developed specifically to target migraine pathogenesis. The main objective of the current work is to carry out a systematic review of randomised controlled trials that specifically analyse the effectivity and safety of anti-CGRP mAb, comparatively to placebo, in patients with resistant chronic migraine and possibly fill the literature gap or be a source of information to health professionals. Additionally the current knowledge on migraine, particularly resistant chronic migraine, was revisited and summarised. Literature search was carried out on MEDLINE, Scopus, Science Direct and ClinicalTrials.gov database, from inception to December 2021. Articles were selected according to prespecified criteria of inclusion and exclusion. Efficacy and safety outcomes included were: change from baseline in monthly migraine days (MMD); ≥50% reduction of MMD values from baseline; change from baseline in monthly acute migraine-specific medication days (MAMD); Migraine-specific Quality of Life Questionnaire (MSQ); and registered adverse events. Additionally, we used the Cochrane risk of bias tool (RoB 2) to assess the risk of bias of the included studies. Four studies were included in this systematic review, involving 2811 resistant chronic migraine patients, 667 in a study using erenumab, 838 in a study using fremanezumab and 1306 in two studies using galcanezumab. When compared to placebo, all investigated anti-CGRP mAb and respective doses demonstrate effectiveness in decreasing MMD, reducing acute medication use and improving the MSQ scores, including, sometimes, reversion of chronic to episodic migraine (efficacy outcomes). Regarding the safety outcomes, the number and type of adverse events did not differ between anti-CGRP mAb-treated and placebo groups. Anti-CGRP or anti-CGRP receptor monoclonal antibodies are a promising preventive migraine therapy which can be particularly useful for resistant chronic migraine patients.


Blood Pressure and Metabolic Changes After 3-Month CPAP Therapy in a Very Elderly Obese with Severe Obstructive Sleep Apnea: A Case Report and Review of the Literature.
Age is one of the main risk factor for the presence of obstructive sleep apnea (OSA). This syndrome is associated with hypertension, cardiovascular disease, cognitive impairment and metabolic abnormalities, such as type 2 diabetes. Continuous positive airway pressure (CPAP) represents the gold standard therapy, but its benefit is still to be determined in very elderly. We report the blood pressure and metabolic changes in a very elderly obese with severe OSA after 3-month CPAP therapy. We have evaluated a very elderly obese male affected by severe symptomatic OSA, poor controlled nocturnal hypertension and insulin resistance. After 3-month CPAP therapy, without any changes in drug therapy, we observed a normalization of circadian blood pressure (BP) pattern, an improved insulin sensitivity, together with a reduced resting energy expenditure, despite no significant change in weight. This case report shows the benefits of OSA treatment with CPAP, not only on BP profile, but also on metabolic parameters in a very elderly, a particular type of patient in which scientific evidence is still scant. Further studies are needed to better investigate the relationship between OSA, CPAP therapy and energy expenditure not only in adults but also in elderly patients.


Making the most of scarcityScarcity Fredrik Albritton Jonsson and Carl Wennerlind Harvard University Press, 2023. 304 pp.
A pair of historians dig into the deep ideological roots of our planetary predicament.


Socioecology and fiction.
We argue that the generation and enjoyment of imaginary worlds do not necessarily rely on an evolved preference for exploration. Rather, we suggest that culture is shaped by socioecological facts on the ground, and we hypothesize about the role of residential mobility, specifically, as an important factor in the popularity of imagined spaces.


Characterization of the DNA mismatch repair proteins MutS and MutL in a hypermutator Acinetobacter baumannii.
Mutations of mutS and mutL genes have been linked with the emergence of hypermutator (HPM) phenotype in several bacteria. Nevertheless, there is scarce evidence that these mutations occurred in HPM Acinetobacter baumannii, therefore, it remains unknown whether the mutations located in domains mediating the functions of MutS and MutL. To address this information gap, the nucleotide sequences of mutS and mutL were characterized and their mutations were identified. Additionally, we proposed in silico models of mutated proteins and analyzed the secondary and tertiary structures, and the interaction interfaces of MutL and MutS. The HPM A. baumannii and a wild-type strain were subjected to PCR amplification of full length mutS and mutL, cloning, and sequencing. Following several reads of both strands of each gene and sequence assembly, the mutations were identified. Thereafter, the three-dimensional (3-D) structure of A. baumannii ATCC 19606 was developed and utilized as a template for homology modeling of the mutated amino acid sequences using the Phyre2 and I-TASSER, VMD 1.9.3, LigPlus v.1.4.5, PyMOL v.0.99 software. Regardless of silent mutations (n = 43), 11 missense mutations were identified in the MutS domains of HPM strain such as A4T, T272S, D278N in N-terminus, connector, and core domains, respectively. Three mutations -I357T, A408S, N447S- and 16 silent mutations were observed in MutL. Secondary structure prediction of MutS revealed that the amount of alpha helices, beta sheets, and coils in HPM were 35, 29, and 63, respectively, while these values were 36, 28, and 63 for A. baumannii ATCC 19606 as non mutator. In the case of MutL, for both HPM and non-mutator, 20, 21, and 39 of complete protein were alpha helices, beta sheets, and coils, respectively. Superimposition of structures of MutS of HPM on non-mutator revealed that T272, D278, G457, S528, A533, Y715, and E747 are closely matched with S272, D278, A457, P528, V533, C715, and K747, respectively in non-mutator strain. When the structure of MutL model in HPM was superimposed on its counterpart in non-mutator, all but residues S447, S408, and T357 were identical. Many mutations along the mutS and mutL were noted, but most of the mutations were observed in the interaction interfaces of MutS and MutL. Other substitutions were predominantly detected in C-terminus of MutS that may lead to reduced ATP binding and hydrolysis. Three substitution mutations were adjacent to C-terminus of MutL and are raising the suggestion of reduction in MutL dimerization. It seems that a combination of these mutations is implicated in increased mutation frequency and accordingly emergence of HPM strain.


The neuroethological approach to defense in rabbit.
In this chapter we review the neuroethological approach correlating behavior and dorsal hippocampal activity recorded in rabbits in laboratory conditions or in a semi-natural enclosure and exposed to intra and interspecific confrontations. Behaviors of the same modality, i.e., immobility, and the same motivation, i.e., defense, can be distinguished by a different pattern of hippocampal activity, in terms of the relative ratio of RSA (rhythmic slow activity), and LIA (large amplitude irregular activity), and of RSA frequencies. In addition, the frequency and the duration of RSA episodes represent critical indicators of the amount of awareness during immobility conditions. The neural pattern is also differentially affected by dynamic (a live cat) and static (a stuffed sparrow hawk) stimuli. On a neuroethological basis, the hippocampal profile of TI, characterized by the prevalence of LIA, is similar to a sparrow-hawk exposure and to the submissive posture in a conspecific confrontation.