Effects of heterogeneities on capillary pressure-saturation-relative permeability relationships.
In theories of multiphase flow through porous media, capillary pressure-saturation and relative permeability-saturation curves are assumed to be intrinsic properties of the medium. Moreover, relative permeability is assumed to be a scalar property. However, numerous theoretical and experimental works have shown that these basic assumptions may not be valid. For example, relative permeability is known to be affected by the flow velocity (or pressure gradient) at which the measurements are carried out. In this article, it is suggested that the nonuniqueness of capillary pressure-relative permeability-saturation relationships is due to the presence of microheterogeneities within a laboratory sample. In order to investigate this hypothesis, a large number of "numerical experiments" are carried out. A numerical multiphase flow model is used to simulate the procedures that are commonly used in the laboratory for the measurement of capillary pressure and relative permeability curves. The dimensions of the simulation domain are similar to those of a typical laboratory sample (a few centimeters in each direction). Various combinations of boundary conditions and soil heterogeneity are simulated and average capillary pressure, saturation, and relative permeability for the "soil sample" are obtained. It is found that the irreducible water saturation is a function of the capillary number; the smaller the capillary number, the larger the irreducible water saturation. Both drainage and imbibition capillary pressure curves are found to be strongly affected by heterogeneities and boundary conditions. Relative permeability is also found to be affected by the boundary conditions; this is especially true about the nonaqueous phase permeability. Our results reveal that there is much need for laboratory experiments aimed at investigating the interplay of boundary conditions and microheterogeneities and their effect on capillary pressure and relative permeability.


Foreign body aspiration.
The clinical manifestations of foreign body (FB) aspiration can range from an asymptomatic presentation to a life-threatening emergency. Patients may present with acute onset cough, chest pain, breathlessness or sub-acutely with unexplained hemoptysis, non-resolving pneumonia and at times, as an incidental finding on imaging. Patients with iatrogenic FB such as an aspirated broken tooth during difficult intubation or a broken instrument are more common scenarios in the intensive care unit (ICU). Patients with post-obstructive pneumonia with or without sepsis, or variable degree of hemoptysis often require ICU level of care and bronchoscopic interventions. Rigid bronchoscopy has traditionally been the modality of choice; however, with the innovation in instrumentation and wider availability of flexible bronchoscopes, most of the FB removal is now successfully performed using flexible bronchoscopy. Proceduralists choose instruments in accordance with their training and expertise. We describe the use of most common instruments including forceps, balloon catheters, and baskets. Role of cryoprobe and LASER in FB removal is reviewed as well. In general, larger working channel bronchoscopes are preferred; however, smaller working channel bronchoscopes may be used in situations when the patients are intubated with a smaller diameter endotracheal or tracheostomy tubes. Large size FB are removed en bloc with the grasping tool, bronchoscope, and endotracheal or tracheostomy tube, requiring preparation to safely re-establish the airway. After FB removal, bronchoscopy is re-performed to identify any residual FB, assess any injury to the airway, suction post-obstructive secretions or pus, control any active bleeding and remove granulation tissue that may be obstructing the airway. Additional interventions like balloon dilatation may be required to dislodge an impacted FB or to maintain patency of bronchial lumen. If bronchoscopic methods fail, surgery may be required for retrieval of FB in symptomatic patients or to resect suppurative or necrotizing lung process. Multidisciplinary approach involving intensivists, surgeons, and anesthesiologists is the key to optimal patient outcomes.


Tracheal intubation using alfentanil and no muscle relaxant: is the choice of hypnotic important?
Administration of alfentanil followed by propofol intravenously (IV) without neuromuscular blockade for induction of anesthesia provides adequate conditions for tracheal intubation. Other hypnotic drugs have not been thoroughly investigated in this regard. Accordingly, 140 ASA physical status I and II premedicated outpatients were randomly assigned to one of seven groups (n = 20/group). Patients in Groups I-VI received alfentanil 40 microg/kg followed by etomidate 0.3 mg/kg, propofol 2 mg/kg, or thiopental 4 mg/kg. One half of these patients (Groups II, IV, VI) also received lidocaine 1 mg/kg IV prior to the administration of the above drugs. Patients in group VII received d-tubocurarine 3 mg followed by thiopental 4 mg/kg and succinylcholine 1 mg/kg. Ninety seconds after induction, laryngoscopy and endotracheal intubation were attempted and graded. Patients in Group V (alfentanil/thiopental) were significantly (P < 0.05) more likely to have a clinically unacceptable response to intubation (55%) (e.g., vigorous coughing, purposeful movement, or requirement for succinylcholine to complete intubation) compared with patients who received propofol (35%) or etomidate (20%). Alfentanil/etomidate yielded intubation conditions comparable to those achieved with alfentanil/propofol and d-tubocurarine/thiopental/succinylcholine. Lidocaine appeared to improve intubating conditions, although this improvement did not reach statistical significance. The results suggest that healthy, premedicated patients with favorable airway anatomy who have received alfentanil 40 microg/kg can be reliably tracheally intubated 90 s after administration of propofol 2 mg/kg or etomidate 0.3 mg/kg.


LRIG1 is a gatekeeper to exit from quiescence in adult neural stem cells.
Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.


[The specialisation in ant working groups involved in trophobiosis with aphids].
The peculiarities of behaviour and organization of taking care of aphids while trophobiosis were studied in ant species predominant in milti-species communities (Formica polyctena Forst, F. aquilonia Yarr., and F. pratensis Retz.). "Professional specialisation" with distinct division of segregation functions of aphid colony protection and honeydew collecting was revealed and described in working groups of ants, which are constant in composition. It is shown that trophobiont working groups include both passive and active foragers. The functions of the former are usually limited to honeydew collecting and transportation. Active foragers are multifunctional: in addition to their basic duties, they may defend symbionts, search for new aphid colonies, and, to some extent, coordinate group activities. It was shown earlier that ants employ different schemes of interactions with aphids, from individual foraging to "professional specialisation" in working groups. Comparative analysis of the schemes of interactions between ants of different species and aphids has shown that the degree of functional differentiation in trophobiont working groups is conditioned by carbohydrate food requirements of the colony. Ant colony size and the condition of available resources (abundance and productivity of symbionts) are the principal factors that determine the emergence of strict specialisation in groups. The trend to further differentiation of functions in trophobiont working groups is observed under increasing ant colony size and under food deficiency; such strict specialisation is facultative.


Can procalcitonin be used to diagnose Gram-negative bloodstream infection? Evidence based on a meta-analysis.
Procalcitonin (PCT) is a useful biomarker for systemic bacterial infection, and many studies have described the correlation between high serum PCT level and Gram-negative bloodstream infection (BSI), whereas the diagnostic accuracy of PCT for this kind of episode has not been summarized. This study aimed to estimate the overall accuracy of serum PCT for diagnosing Gram-negative BSI through a meta-analysis. We searched PubMed, EMBASE, Web of Science, and Scopus database for studies that met the inclusion criteria. The pooled sensitivity, specificity, positive/negative likelihood ratio (PLR/NLR), and diagnostic odds ratio (DOR) were calculated using bivariate random-effects models. Summary receiver operating characteristic (SROC) curve and area under the curve (AUC) were used to summarize overall diagnostic accuracy. Our meta-analysis included 13 studies involving 4,513 subjects. Summary estimates for PCT in diagnosing Gram-negative BSI were as follows: sensitivity, 0.73 (95% CI 0.68 to 0.78); specificity, 0.74 (95% CI 0.64 to 0.81); PLR, 2.77 (95% CI 2.07 to 3.70); NLR, 0.37 (95% CI 0.31 to 0.42); DOR, 7.59 (95% CI 5.31 to 10.85); AUC, 0.79 (95% CI 0.75 to 0.82). The corresponding summary performance estimates for using PCT in differentiating Gram-negative BSI from gram-positive BSI were as follows: sensitivity, 0.73 (95% CI 0.66 to 0.78); specificity, 0.70 (95% CI 0.59 to 0.78); PLR, 2.40 (95% CI, 1.83 to 3.15); NLR, 0.39 (95% CI 0.33 to 0.46); DOR, 6.15 (95% CI 4.40 to 8.60); AUC, 0.77 (95% CI 0.73 to 0.81). PCT may have a limited diagnostic value for Gram-negative BSI.


[Formation of transfecting DNA in acute cellular infection with the tick-borne encephalitis virus mediated by an oncogenic virus].
To prove the association of the transfecting activity of nucleic acid from cells co-infected with TBE and SV40 viruses with DNA, experiments were carried out using fractionation of nucleic acid preparations in cesium sulphate gradient an on a column with HAP. The experiments led to a conclusion that the infectivity of the preparations used was associated with double-stranded DNA. Investigation of nucleic acid infectivity form cytochalasine-enucleated cells indicated that the function of the nucleus was necessary for formation of transfecting DNA in mixed TBE and SV40 infection of cell. No formation of transfecting DNA was observed in experiments of blocking replication and transcription of cellular genome. The retention of the transfecting activity of DNA during 6 passages of cells at approximately the same level indicated the lack of selective preferences or inhibition of cells containing transfecting DNA.


Multiscale modelling in biofluidynamics: application to reconstructive paediatric cardiac surgery.
Multiscale computing is a challenging area even in biomechanics. Application of such a methodology to quantitatively compare postoperative hemodynamics in congenital heart diseases is very promising. In the treatment of hypoplastic left heart syndrome, which is a congenital heart disease where the left ventricle is missing or very small, the necessity to feed the pulmonary and systemic circulations is obtained with an interposition shunt. Two main options are available and differ from the sites of anastomoses: (i) the systemic-to-pulmonary conduit (Blalock-Taussig shunt known as the Norwood Operation (NO)) connecting the innominate artery (NO-BT) or the aorta (NO-CS) to the right pulmonary artery and (ii) the right ventricle to pulmonary artery shunt (known as Sano operation (SO)). The proposition that the SO is superior to the NO remains controversial. 3-D computer models of the NO (NO-BT and NO-CS) and SO were developed and investigated using the finite volume method. Conduits of 3, 3.5 and 4 mm were used in the NO models, whereas conduits of 4, 5 and 6 mm were used in the SO model. The hydraulic nets (lumped resistances, compliances, inertances and elastances) which represent the systemic, coronary and pulmonary circulations and the heart were identical in the two models. A multiscale approach was adopted to couple the 3-D models with the circulation net. Computer simulation results were compared with post-operative catheterization data. Results showed that (i) there is a good correlation between predicted and observed data: higher aortic diastolic pressure, decreased pulmonary arterial pressure, lower pulmonary-to-systemic flow ratio and higher coronary perfusion pressure in SO; (ii) there is a minimal regurgitant flow in the SO conduit. The close correlation between predicted and observed clinical data supports the use of mathematical modelling, with a mandatory multiscale approach, in the design and assessment of surgical procedures.


Communicating worst-case scenarios: neighbors' views of industrial accident management.
The prospect of industrial accidents motivated the U.S. Congress to require in the Clean Air Act of 1990 that manufacturing facilities develop Risk Management Plans (RMP) to submit to the U.S. Environmental Protection Agency (USEPA) by July 1999. Industry worried that the requirement to communicate to the public a "worst-case scenario" would arouse unnecessary and counterproductive fears among industry neighbors. We report here the results of focus groups and surveys with such neighbors, focusing particularly upon their reactions to messages about a hypothetical worst-case scenario and management of these risks by industry, government, and other parties. Our findings confirmed our hypotheses that citizens would be skeptical of the competence and trustworthiness of these managers and that this stance would color their views of industrial-facility accident risks. People with job ties to industry or who saw industrial benefits to the community as exceeding its risks had more positive views of industrial risks, but still expressed great concern about the risk and doubt about accident management. Notwithstanding these reactions, overall respondents welcomed this and other related information, which they wanted their local industries to supply. Respondents were not more reassured by additional text describing management of accidents by government and industry. However, respondents did react very positively to the concept of community oversight to review plant safety. Claims about the firm's moral obligation or financial self-interest in preventing accidents were also received positively. Further research on innovative communication and management of accident risks is warranted by these results, even before recent terrorist attacks made this topic more salient.


Psychoactive drug advertising: content analysis.
The goal of this study was to describe the human figures portrayed in psychoactive drug advertising in terms of gender, age, ethnic group, and social context. Content analysis for 86 new pieces of printed advertisements released in 2005 was carried out. Fisher exact test was used to analyze the association between categories. There was a preponderance of women (62.8%) who were four times more present in advertisements for antidepressants and anxyolitics than men. Most of the people shown were Caucasian (98.8%) young adults (72%). These people were pictured in leisure activities (46.5%), at home (29%), or in contact with nature (16.2%). The message conveyed was that the drugs treat routinely felt subjective symptoms of discomfort, inducing in an irrational appeal that may affect drug prescription.


[Some reflexions to guide the parents toward adoption].
The successive steps of the long way facing all French couples applying for child adoption are described. Main problems are the legal adoption authorization, the origin of children (French children under the care of the State, foreign children either through private institutions or after an individual approach). Pediatricians play an important role in counselling and evaluating the health status of the children (study of medical files, requests for biochemical tests) before the formal decision is made.


Biochemistry of aerobic biological methane oxidation.
Methanotrophic bacteria represent a potential route to methane utilization and mitigation of methane emissions. In the first step of their metabolic pathway, aerobic methanotrophs use methane monooxygenases (MMOs) to activate methane, oxidizing it to methanol. There are two types of MMOs: a particulate, membrane-bound enzyme (pMMO) and a soluble, cytoplasmic enzyme (sMMO). The two MMOs are completely unrelated, with different architectures, metal cofactors, and mechanisms. The more prevalent of the two, pMMO, is copper-dependent, but the identity of its copper active site remains unclear. By contrast, sMMO uses a diiron active site, the catalytic cycle of which is well understood. Here we review the current state of knowledge for both MMOs, with an emphasis on recent developments and emerging hypotheses. In addition, we discuss obstacles to developing expression systems, which are needed to address outstanding questions and to facilitate future protein engineering efforts.


A comparison of the effects of 4-dimethylaminopyridine and 4-aminopyridine on isolated cardiac and skeletal muscle preparations.
The actions of 4-dimethylaminopyridine (4-dimethyl-AP) on the isolated rat diaphragm and guinea-pig atria were examined and compared with those of 4-aminopyridine (4-AP). In the rat diaphragm, 4-dimethyl-AP slightly (27%) increased indirectly evoked maximal twitches, and was a weak antagonist of d-tubocurarine-induced neuromuscular block, while 4-AP increased indirect twitches by about 250%, and produced rapid and complete reversal of d-tubocurarine block. In directly stimulated preparations, 4-AP but not 4-dimethyl-AP produced marked augmentation of maximal twitches (220%). In electrically-driven guinea-pig left atria, both compounds produced positive inotropic effects (PIE), which were partially inhibited by L-propranolol or by pretreatment with intraperitoneal syrosyngopine or 6-hydroxydopamine, suggesting that part of the response was due to noradrenaline (NA) release. Nifedipine or methoxyverapamil (D-600) produced negative inotropic effects (NIE) and prevented the PIE of both aminopyridines. The NIE of these Ca2+ entry blockers was reversed by excess CaCl2 or NA. It is concluded that 4-dimethyl-AP, like 4-AP is a powerful cardiac inotropic agent in vitro. 4-Dimethyl-AP which, unlike 4-AP, possesses weak effects on neuromuscular transmission and on muscle contractility in the rat diaphragm, therefore appears to possess a greater specificity for cardiac muscle.


Indium 111-mercaptopyridine N-oxide-labeled human leukocytes and platelets: mechanism of labeling and intracellular location of 111In and mercaptopyridine N-oxide.
Human leukocytes and platelets were labeled in plasma with indium 111, by incubating cells first with 2-mercaptopyridine N-oxide (Merc) and then with ionic or weakly chelated 111In citrate. We investigated the mechanism by which this procedure enabled us to label cells in plasma. The interactions of 111In and Merc with cell membrane and cytoplasm were studied by homogenizing labeled cells and analyzing the homogenate by gel filtration. Studies were facilitated by use of sulfur 35-labeled Merc. Although 65% +/- 12.8% of added 111-In was incorporated in cells in presence of extracellular Merc, only 0.8% +/- 0.1% and 5.1% +/- 3.2% 35S-Merc was associated with 10(8) leukocytes and 10(10) platelets, respectively. In the absence of extracellular Merc, only 4.5% +/- 0.3% 111In was taken up by the cells. In each type of cell 83% to 99% of the cell-incorporated 35S Merc was associated with a cytoplasmic component with apparent molecular weight 5200 daltons, independently of the presence or absence of radioactive or stable indium. An approximately equal proportion of 111In was bound to similar cytoplasmic components in both types of cells. On adenosine diphosphate-induced platelet aggregation, less than 3% of platelet-bound 111In or 35S-Merc was released. These results indicate that it is the extracellular Merc that facilitates 111In labeling. It does not bind to cell membrane, but forms a lipid-soluble complex with 111In. This complex passively diffuses through the cell membrane, allows 111In to bind to cytoplasmic components, and provides a stable cell label.


Analysing the oviposition behaviour of malaria mosquitoes: design considerations for improving two-choice egg count experiments.
Choice egg-count bioassays are a popular tool for analysing oviposition substrate preferences of gravid mosquitoes. This study aimed at improving the design of two-choice experiments for measuring oviposition substrates preferences of the malaria vector Anopheles gambiae senso lato, a mosquito that lays single eggs. In order to achieve high egg-laying success of female An. gambiae sensu stricto (s.s.) and Anopheles arabiensis mosquitoes in experiments, four factors were evaluated: (1) the time provided for mating; (2) the impact of cage size, mosquito age and female body size on insemination; (3) the peak oviposition time; and, (4) the host sources of blood meal. Choice bioassays, with one mosquito released in each cage containing two oviposition cups both with the same oviposition substrate (100 ml water), were used to measure and adjust for egg-laying characteristics of the species. Based on these characteristics an improved design for the egg-count bioassay is proposed. High oviposition rates [84%, 95% confidence interval (CI) 77-89%] were achieved when 300 male and 300 blood-fed female An. gambiae s.s. were held together in a cage for 4 days. The chances for oviposition dropped (odds ratio 0.30; 95% CI 0.14-0.66) when human host source of blood meal was substituted with a rabbit but egg numbers per female were not affected. The number of eggs laid by individual mosquitoes was overdispersed (median = 52, eggs, interquartile range 1-214) and the numbers of eggs laid differed widely between replicates, leading to a highly heterogeneous variance between groups and/or rounds of experiments. Moreover, one-third of mosquitoes laid eggs unequally in both cups with similar substrates giving the illusion of choice. Sample size estimations illustrate that it takes 165 individual mosquitoes to power bioassays sufficiently (power = 0.8, p = 0.05) to detect a 15% shift in comparative preferences of two treatments. Two-choice egg count bioassays with Anopheles are best done with a two-tier design that (1) implements a parallel series of experiments with mosquitoes given a choice of two identical substrates choices and, (2) uses a single mosquito in each test cage rather than groups of mosquitoes to assess the preference of a test or control solution. This approach, with sufficient replication, lowers the risk detecting pseudopreferences.


Conversion pattern and predictive factor of mild cognitive impairment in elderly Koreans.
We aimed to understand conversion characteristics of mild cognitive impairment (MCI) in elderly Koreans. We analyzed clinical data of 760 individuals who participated in a two-year follow-up study. Neuropsychological assessments and clinical examination were conducted in the follow-ups. Logistic regression model was used to estimate predictive risk factors of MCI conversion. The participants at baseline (n=760) represented 462 cognitively normal individuals (60.8%), 286 individuals with MCI (37.6%), and 12 individuals with dementia (1.6%). Among the cognitively normal individuals (n=462), 108 (23.4%) progressed to MCI during the two-year follow-up period, including 92 with amnestic mild cognitive impairment (aMCI; 19.9%) and 16 with non-amnestic mild cognitive impairment (non-aMCI; 3.5%). Interestingly, 3.7% of participants with aMCI converted to non-aMCI, while 45.5% of participants with non-aMCI converted to aMCI. Moreover, a higher proportion of non-aMCI (27.3%) reverted to a cognitively normal state, compared to aMCI participants (18.6%), indicating that non-amnestic cognitive impairment is more unstable than amnestic cognitive impairment, and probably converges toward aMCI. Additionally, we found that weight loss was associated with incident MCI and future MCI. Weight loss was negatively correlated with Clinical Dementia Rating (p=0.005), and significantly associated with a higher risk of MCI conversion from a cognitively normal state (OR=1.10, 95% CI: 1.00-1.21, p=0.042). This study supports that non-amnestic MCI is prone to converge toward amnestic MCI, and the elderly people with weight loss are at risk for developing cognitive decline.


Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options.
Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.


The adherence of pilate and non-pilate strains of Neisseria gonorrhoeae to human and guinea-pig epithelial tissues.
Strains of Neisseria gonorrhoeae adhered to pieces of human endocervix and appeared to be embedded in the surface mucus. Although a pilate strain adhered better than a non-pilate strain, the difference was small and pilation did not appear to be exclusively responsible for adherence. The pilate strain showed better adherence to pieces of human ectocervix and fallopian tube, but both strains were similarly adsorbed to human bronchus and guinea-pig uterus, cervix, male urethra and bladder, although to different degrees for different tissues. Since gonococci adhered to all tissues examined, their ability to infect human endocervix and fallopian tube and their failure to infect human ectocervix or guinea-pig urogenital tract mucosae are determined by factors other than a capacity for primary adherence to the tissue.


Arginine and Arginine-Rich Peptides as Modulators of Protein Aggregation and Cytotoxicity Associated With Alzheimer's Disease.
A substantial body of evidence indicates cationic, arginine-rich peptides (CARPs) are effective therapeutic compounds for a range of neurodegenerative pathologies, with beneficial effects including the reduction of excitotoxic cell death and mitochondrial dysfunction. CARPs, therefore, represent an emergent class of promising neurotherapeutics with multimodal mechanisms of action. Arginine itself is a known chaotrope, able to prevent misfolding and aggregation of proteins. The putative role of proteopathies in chronic neurodegenerative diseases such as Alzheimer's disease (AD) warrants investigation into whether CARPs could also prevent the aggregation and cytotoxicity of amyloidogenic proteins, particularly amyloid-beta and tau. While monomeric arginine is well-established as an inhibitor of protein aggregation in solution, no studies have comprehensively discussed the anti-aggregatory properties of arginine and CARPs on proteins associated with neurodegenerative disease. Here, we review the structural, physicochemical, and self-associative properties of arginine and the guanidinium moiety, to explore the mechanisms underlying the modulation of protein aggregation by monomeric and multimeric arginine molecules. Arginine-rich peptide-based inhibitors of amyloid-beta and tau aggregation are discussed, as well as further modulatory roles which could reduce proteopathic cytotoxicity, in the context of therapeutic development for AD.


Chemoembolization with Drug-eluting Microspheres Loaded with Doxorubicin for the Treatment of Cholangiocarcinoma.
To report clinical outcomes of transarterial chemoembolization (TACE) using drug-eluting beads (DEBs) loaded with doxorubicin for the treatment of unresectable intrahepatic cholangiocarcinoma (CCA). We treated 127 patients with doxorubicin via TACE. Inclusion criteria were: diagnosis of unresectable CCA; indication for TACE, performance status (PS) 0-2, >3 months of life expectancy, >18 years old, written consent. TACE was performed using DEBs for 109 (86%) patients and polythylene glycol drug-elutable microspheres (PEG) loaded with doxorubicin for 18 (14%) patients. Tumor response of the whole sample of 127 patients was partial response (PR) in 19 (15%) patients, stable disease (SD) in 101 (80%) and progressive disease (PD) in seven (5%) 3 months after therapy, with no complete responses. There were differences between type of embolics: PR was 7% and 77%, SD was 88% and 8%, and PD was 5% and 15%, and the disease control rate was 95% and 85% in the DEB and PEG groups, respectively. Most frequent side-effects were: abdominal pain, fever, nausea, and transaminase rise. TACE was effective and safe for CCA treatment, with a high disease control rate. The best response of PEG-TACE was PR, whereas it was SD for DEB-TACE.


Diurnal variation in P-glycoprotein-mediated transport and cerebrospinal fluid turnover in the brain.
Nearly all bodily processes exhibit circadian rhythmicity. As a consequence, the pharmacokinetic and pharmacodynamic properties of a drug may also vary with time of day. The objective of this study was to investigate diurnal variation in processes that regulate drug concentrations in the brain, focusing on P-glycoprotein (P-gp). This efflux transporter limits the distribution of many drugs in the brain. To this end, the exposure to the P-gp substrate quinidine was determined in the plasma and brain tissue after intravenous administration in rats at six different time points over the 24-h period. Our results indicate that time of administration significantly affects the exposure to quinidine in the brain. Upon inhibition of P-gp, exposure to quinidine in brain tissue is constant over the 24-h period. To gain more insight into processes regulating brain concentrations, we used intracerebral microdialysis to determine the concentration of quinidine in brain extracellular fluid (ECF) and cerebrospinal fluid (CSF) after intravenous administration at two different time points. The data were analyzed by physiologically based pharmacokinetic modeling using NONMEM. The model shows that the variation is due to higher activity of P-gp-mediated transport from the deep brain compartment to the plasma compartment during the active period. Furthermore, the analysis reveals that CSF flux is higher in the resting period compared to the active period. In conclusion, we show that the exposure to a P-gp substrate in the brain depends on time of administration, thereby providing a new strategy for drug targeting to the brain.


On-going consequences of in utero exposure of Pb: An epigenetic perspective.
Epigenetic modifications by toxic heavy metals are one of the intensively investigated fields of modern genomic research. Among a diverse group of heavy metals, lead (Pb) is an extensively distributed toxicant causing an immense number of abnormalities in the developing fetus via a wide variety of epigenetic changes. As a divalent cation, Pb can readily cross the placental membrane and the fetal blood brain barrier leading to far-reaching alterations in DNA methylation patterns, histone protein modifications, and micro-RNA expression. Over recent years, several human cohorts and animal model studies have documented hypermethylation and hypomethylation of developmental genes along with altered DNA methyl-transferase expression by in utero Pb exposure in a dose-, duration-, and sex-dependent manner. Modifications in the expression of specific histone acetyltransferase enzymes along with histone acetylation and methylation levels have been reported in rodent and murine models. Apart from these, down-regulation and up-regulation of certain microRNAs crucial for fetal development have been shown to be associated with in utero Pb exposure in human placenta samples. All these modifications in the developing fetus during the prenatal and perinatal stages reportedly caused severe abnormalities in early or adult age, such as impaired growth, obesity, autism, diabetes, cardiovascular diseases, risks of cancer development, and Alzheimer's disease. In this review, currently available information on Pb-mediated alterations in the fetal epigenome is summarized. Further research on Pb-induced epigenome modification will help to understand the mechanisms in detail and will enable us to formulate safety guidelines for pregnant women and developing children.


redGEM: Systematic reduction and analysis of genome-scale metabolic reconstructions for development of consistent core metabolic models.
Genome-scale metabolic reconstructions have proven to be valuable resources in enhancing our understanding of metabolic networks as they encapsulate all known metabolic capabilities of the organisms from genes to proteins to their functions. However the complexity of these large metabolic networks often hinders their utility in various practical applications. Although reduced models are commonly used for modeling and in integrating experimental data, they are often inconsistent across different studies and laboratories due to different criteria and detail, which can compromise transferability of the findings and also integration of experimental data from different groups. In this study, we have developed a systematic semi-automatic approach to reduce genome-scale models into core models in a consistent and logical manner focusing on the central metabolism or subsystems of interest. The method minimizes the loss of information using an approach that combines graph-based search and optimization methods. The resulting core models are shown to be able to capture key properties of the genome-scale models and preserve consistency in terms of biomass and by-product yields, flux and concentration variability and gene essentiality. The development of these "consistently-reduced" models will help to clarify and facilitate integration of different experimental data to draw new understanding that can be directly extendable to genome-scale models.


Development of an automated laser drilling algorithm to compare stone ablation patterns from different laser pulse modes.
To develop a novel automated three-dimensional (3D) laser drilling algorithm to further investigate laser-stone interaction with different laser pulse modes. Comparison of post-ablative lattice architecture combined with mass of stone ablated can provide a more complete understanding of differences between pulse mode. A 3D positioner (securing laser fiber) was programmed to create a 5 × 5 grid of drill holes spaced 1 mm apart on 15:5 cylindrical BegoStones. Beginning 0.5 mm above the stone surface, the laser fiber was activated and advanced 2 mm toward and into the stone for all 25 points. Four trials for each pulse mode [short pulse (SP), long pulse (LP), Moses Contact (MC), Moses Distance (MD)] were completed. Outcome measures were assessment of lattice preservation and mass of ablated stone. MC exhibited the greatest lattice preservation and least stone mass ablated (50.5 ± 2.2 mg). SP (69.4 ± 4.3 mg) and MD (70.0 ± 2.6 mg) had the greatest lattice destruction and stone mass ablated. The differences in stone ablated between MC and MD (p = 0.00003), MC and SP (p = 0.0002), and LP and MD (p = 0.004) were statistically significant. Consistent quantitative and qualitative differences between pulse modes were observed with a novel automated 3D laser drilling algorithm applied to BegoStone. The laser drilling algorithm developed here can be used to further enhance mechanistic understanding of laser-stone interactions and facilitate selection of appropriate laser pulse modes to balance precision and efficiency across the range of laser lithotripsy techniques.


Risperidone in the elderly: a pharmacoepidemiologic study.
The possibly limited adverse effects of risperidone encourage interest in its use in geriatric patients. Medical records of 122 hospitalized psychogeriatric patients (> or = 65 years old) newly treated with risperidone were reviewed and scored for indications, doses, and effects of this novel neuroleptic. Subjects (83 women, 39 men), mean +/- SD age = 76.5 +/- 6.8 years (range, 65-95), were given risperidone for agitation or psychosis associated with dementia (53%), a major mood disorder (29%), or other disorders (18%). Most (77%) were also medically ill and received other psychotropic (76%) or cardiovascular agents (70%). Daily doses of risperidone averaged 1.6 +/- 1.1 mg (range, 0.25-8.0) (0.025 mg/kg body wt.); 78% received 2.0 mg. Risperidone appeared to be effective in 85% of cases, but 18% were discontinued due to intolerability (11%) or inefficacy (7%). Adverse events occurred in 32% of the patients (36% of those discontinued). These adverse events included hypotension (29%) or symptomatic orthostasis (10%), cardiac arrest (1.6%) with fatality (0.8%), and extrapyramidal effects (11%) or delirium (1.6%). Benefits were associated with younger age and male gender, but not risperidone dose. Adverse effects were associated with cardiovascular disease and its treatment, cotreatment with an SRI antidepressant or valproate, and relatively rapid dose increases. Risperidone appeared to be effective and may be safe for many elderly psychiatric patients with comorbid medical conditions provided that doses are low and increased slowly. Particular caution is advised in the presence of cardiovascular disease or cotreatment with other psychotropic agents.


Electronic Property and Negative Thermal Expansion Behavior of Si136-xGex (x = 8, 32, 40, 104) Clathrate Solid Solution from First Principles.
We present the electronic and vibrational studies on Si136-xGex (x = 8, 32, 40, 104) alloys, using the local density approximation (LDA) scheme. We find that a "nearly-direct" band gap exists in the band structure of Si104Ge32 and Si96Ge40, when compared with the similarly reported results obtained using a different computational code. The calculated electronic density of state (EDOS) profiles for the valence band remain nearly identical and independent of the Ge concentration (x = 32, 40, 104) even though some variation is found in the lower conduction band (tail part) as composition x is tuned from 8 (or 40) to 104. The negative thermal expansion (NTE) phenomenon is explored using quasi-harmonic approximation (QHA), which takes the volume dependence of the vibrational mode frequencies into consideration, while neglecting the temperature effect on phonon anharmonicity. Determined macroscopic Grüneisen parameter trends show negative values in the low temperature regime (1 K < T < 115 K), indicating the NTE behavior found in Si128Ge8 is analogous to the experimental result for Si136. Meanwhile, calculations for the ratio of the vibrational entropy change to the volume change at several characteristic temperatures reconfirm the existence of NTE in Si128Ge8 and Si104Ge32.


[Analysis of the effect of noradrenaline on the response of the vas deferens of the rat to transmural stimulation].
In the rat isolated vas deferens, exogenous noradrenaline (NA) in concentrations of 5 X 10(-7)-5 X 10(-6) M acting for 10-15 min produced an increase whereas in concentrations above 10(-5) M it produced a decrease of the response to transmural stimulation: the increase being due to raising of the level of its secretion produced by accumulation of NA in nerve endings as well as to augmentation of postsynaptic response to NA resulting from a decrease in its reversal neuronal uptake. The decrease in the organ response to stimulation under the effect of NA at concentrations above 1 X 10(-5) M is due to desensitization of postsynaptic alpha-adrenoceptors.


MiRNA-488-3p inhibits malignant progression of NSCLC by modulating ADAM9.
The purpose of this study was to investigate the role of microRNA-488-3p in the proliferation, invasion and migration of lung cancer cells and to further explore the potential regulatory mechanisms. MicroRNA-488-3p expression in 46 pairs of tumor tissue and paracancerous tissue specimens collected from non-small cell lung cancer (NSCLC) patients were measured through quantitative real-time polymerase chain reaction (qRT-PCR) method, and the interplay between microRNA-488-3p expression and some clinical indicators of these subjects was also analyzed. In addition, microRNA-488-3p overexpression models were constructed in NSCLC cell lines, and then Cell Counting Kit-8 (CCK-8) test and transwell assays were carried out to evaluate the effect of microRNA-488-3p on the NSCLC cell functions. Furthermore, bioinformatics analysis and luciferase reporter gene assay were carried out to uncover the potential interaction between microRNA-488-3p and its downstream gene ADAM9. QPCR results revealed that microRNA-488-3p showed a significant lower expression in NSCLC tissue samples than in adjacent normal ones. In comparison to patients with high expression of microRNA-488-3, patients with low expression of microRNA-488-3 exhibited higher incidence of lymph node or distant metastasis and lower survival rate. In vitro cell experiments showed that, in comparison to control group, overexpression of microRNA-488-3p significantly weakened the proliferation ability as well as the invasion and migration of NSCLC cells. Subsequently, a significant increase in ADAM9 expression in NSCLC tissue samples was found, which indicated its negative correlation with microRNA-488-3p. In addition, cell recovery experiment demonstrated that overexpression of ADAM9 could counteract the impact of microRNA-488-3p upregulation on the proliferation and invasion ability of NSCLC cells, and the two may thus together affect the malignant progression of NSCLC. It can be concluded that microRNA-488-3p, which is associated with the incidence of metastasis in NSCLC patients, can inhibit the malignant progression of NSCLC cells by modulating ADAM9 expression.


A physiological approach to fluid and electrolyte management of the preterm infant: Review.
Despite the fact that hundreds of thousands of preterm infants receive parenteral fluids each year, study of optimal fluid and electrolyte management in this population is limited. Compared to older children and adults, preterm infants have an impaired capacity to regulate water and electrolyte balance. Appropriate fluid and electrolyte management is critical for optimal care of low birth weight or sick infants, as fluid overload and electrolyte abnormalities pose significant morbidity. This review highlights basic physiological principles which need to be applied when prescribing parenteral fluids and builds upon published literature to outline a rational approach to initial fluid and electrolyte management of the preterm infant.


Perlecan in the basement membrane of corneal epithelium serves as a site for P. aeruginosa binding.
To determine whether binding of Pseudomonas aeruginosa (P. aeruginosa) to the scarified mouse cornea depends on interaction with proteoglycans (PGs). Scarified corneas were treated with anti-proteoglycan monoclonal antibodies (MAbs), glycosaminoglycans (GAGs), heparinase III or chondroitin ABC lyase before inoculation with P. aeruginosa strain ATCC 19660 or PAO1. Scanning electron microscopy (SEM) was used to quantitate adherent bacteria. Frozen sections of unwounded and wounded mouse cornea, the latter treated or not treated with heparinase III were stained to spatially localize perlecan [core protein or heparan sulfate (HS) side chains]. Anti-perlecan MAb against the heparan sulfate proteoglycan core protein and succinyl wheat germ agglutinin (sWGA), a lectin which recognizes N-acetyl-glucosamine in heparan sulfate, respectively were used. Anti-perlecan MAb, as well as heparan sulfate, heparin and heparinase III decreased the binding of both bacterial strains to cornea, and the decrease was concentration-dependent. Fluorescence microscopic analysis of sections of mouse cornea immunostained with anti-perlecan MAb showed that perlecan was localized to the epithelial basement membrane. Scarification of the mouse cornea exposed perlecan in the basement membrane and increased bacterial binding to this site was consistent with this exposure. Lectin staining revealed that heparinase treatment removed heparan sulfate side chains of perlecan from the exposed basement membrane, and this removal was consistent with a decrease in bacterial binding. These studies provide evidence that perlecan, core protein and its heparan sulfate side chains serve as a binding site for Pseudomonas aeruginosa when the basement membrane of the cornea is exposed.


Blocking Accretion Enables Dimension Reduction of Metal-Organic Framework for Photocatalytic Performance.
The evolution and formation process of two-dimensional metal-organic frameworks (MOFs) primarily arise from the anisotropic growth of crystals, leading to variations in photocatalytic performance. It is crucial to achieve a synergistic combination of anisotropic electron transfer direction and dimension reduction strategies. In this study, a novel approach that effectively blocks crystal growth accretion through the coordination of solvent molecules is presented, achieving the successful synthesis of impurity-free two-dimensional nanosheet Zn-PTC with exceptional hydrogen evolution reaction (HER) performance (15.4 mmol g-1 h-1 ). The structural and photophysical characterizations validate the successful prevention of crystal accretion, while establishing correlation between structural anisotropy and intrinsic charge transfer mode through transient spectroscopy. These findings unequivocally demonstrate that electron transfer along the [001] direction plays a pivotal role in the redox performance of nano-Zn-PTC. Subsequently, by coupling the photocatalytic performance and density functional theory (DFT) simulation calculations, the carrier diffusion kinetics is explored, revealing that effective dimension reduction along the ligand-to-metal charge transfer (LMCT) direction is the key to achieving superior photocatalytic performance.


Older People's Nonphysical Contacts and Depression During the COVID-19 Lockdown.
With the goal of slowing down the spread of the SARS-CoV-2 virus, restrictions to physical contacts have been taken in many countries. We examine to what extent intergenerational and other types of nonphysical contacts have reduced the risk of increased perceived depressive feelings during the lockdown for people aged 50+. We implemented an online panel survey based on quota sampling in France, Italy, and Spain in April 2020, about 1 month after the start of the lockdown. Our analyses are based on logistic regression models and use post-stratification weights. About 50% of individuals aged 50+ felt sad or depressed more often than usual during the lockdown in the 3 considered countries. Older people who increased or maintained unchanged nonphysical contacts with noncoresident individuals during the lockdown were at a lower risk of increased perceived depressive feelings compared to those who experienced a reduction in nonphysical contacts. The beneficial effect of nonphysical contacts was stronger for intergenerational relationships. The effects were similar by gender and stronger among individuals aged 70+, living in Spain and not living alone before the start of the lockdown. In the next phases of the COVID-19 pandemic, or during any future similar pandemic, policy makers may implement measures that balance the need to reduce the spread of the virus with the necessity of allowing for limited physical contacts. Social contacts at a distance may be encouraged as a means to keep social closeness, while being physically distant.


Electron sharing indexes at the correlated level. Application to aromaticity calculations.
Electron sharing indexes (ESI) have been applied to numerous bonding situations to provide an insight into the nature of the molecular electronic structures. Some of the most popular ESI given in the literature, namely, the delocalization index (DI), defined in the context of the quantum theory of atoms in molecules (QTAIM), and the Fuzzy-Atom bond order (FBO), are here calculated at a correlated level for a wide set of molecules. Both approaches are based on the same quantity, the exchange-correlation density, to recover the electron sharing extent, and their differences lie in the definition of an atom in a molecule. In addition, while FBO atomic regions enable accurate and fast integrations, QTAIM definition of an atom leads to atomic domains that occasionally make the integration over these ones rather cumbersome. Besides, when working with a many-body wavefunction one can decide whether to calculate the ESI from first-order density matrices, or from second-order ones. The former way is usually preferred, since it avoids the calculation of the second-order density matrix, which is difficult to handle. Results from both definitions are discussed. Although these indexes are quite similar in their definition and give similar descriptions, when analyzed in greater detail, they reproduce different features of the bonding. In this manuscript DI is shown to explain certain bonding situations that FBO fails to cope with. Finally, these indexes are applied to the description of the aromaticity, through the aromatic fluctuation (FLU) and the para-DI (PDI) indexes. FLU and PDI indexes have been successfully applied using the DI measures, but other ESI based on other partitions such as Fuzzy-Atom can be used. The results provided in this manuscript for carbon skeleton molecules encourage the use of FBO for FLU and PDI indexes even at the correlated level.


Management of epilepsy in brain tumors.
Epilepsy in brain tumors (BTE) may require medical attention for a variety of unique concerns: epileptic seizures, possible serious adverse effects of antineoplastic and antiepileptic drugs (AEDs), physical disability, and/or neurocognitive disturbances correlated to tumor site. Guidelines for the management of tumor-related epilepsies are lacking. Treatment is not standardized, and overall management might differ according to different specialists. The aim of this document was to provide directives on the procedures to be adopted for a correct diagnostic-therapeutic path of the patient with BTE, evaluating indications, risks, and benefits. A board comprising neurologists, epileptologists, neurophysiologists, neuroradiologists, neurosurgeons, neuro-oncologists, neuropsychologists, and patients' representatives was formed. The board converted diagnostic and therapeutic problems into seventeen questions. A literature search was performed in September-October 2017, and a total of 7827 unique records were retrieved, of which 148 constituted the core literature. There is no evidence that histological type or localization of the brain tumor affects the response to an AED. The board recommended to avoid enzyme-inducing antiepileptic drugs because of their interference with antitumoral drugs and consider as first-choice newer generation drugs (among them, levetiracetam, lamotrigine, and topiramate). Valproic acid should also be considered. Both short-term and long-term prophylaxes are not recommended in primary and metastatic brain tumors. Management of seizures in patients with BTE should be multidisciplinary. The panel evidenced conflicting or lacking data regarding the role of EEG, the choice of therapeutic strategy, and timing to withdraw AEDs and recommended high-quality long-term studies to standardize BTE care.


SK channel blockade promotes burst firing in dorsal raphe serotonergic neurons.
Previous in vivo studies have shown that blockade of small-conductance Ca(2+)-activated potassium (SK) channels enhances burst firing in dopaminergic neurons. As bursting has been found to be physiologically relevant for the synaptic release of serotonin (5-HT), we investigated the possible role of SK channels in the control of this firing pattern in 5-HT neurons of the dorsal raphe nucleus. In these cells, bursts are usually composed of doublets consisting of action potentials separated by a small interval (< 20 ms). Both in vivo and in vitro extracellular recordings were performed, using anesthetized rats and rat brain slices, respectively. In vivo, the specific SK blocker UCL 1684 (200 microm) iontophoresed onto presumed 5-HT neurons significantly increased the production of bursts in 13 out of 25 cells. Furthermore, the effect of UCL 1684 persisted in the presence of both the GABA(A) antagonist SR 95531 (10 mm) and the GABA(B) antagonist CGP 35348 (10 mm), whereas these agents by themselves did not significantly influence the neuronal firing pattern. In vitro, bath superfusion of the SK channel blocker apamin (300 nm) induced bursting in only three out of 18 neurons, although it increased the coefficient of variation of the interspike intervals in all the other cells. Our results suggest that SK channel blockade promotes bursting activity in 5-HT neurons via a direct action. An input which is present only in vivo seems to be important for the induction of this firing pattern in these cells.


Workforce problems at rural public health-centres in India: a WISN retrospective analysis and national-level modelling study.
Rural India has a severe shortage of human resources for health (HRH). The National Rural Health Mission (NRHM) deploys HRH in the rural public health system to tackle shortages. Sanctioning under NRHM does not account for workload resulting in inadequate and inequitable HRH allocation. The Workforce Indicators of Staffing Needs (WISN) approach can identify shortages and inform appropriate sanctioning norms. India currently lacks nationally relevant WISN estimates. We used existing data and modelling techniques to synthesize such estimates. We conducted a retrospective analysis of existing survey data for 93 facilities from 5 states over 8 years to create WISN calculations for HRH cadres at primary and community health centres (PHCs and CHCs) in rural areas. We modelled nationally representative average WISN-based requirements for specialist doctors at CHCs, general doctors and nurses at PHCs and CHCs. For 2019, we calculated national and state-level overall and per-centre WISN differences and ratios to depict shortage and workload pressure. We checked correlations between WISN ratios for cadres at a given centre-type to assess joint workload pressure. We evaluated the gaps between WISN-based requirements and sanctioned posts to investigate suboptimal sanctioning through concordance analysis and difference comparisons. In 2019, at the national-level, WISN differences depicted workforce shortages for all considered HRH cadres. WISN ratios showed that nurses at PHCs and CHCs, and all specialist doctors at CHCs had very high workload pressure. States with more workload on PHC-doctors also had more workload on PHC-nurses depicting an augmenting or compounding effect on workload pressure across cadres. A similar result was seen for CHC-specialist pairs-physicians and surgeons, physicians and paediatricians, and paediatricians and obstetricians-gynaecologists. We found poor concordance between current sanctioning norms and WISN-based requirements with all cadres facing under-sanctioning. We also present across-state variations in workforce problems, workload pressure and sanctioning problems. We demonstrate the use of WISN calculations based on available data and modelling techniques for national-level estimation. Our findings suggest prioritising nurses and specialists in the rural public health system and updating the existing sanctioning norms based on workload assessments. Workload-based rural HRH deployment can ensure adequate availability and optimal distribution.


Cervical Gardnerella vaginalis in women with preterm prelabor rupture of membranes.
To determine the association between microbial invasion of the amniotic cavity (MIAC) and/or intra-amniotic inflammation (IAI) and the cervical prevalence of Gardnerella vaginalis DNA in pregnancies with preterm prelabor rupture of membrane (PPROM). In total, 405 women with singleton pregnancies complicated with PPROM were included. Cervical fluid and amniotic fluid samples were collected at the time of admission. Bacterial and G. vaginalis DNA were assessed in the cervical fluid samples using quantitative PCR technique. Concentrations of interleukin-6 and MIAC were evaluated in the amniotic fluid samples. Loads of G. vaginalis DNA ≥ 1% of the total cervical bacterial DNA were used to define the cervical prevalence of G. vaginalis as abundant. Based on the MIAC and IAI, women were categorized into four groups: with intra-amniotic infection (both MIAC and IAI), with sterile IAI (IAI without MIAC), with MIAC without IAI, and without either MIAC or IAI. The presence of the abundant cervical G. vaginalis was related to MIAC (with: 65% vs. without: 44%; p = 0.0004) but not IAI (with: 52% vs. without: 48%; p = 0.70). Women with MIAC without IAI had the highest load of the cervical G. vaginalis DNA (median 2.0 × 104 copies DNA/mL) and the highest presence of abundant cervical G. vaginalis (73%). In women with PPROM, the presence of cervical G. vaginalis was associated with MIAC, mainly without the concurrent presence of IAI.


Contrasting management regimes indicative of mesopredator release in temperate coastal fish assemblages.
The absence of functional top predators has been proposed as a mechanism acting to shape fish assemblages in temperate marine ecosystems, with cascading effects on lower trophic levels. We explore this scenario by comparing the trophic and functional status of fish assemblages in Norwegian marine national parks, open to fishing, to a nearby coastal seascape that harbors a system of marine protected areas (MPAs) including a no-take zone. Demersal fish assemblages were sampled using fyke nets over three consecutive seasons. Atlantic cod (Gadus morhua) is potentially a dominant top predator in this ecosystem, and historically, this and other gadids have been targeted by the full range of former and present fisheries. In the present study, we find that average body size of the Atlantic cod was significantly larger in the zoned seascape compared to the unprotected areas (mean ± SD: 36.6 cm ± 14.38 vs. 23.4 ± 7.50; p < .001) and that the unprotected seascape was characterized by a higher abundance of mesopredator fish species. These observations are consistent with the hypothesis that the protection of top predators within MPAs aids to control the mesopredator populations and provides empirical support to the notion that the present state of many coastal fish assemblages is driven by mesopredator release linked to functional depletion of large top predators.


Characteristics and surgical treatment of dolichoectatic and fusiform aneurysms.
Dolichoectatic and fusiform aneurysms represent a small subset of cerebral aneurysms and are often among the most difficult to treat. A consecutive series of 40 patients with 41 of these two types of aneurysms is presented, including their clinical characteristics and surgical treatments. Common to all aneurysms was the pathological involvement of a length of blood vessel with separate inflow and outflow sites (nonsaccular). However, dolichoectatic aneurysms have markedly different symptoms and surgical treatments depending on their location in either the anterior or posterior circulation. Anterior circulation aneurysms involved the petrous internal carotid artery (ICA) in one, the supraclinoid ICA in three, the middle cerebral artery in 13, and the anterior cerebral artery in four patients. Posterior circulation aneurysms involved the basilar artery in 13, the vertebral artery in six, and the posterior inferior cerebellar artery in one patient. Various surgical procedures were performed, including direct clipping, trapping with bypass, proximal occlusion, resection with reanastomosis, transposition, aneurysmorrhaphy with thrombectomy, and wrapping. There was no surgical mortality in the patient series, and treatment was effective in many patients. Overall, outcome at late follow up was good (Glasgow Outcome Scale scores 1-2) in 78% of patients. Patients with anterior circulation aneurysms had better outcomes than patients with posterior circulation aneurysms, with good outcomes in 90% and 65% of the cases, respectively. Dolichoectatic and giant serpentine aneurysms may develop from smaller fusiform aneurysms and represent a spectrum of the same pathological entity. Arterial dissection may also play a role in the initial development of these aneurysms.


Fibromyalgia. 2. Management guidelines and research findings.
Treatment of fibromyalgia includes various forms of therapy--physical, behavioral, psychological, and pharmacologic. No drug therapy has proved uniformly successful, but some drugs provide temporary relief from pain. After an initial therapy program has been established, patients can assume the major responsibility for management. Research studies aimed at defining the cause of fibromyalgia have linked it to sleep disorders, neurogenic mediators, immune mechanisms, muscle disease, and psychological disturbances.


Influence of dietary n-3 polyunsaturated fatty acid on experimental tooth movement in rats.
This study was conducted to investigate the influence of dietary n-3 polyunsaturated fatty acid on experimental tooth movement. This acid substantially reduces the production of arachidonic acid. Sixty 4-week-old male Wistar strain rats were divided into experimental and control groups. Animals in the experimental group were fed a purified diet containing 10% refined fish oil (rich in n-3 fatty acid); control animals were fed a diet containing 10% corn oil (rich in n-6 fatty acid). After 6 weeks, the maxillary first molars were moved buccally with an initial force of 20 g for periods of 0, 3, 7, or 14 days. Tooth movement in the experimental group was 80% of that seen in the controls. The number of osteoclasts on the pressure side during tooth movement was nearly 60% of that seen in controls, and the degree of bone resorption was 80%. The data suggest that a diet enriched with fish oil reduces osteoclastic activity and subsequent alveolar bone resorption that is the key to experimental tooth movement.


[Initial treatment of acute childhood leukemia with extreme leukocytosis by blood exchange transfusion -- rheological aspects (author's transl)].
In leukemia patients with extremely high leukocytosis the great number of poorly deformable lymphoblasts compared to normally deformable red cells greatly influences the flow properties of leukemic blood. The increased blood viscosity implies a great risk of disturbance of the microcirculation by leukostasis and bleeding. Removal of large amounts of leukemic cells by exchange transfusion with fresh blood diminished leukemic cell burden and reduced the initial elevated leukocyte counts by more than 50% in 3 patients. In addition, anemia and thrombocytopenia improved and the disturbed plasma coagulation returned to normal. One of the patients with additional risk factors treated by exchange transfusion died 8 months after diagnosis in hematologic release. The two other patients perform well without relapse six and nine months after diagnosis, respectively. Exchange transfusion with 150 ml/kg of fresh blood is considered to be of value to avoid severe early complications as e.g. massive intracerebral hemorrhage observed in 3 other patients and to correct hematological and rheological abnormalities in childhood leukemia with extreme leukocytosis. Possible favourable effects as to long term prognosis have to be awaited.


Effect of phosphodiesterase-5 inhibition on joint and muscle damage in rats with adjuvant arthritis
Background/aim: This study was designed to examine the effect of tadalafil, a phosphodiesterase (PDE)5 inhibitor, on the severity of joint and muscle damage in rats with adjuvant-induced arthritis (AA). Materials and methods: AA was induced by intradermal inoculation into right hind paw of male Sprague Dawley rats (300-450g) with complete Freund's adjuvant (CFA; 0.1 mL). AA rats were treated with either tadalafil (10 mg/kg; per oral) alone or along with the soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 mg/kg; intraperitoneally). After decapitation on day 16, trunk blood was collected for total oxidant status (TOS) and total antioxidant capacity (TAC) assays. The left metatarsophalangeal joint and gastrocnemius muscle were excised for microscopic examination. Muscle samples were also evaluated in terms of malondialdehyde (MDA), glutathione, and chemiluminescence (CL) levels. Results: In tadalafil-treated AA rats, metatarsophalangeal joints revealed regular morphology of the cartilage with slight destruction and less inflammatory cell infiltration and vascularization in comparison to the controls (microscopic score: 1.17 ± 0.31 vs. 4.17 ± 0.79; P < 0.01). AA rats presented increased gastrocnemius muscle MDA, glutathione, and CL levels compared to the controls (P < 0.01, for MDA; P < 0.05, for glutathione; P < 0.05 for CL). Tadalafil attenuated the increase in CL levels (P < 0.01, for luminol and P < 0.001, for lucigenin). Serum TOS showed significant reductions by tadalafil. Conclusion: The long-acting PDE5 inhibitor tadalafil provides partial protection in a rat model of CFA-induced arthritis possibly via suppression of oxidant generation.


Reduced EBP50 expression levels are correlated with unfavorable clinicopathological features of extrahepatic bile duct carcinoma and promote the proliferation and migration of QBC939 cells.
The present study aimed to clarify the association between ezrin-radixin-moesin-binding phosphoprotein-50 (EBP50) expression level and the tumor phenotype and clinicopathological features of extrahepatic bile duct carcinoma. Tissue samples from patients with extrahepatic bile duct carcinoma (54 cases) and patients with normal bile duct epithelia from gallbladder of cholecystitis (20 cases) were collected, and immunohistochemical staining was used to detect the expression levels of EBP50 in these tissues. In addition, small interfering (si)RNA-EBP50 was used to knock down the expression of EBP50 in the QBC939 human cholangiocarcinoma (CC) cell line. The effect of EBP50 expression on QBC939 cell proliferation and migration was analyzed using the Cell Counting kit-8 and wound healing assays, respectively. EBP50 expression was significantly downregulated in CC tissue samples (P<0.01), with low EBP50 expression levels positively correlated with a high pathological stage and a poor differentiation degree (P<0.01 and P<0.001, respectively). EBP50 expression in QBC939 cells was knocked down by ≤80% using siRNA-EBP50, and EBP50 knockdown significantly promoted QBC939 cell proliferation, as compared with the vector control cells (P=0.04). EBP50 knockdown also significantly enhanced the wound healing ability of QBC939 cells (P=0.02). These results demonstrated that EBP50 expression levels are significantly correlated with a malignant phenotype in patients with CC, and decreased expression levels of EBP50 may promote CC cell proliferation and migration. These findings provide insight into novel potential diagnostic and therapeutic approaches for patients with CC.


Comorbid anxiety disorders in depressed elderly patients.
Anxiety disorders are common in adults with depressive disorders, but several studies have suggested a relatively low prevalence of anxiety disorders in older individuals with depression. This cross-sectional study measured current and lifetime rates and associated clinical features of anxiety disorders in depressed elderly patients. History of anxiety disorders was assessed by using a structured diagnostic instrument in 182 depressed subjects aged 60 and older seen in primary care and psychiatric settings. Associations between comorbid anxiety disorders and baseline characteristics were measured. The modified structured instrument allowed detection of symptoms that met inclusion criteria for generalized anxiety disorder in a depressive episode. Thirty-five percent of older subjects with depressive disorders had at least one lifetime anxiety disorder diagnosis, and 23% had a current diagnosis. The most common current comorbid anxiety disorders were panic disorder (9.3%), specific phobias (8.8%), and social phobia (6.6%). Symptoms that met inclusion criteria for generalized anxiety disorder, measured separately, were present in 27.5% of depressed subjects. Presence of a comorbid anxiety disorder was associated with poorer social function and a higher level of somatic symptoms. Symptoms of generalized anxiety disorder were associated with a higher level of suicidality. Contrary to previous reports, the present study found a relatively high rate of current and lifetime anxiety disorders in elderly depressed individuals. Comorbid anxiety disorders and symptoms of generalized anxiety disorder were associated with a more severe presentation of depressive illness in elderly subjects.


Optical recording of calcium and voltage transients following impulses in cell bodies and processes of identified leech neurons in culture.
Optical methods were used to examine the spread of electrical potentials and the distribution and time course of calcium transients in individual identified nerve cells isolated from the leech. A photodiode array detected voltage transients by measuring absorbance changes of cells stained with the voltage-sensitive dye RH155 added to the bath. Calcium transients were recorded by measuring absorbance changes of the dye arsenazo III, which had been injected into the cells. In addition, Lucifer yellow was injected to outline the some and processes. Calcium changes resulting from individual action potentials were recorded from N, P, and Retzius cells without averaging. Signals from T cells and anterior pagoda (AP) cells were weaker but could be detected with averaging. These results are in accord with previous studies on calcium contributions to action potentials in these cells. For all cells, larger or wider action potentials gave bigger signals. Calcium changes from each of a train of action potentials were of equal amplitude, showing no sign of facilitation. Calcium transients from Retzius cells that had formed chemical synapses with P cells had properties similar to those of isolated cells. We were also able to detect responses from prolonged subthreshold depolarizations to -40 mV from a hyperpolarized membrane potential (-65 mV). These signals rose throughout the duration of the pulse (1-2 sec). With the photodiode array we mapped the distribution of the calcium signals. The amplitudes from each pixel are proportional to the amount of calcium entering that element in response to the stimulating pulse, if the simplifying assumption is made that the calcium buffering of the cytoplasm is uniform throughout the cell. The largest signals were detected over the axon stump left from the cell isolation procedure. Large signals were also detected from the soma. Weak signals were detected from the processes of some cells. From many Retzius cells, no signals at all were detected from the newly formed processes. Using the photodiode array, we also recorded voltage transients from the cells. Signals were recorded from all over the arborization of the neuron, with no obvious variation in time course, showing that the entire cell, including fine slender processes and broad growth cones, was essentially isopotential. Combining these observations with the measured distribution of calcium transients in the same cell suggests that the density of calcium channels in most cells is less in the outgrowing processes than in the soma or axon stump.


3D integral imaging display by smart pseudoscopic-to-orthoscopic conversion (SPOC).
Previously, we reported a digital technique for formation of real, non-distorted, orthoscopic integral images by direct pickup. However the technique was constrained to the case of symmetric image capture and display systems. Here, we report a more general algorithm which allows the pseudoscopic to orthoscopic transformation with full control over the display parameters so that one can generate a set of synthetic elemental images that suits the characteristics of the Integral-Imaging monitor and permits control over the depth and size of the reconstructed 3D scene.


Bilateral posterior periventricular nodular heterotopia: a recognizable cortical malformation with a spectrum of associated brain abnormalities.
Bilateral posterior PNH is a distinctive complex malformation with imaging features distinguishing it from classic bilateral PNH associated with FLNA mutations. The purpose of this study was to define the imaging features of posterior bilateral periventricular nodular heterotopia and to determine whether associated brain malformations suggest specific subcategories. We identified a cohort of 50 patients (31 females; mean age, 13 years) with bilateral posterior PNH and systematically reviewed and documented associated MR imaging abnormalities. Patients were negative for mutations of FLNA. Nodules were often noncontiguous (n = 28) and asymmetric (n = 31). All except 1 patient showed associated developmental brain abnormalities involving a spectrum of posterior structures. A range of posterior fossa abnormalities affected the cerebellum, including cerebellar malformations and posterior fossa cysts (n = 38). Corpus callosum abnormalities (n = 40) ranged from mild dysplasia to agenesis. Posterior white matter volume was decreased (n = 22), and colpocephaly was frequent (n = 26). Most (n = 40) had associated cortical abnormalities ranging from minor to major (polymicrogyria), typically located in the cortex overlying the PNH. Abnormal Sylvian fissure morphology was common (n = 27), and hippocampal abnormalities were frequent (n = 37). Four family cases were identified-2 with concordant malformation patterns and 2 with discordant malformation patterns. The associations of bilateral posterior PNH encompass a range of abnormalities involving brain structures inferior to the Sylvian fissures. We were unable to identify specific subgroups and therefore conceptualize bilateral posterior PNH as a continuum of infrasylvian malformations involving the posterior cerebral and hindbrain structures.


Human arm endpoint-impedance in rhythmic human-robot interaction exhibits cyclic variations.
Estimating the human endpoint-impedance interacting with a physical environment provides insights into goal-directed human movements during physical interactions. This work examined the endpoint-impedance of the upper limb during a hybrid ball-bouncing task with simulated haptic feedback while participants manipulated an admittance-controlled robot. Two experiments implemented a force-perturbation method to estimate the endpoint parameters of 31 participants. Experimental conditions of the ball-bouncing task were simulated in a digital environment. One experiment studied the influence of the target height, while the other explored the impedance at three cyclic phases of the rhythmic movement induced by the task. The participants' performances were analyzed and clustered to establish a potential influence of endpoint impedance on performance in the ball-bouncing task. Results showed that endpoint-impedance parameters ranged from 45 to 445 N/m, 2.2 to 17.5 Ns/m, and 227 to 893 g for the stiffness, damping, and mass, respectively. Results did not support such a critical role of endpoint impedance in performance. Nevertheless, the three endpoint-impedance parameters described significant variations throughout the arm cycle. The stiffness is linked to a quasi-linear increase, with a maximum value reached before the ball impacts. The observed damping and mass cyclic variations seemed to be caused by geometric and kinematic variations. Although this study reveals rapid and within-cycles variations of endpoint-impedance parameters, no direct relationship between endpoint-impedance values and performance levels in ball-bouncing could be found.


Clozapine reverses schizophrenia-related behaviours in the metabotropic glutamate receptor 5 knockout mouse: association with N-methyl-D-aspartic acid receptor up-regulation.
Abnormalities in glutamatergic signalling are proposed in schizophrenia in light of the schizophreniform psychosis elicited by NMDA antagonists. The metabotropic glutamate receptor 5 (mGluR5) interacts closely with the NMDA receptor and is implicated in several behavioural endophenotypes of schizophrenia. We have demonstrated that mice lacking mGluR5 have increased sensitivity to the hyperlocomotive effects of the NMDA antagonist MK-801. Mice lacking mGluR5 also show abnormal locomotor patterns, reduced prepulse inhibition (PPI), and deficits on performance of a short-term spatial memory task on the Y-maze. Chronic administration of the antipsychotic drug clozapine ameliorated the locomotor disruption and reversed the PPI deficit, but did not improve Y-maze performance. Chronic clozapine increased NMDA receptor binding ([3H]MK-801) but did not alter dopamine D2 ([3H]YM-09151), 5-HT2A ([3H]ketanserin), or muscarinic M1/M4 receptor ([3H]pirenzepine), binding in these mice. These results demonstrate behavioural abnormalities that are relevant to schizophrenia in the mGluR5 knockout mouse and a reversal of behaviours with clozapine treatment. These results highlight both the interactions between mGluR5 and NMDA receptors in the determination of schizophreniform behaviours and the potential for the effects of clozapine to be mediated by NMDA receptor regulation.


The impact of additional life-table variables on excess mortality estimates.
Regression-based relative survival models are commonly used in population-based cancer studies to estimate the real impact on the excess mortality of covariates that influence overall mortality. Usually, the mortality observed in a study cohort is corrected by the expected mortality hazard in the general population, which is given by life tables provided by national statistics institutes. These life tables are stratified by age, sex, calendar year, and, sometimes, other demographic data (ethnicity, deprivation, and others). However, in most cases, the same demographic data are not available for the study cohort and the general population; this leads to differences between the expected mortality of the general population and that of the study cohort. More generally, the absence of some demographic variables in life tables may introduce a measurement bias into the estimation of the excess mortality. In the present article, we used a simulation approach with different plausible scenarios to evaluate the impact of an additional life-table variable on excess mortality estimates and study the extent and the direction of the biases in estimating the effect of each covariate on the excess mortality. We showed that the use of life table that lacks stratification by a variable present in the excess hazard model results in a measurement bias not only in the estimate of the effect of this variable but also, to a lesser extent, in the estimates of the effects of the other covariates included in the model. We also demonstrated this measurement bias by a population-based colorectal cancer analysis.


Biochemical Deconstruction and Reconstruction of Nuclear Matrix Reveals the Layers of Nuclear Organization.
Nuclear matrix (NuMat) is the fraction of the eukaryotic nucleus insoluble to detergents and high-salt extractions that manifests as a pan-nuclear fiber-granule network. NuMat consists of ribonucleoprotein complexes, members of crucial nuclear functional modules, and DNA fragments. Although NuMat captures the organization of nonchromatin nuclear space, very little is known about components organization within NuMat. To understand the organization of NuMat components, we subfractionated it with increasing concentrations of the chaotrope guanidinium hydrochloride (GdnHCl) and analyzed the proteomic makeup of the fractions. We observe that the solubilization of proteins at different concentrations of GdnHCl is finite and independent of the broad biophysical properties of the protein sequences. Looking at the extraction pattern of the nuclear envelope and nuclear pore complex, we surmise that this fractionation represents easily solubilized/loosely bound and difficultly solubilized/tightly bound components of NuMat. Microscopic analyses of the localization of key NuMat proteins across sequential GdnHCl extractions of in situ NuMat further elaborate on the divergent extraction patterns. Furthermore, we solubilized NuMat in 8M GdnHCl and upon removal of GdnHCl through dialysis, en masse renaturation leads to RNA-dependent self-assembly of fibrous structures. The major proteome component of the self-assembled fibers comes from the difficultly solubilized, tightly bound component. This fractionation of the NuMat reveals different organizational levels within it which may reflect the structural and functional organization of nuclear architecture.


Physicians' self-reported practice behaviour regarding fertility-related discussions in paediatric oncology in Sweden.
The aim of this study was to investigate practice behaviours of Swedish physicians with regard to discussing the impact of cancer treatment on fertility with paediatric oncology patients and their parents, and to identify factors associated with such discussions. A cross-sectional survey study was conducted targeting all physicians in Sweden working in paediatric oncology care settings. Participants responded to a questionnaire measuring practice behaviour, attitudes, barriers, and confidence in knowledge. Multivariable logistic regression was used to determine factors associated with seldom discussing fertility. More than half of the physicians routinely talked with their patients/parents about the treatment's potential impact on fertility (male patients: 62%; female patients: 57%; P = 0.570). Factors associated with less frequently discussing fertility with patients/parents were working at a non-university hospital (male patients: OR 11.49, CI 1.98-66.67; female patients: OR 33.18, CI 4.06-271.07), concerns that the topic would cause worry (male patients: OR 8.23, CI 1.48-45.89; female patients: OR 12.38, CI 1.90-80.70), and perceiving the parents as anxious (male patients: OR 7.18, CI 1.20-42.85; female patients: OR 11.65, CI 1.32-103.17). Based on our findings, we recommend structured training in how to communicate about fertility issues in stressful situations, which in turn might increase fertility-related discussions in paediatric oncology.


Elucidating drought responsive networks in tef (Eragrostis tef) using phenomic and metabolomic approaches.
Drought is a major abiotic stress that limits crop productivity and is driving the need to introduce new tolerant crops with better economic yield. Tef (Eragrostis tef) is a neglected (orphan) Ethiopian warm-season annual gluten-free cereal with high nutritional and health benefits. Further, tef is resilient to environmental challenges such as drought, but the adaptive mechanisms remain poorly understood. In this study, metabolic changes associated with drought response in 11 tef accessions were identified using phenomic and metabolomic approaches under controlled conditions. Computerized image analysis of droughted plants indicated reductions in leaf area and green pigments compared with controls. Metabolite profiling based on flow-infusion electrospray-high-resolution mass spectroscopy (FIE-HRMS) showed drought associated changes in flavonoid, phenylpropanoid biosynthesis, sugar metabolism, valine, leucine and isoleucine biosynthesis, and pentose phosphate pathways. Flavonoid associated metabolites and TCA intermediates were lower in the drought group, whereas most of the stress-responsive amino acids and sugars were elevated. Interestingly, after drought treatment, one accession Enatite (Ent) exhibited a significantly higher plant area than the others, and greater accumulation of flavonoids, amino acids (serine and glycine), sugars (ribose, myo-inositol), and fatty acids. The increased accumulation of these metabolites could explain the increased tolerance to drought in Ent compared with other accessions. This is the first time a non-targeted metabolomics approach has been applied in tef, and our results provide a framework for a better understanding of the tef metabolome during drought stress that will help to identify traits to improve this understudied potential crop.


Cyber anthropology or anthropology in cyberspace.
As a variety of anthropology, cyber anthropology is considered to be the fastest growing sub branch in the science. It is based on synergic effects of multimedia systems and hypermedia, using their comparative advantages. One of the least researched fields of cyber anthropology is the relationship of individuals and social groups with a multimedia document in terms of their perception of such subject. This is because the foundation of social-informatics perception in the society is created based on the evidence of a real life, whereas here the perception is established at the level of virtual, i.e. online life. The rhetorical question here is whether an identical content causes the same or different user reactions, depending on whether it was perceived offline or online, i.e. to what extend does the medium (and not the information content) dictate the user perception. In this respect the research titled "Perception of online museum content creators and actual habits of Croatian online museum visitors" can be a "case study" for the impact of "cyber potential" on the classic anthropological paradigm.


Reoxygenation-derived toxic reactive oxygen/nitrogen species modulate the contribution of bone marrow progenitor cells to remodeling after myocardial infarction.
The core region of a myocardial infarction is notoriously unsupportive of cardiomyocyte survival. However, there has been less investigation of the potentially beneficial spontaneous recruitment of endogenous bone marrow progenitor cells (BMPCs) within infarcted areas. In the current study we examined the role of tissue oxygenation and derived toxic species in the control of BMPC engraftment during postinfarction heart remodeling. For assessment of cellular origin, local oxygenation, redox status, and fate of cells in the infarcted region, myocardial infarction in mice with or without LacZ(+) bone marrow transplantation was induced by coronary ligation. Sham-operated mice served as controls. After 1 week, LacZ(+) BMPC-derived cells were found inhomogeneously distributed into the infarct zone, with a lower density at its core. Electron paramagnetic resonance (EPR) oximetry showed that pO2 in the infarct recovered starting on day 2 post-myocardial infarction, concomitant with wall thinning and erythrocytes percolating through muscle microruptures. Paralleling this reoxygenation, increased generation of reactive oxygen/nitrogen species was detected at the infarct core. This process delineated a zone of diminished BMPC engraftment, and at 1 week infiltrating cells displayed immunoreactive 3-nitrotyrosine and apoptosis. In vivo treatment with a superoxide dismutase mimetic significantly reduced reactive oxygen species formation and amplified BMPC accumulation. This treatment also salvaged wall thickness by 43% and left ventricular ejection fraction by 27%, with significantly increased animal survival. BMPC engraftment in the infarct inversely mirrored the distribution of reactive oxygen/nitrogen species. Antioxidant treatment resulted in increased numbers of engrafted BMPCs, provided functional protection to the heart, and decreased the incidence of myocardial rupture and death.


Statistical methods for the analysis of the association between bronchial responsiveness and pulmonary function changes.
An autoregressive model for the analysis of longitudinal data was applied in the context of investigating the effect of bronchial responsiveness on the growth of pulmonary function in children. In the model used, the correlation between pulmonary function values within an individual decreases exponentially as the time between visits increases. The model incorporates both fixed and time-dependent covariates in a unified fashion and does not require complete data in all visits for each individual. Furthermore, the change in pulmonary function is not assumed to be linear over time. Using response to cold air data as a measure of bronchial responsiveness, we found that children who responded to cold air have a slower rate of growth in pulmonary function. In addition, the data suggested that the effect of cigarette smoking may be greater as the response to cold air increases. Extensions of the autoregressive approach to other correlation structures and to the case of unequidistant observations are discussed.


Neurologic manifestations of infective endocarditis: a 17-year experience in a teaching hospital in Finland.
Many previous studies have endeavored to find appropriate means to reduce the occurrence of neurologic manifestations in patients with infective endocarditis (IE). We evaluated patients with IE-associated neurologic complications and compared them with patients with IE who did not have neurologic symptoms. Particular attention was focused on assessing the impact of cardiac surgery and the presence of potential risk factors for complications on the outcome of the patients. A total of 218 episodes designated as definite or possible IE according to Duke criteria and treated during the years 1980 through 1996 in a Finnish teaching hospital were retrospectively evaluated for neurologic manifestations. Neurologic complications were identified in 55 episodes (25%), with an embolic event as the most frequent manifestation (23/55; 42%). In the majority (76%) of episodes, the neurologic manifestation was evident before antimicrobial treatment was started, being the first sign of IE in 47% of episodes. Only 1 recurrent cerebral embolization was observed. Neurologic complications were significantly associated with Staphylococcus aureus infection (29% vs 10%; P =.001) and with IE affecting both the aortic and the mitral valves (56% vs 23%; P<.01), but not with echocardiographic detection of vegetations or anticoagulant therapy. Death during the acute phase of IE occurred in 13 episodes (24%) with neurologic complications and in 17 episodes (10%) without neurologic complications (P<.03). In episodes with neurologic complications, the IE-associated mortality rate was 25% (10/40) in the medical treatment group and 20% (3/15) in the surgical group. No neurologic deterioration was observed in these surgically treated patients postoperatively. Our results reinforce the belief that rapid diagnosis and initiation of antimicrobial therapy may still be the most effective means to prevent neurologic complications. These data underscore the importance of diagnostic alertness to the prognosis of patients with IE.


Multidrug resistant Acinetobacter baumannii: a descriptive study in a city hospital.
Multidrug resistant Acinetobacter baumannii, (MRAB) is an important cause of hospital acquired infection. The purpose of this study is to determine the risk factors for MRAB in a city hospital patient population. This study is a retrospective review of a city hospital epidemiology data base and includes 247 isolates of Acinetobacter baumannii (AB) from 164 patients. Multidrug resistant Acinetobacter baumannii was defined as resistance to more than three classes of antibiotics. Using the non-MRAB isolates as the control group, the risk factors for the acquisition of MRAB were determined. Of the 247 AB isolates 72% (177) were multidrug resistant. Fifty-eight percent (143/247) of isolates were highly resistant (resistant to imipenem, amikacin, and ampicillin-sulbactam). Of the 37 patients who died with Acinetobacter colonization/infection, 32 (86%) patients had the organism recovered from the respiratory tract. The factors which were found to be significantly associated (p < or = 0.05) with multidrug resistance include the recovery of AB from multiple sites, mechanical ventilation, previous antibiotic exposure, and the presence of neurologic impairment. Multidrug resistant Acinetobacter was associated with significant mortality when compared with sensitive strains (p < or = 0.01). When surgical patients (N = 75) were considered separately, mechanical ventilation and multiple isolates remained the factors significantly associated with the development of multidrug resistant Acinetobacter. Among surgical patients 46/75 (61%) grew a multidrug resistant strain of AB and 37/75 (40%) were resistant to all commonly used antibiotics including aminoglycosides, cephalosporins, carbepenems, extended spectrum penicillins, and quinolones. Thirty-five percent of the surgical patients had AB cultured from multiple sites and 57% of the Acinetobacter isolates were associated with a co-infecting organism, usually a Staphylococcus or Pseudomonas. As in medical patients, the isolation of Acinetobacter from multiple sites and the need for mechanical ventilation were significantly associated with the development of MRAB. The factors significantly associated with MRAB in both the general patient population and surgical patients were mechanical ventilation and the recovery of Acinetobacter from multiple anatomic sites. Previous antibiotic use and neurologic impairment were significant factors in medical patients. Colonization or infection with MRAB is associated with increased mortality.


Demographic, socioeconomic and lifestyle factors associated with sugar-sweetened beverage intake: a population-based study.
The intake of sugar-sweetened beverages (SSB) varies according to the characteristics of the population. To investigate the SSB intake and demographic, socioeconomic and lifestyle factors associated with its consumption in adolescents, adults, and older adults in São Paulo. Data were drawn from the Health Survey of São Paulo, a cross-sectional population-based study including 1,662 individuals aged 12 years or more. SSB were classified into six groups: sugar-sweetened sodas, sweetened coffee and tea, sweetened milk and dairy products, sweetened fruit juice, sweetened fruit drink, and total SSB. The association of each group with demographic, socioeconomic and lifestyle variables was assessed using linear regression models. The mean SSB intake was 668.4 mL in adolescents, 502.6 mL in adults, and 358.2 mL in elderly adults. Sodas and sweetened coffee and tea represented had the greatest contribution to energy intake. SSB consumption was lower among female sex and higher among overweight adolescents, among sufficiently active adults, and among lower household per capita income older adults. Consumption of SSB was high, particularly among adolescents. Public policies are required in order to decrease the consumption of these beverages. Age group, sex, household per capita income, and body mass index status were associated with SSB intake.


The formation of a socioeconomic health disparity: the case of cocaine use during the 1980s and 1990s.
Despite the substantial and prolonged sociological interest in health disparities, much remains unknown about the processes that initiate them. To investigate this topic, we focus on the case study of cocaine use, for which a socioeconomic disparity emerged across all age groups in a short period of time around 1990. We examine whether the newly-formed disparity represents a selective remnant of previous users or, instead, a selective recruitment of new users. To evaluate these two potential processes we use latent class regression on a nationally representative cohort with repeated measures of past-year cocaine use before and after 1990. Results support the "remnant" hypothesis and show that the newly-formed disparity resulted primarily because people in the lower social strata were less likely to have a trajectory of cocaine use with a sharp drop in use after 1990. These results point to the "remnant" concept as a way to bring together disparity analysis of very different and diverse health outcomes.


Deceptive vulvar papillomavirus infection. A possible explanation for certain cases of vulvodynia.
Use of the colposcope for vulvar and vaginal examination in four cases of long-standing vulvodynia led to the identification of lesions with an unusual appearance. In the vulvar vestibule, epithelial projections resembling cactus, camel humps or stony colonial pavement were observed. In the vagina, the lesions looked more like cerebral folds. Biopsies of these lesions showed histopathologic changes diagnostic of human papillomavirus infection, scored according to Reid's criteria. In one case, capsid antigen was detected with the peroxidase technique in the nuclei of the superficial cells. Past history and positive findings in the sexual partners of some of the patients suggested long-standing herpesvirus activity in the lower genital tract. In some cases of recalcitrant vulvodynia, colposcopic examination of the vulva and vagina may lead to a viral explanation for symptoms previously considered psychosomatic in origin.