EFFECTS OF ETHYLENE ON TETRASPOROGENESIS IN PTEROCLADIELLA CAPILLACEA (RHODOPHYTA)(1).
The effects of ethylene (C2 H4 ) on tetrasporogenesis of the red seaweed Pterocladiella capillacea (S. G. Gmelin) Bornet were investigated. Ethylene is a gaseous hormone that is involved in a variety of physiological processes (e.g., flowering, fruit abscission) in higher plants. To study the effects of ethylene on the reproduction of the red seaweed P. capillacea, immature tetrasporophytic thalli were exposed to a flow of ethylene for different time periods. Maximum maturation of tetrasporangia was observed at 7 d in thalli exposed to ethylene for 15 min. This maturation was accompanied by a significant increase in the free fraction of putrescine (Put) and a 5-fold increase in the level of total RNA. These changes were specifically due to ethylene since they were blocked by the presence of the ethylene perception inhibitor silver thiosulphate (STS). Moreover, P. capillacea was determined to produce ethylene at a rate of 1.12 ± 0.06 nmol ethylene · h(-1) · g(-1) fresh weight (fwt) with specific activities for 1-aminocyclopropane-1-acrylic acid (ACC) synthase of 11.21 ± 1.19 nmol ethylene · h(-1) · mg(-1) protein and for ACC oxidase (ACO) of 7.12 ± 0.11 nmol ethylene · h(-1) · mg(-1) protein. We conclude that ethylene may indeed be a physiological regulator of tetrasporogenesis in this red seaweed.


In-vivo shift of the microbiota in oral biofilm in response to frequent sucrose consumption.
Caries is associated with shifts of microbiota in dental biofilms and primarily driven by frequent sucrose consumption. Data on environmentally induced in vivo microbiota shifts are scarce therefore we investigated the influence of frequent sucrose consumption on the oral biofilm. Splint systems containing enamel slabs were worn for 3 × 7 days with 7-day intervals to obtain oral biofilm samples. After a three-month dietary change of sucking 10 g of sucrose per day in addition to the regular diet, biofilm was obtained again at the end of the second phase. The microbiota was analysed using Illumina MiSeq amplicon sequencing (v1-v2 region). In addition, roughness of the enamel surface was measured with laser scanning microscopy. The sucrose phase resulted in significant differences in beta-diversity and significantly decreased species richness. It was marked by a significant increase in abundance of streptococci, specifically Streptococcus gordonii, Streptococcus parasanguinis and Streptococcus sanguinis. Enamel surface roughness began to increase, reflecting initial impairment of dental enamel surface. The results showed that frequent sucrose consumption provoked compositional changes in the microbiota, leading to an increase of non-mutans streptococci, hence supporting the extended ecological plaque hypothesis and emphasizing the synergy of multiple bacterial species in the development of caries.


Association of the metabolic syndrome with pulmonary venous hypertension.
Pulmonary venous hypertension (PVH) is a well-described cause of pulmonary hypertension (PH) in patients with left heart disease associated with elevated left heart filling pressure. PVH results from a number of processes, including left-sided valvular disease, constrictive pericardial disease, restrictive cardiomyopathies, and left ventricular (LV) systolic dysfunction. PVH in patients with normal LV systolic function, commonly referred to as diastolic dysfunction, is not well characterized. We observed that many patients with PH due to PVH have obesity, hypertension, diabetes mellitus, and hypercholesterolemia, which are clinical features of the metabolic syndrome (MS), a previously identified cause for systemic vascular disease. We evaluated 122 consecutive patients referred for diagnosis and treatment of PH and compared the prevalence of features of the MS between patients with PVH and those with pulmonary arterial hypertension (PAH). We also compared clinical and hemodynamic characteristics between these two groups. Compared to patients with PAH, patients with PVH had a higher frequency of hypertension, obesity, diabetes mellitus, and hyperlipidemia. Two or more features of the MS were found in 16 of 17 patients with PVH (94.1%) compared with 34.3% of patients with PAH (p < 0.001; odds ratio, 30.7; 95% confidence interval, 3.6 to 260.0). PH was substantial, but less severe overall, in patients with PVH compared to those with PAH (mean pulmonary artery pressure, 45 +/- 17 mm Hg [range, 26 to 71 mm Hg] vs 53 +/- 10 [range, 33 to 72 mm Hg], respectively [p = 0.041]; and pulmonary vascular resistance, 4.4 +/- 2.9 units [range, 1.2 to 10.8 units] vs 10.8 +/- 4.7 units [range, 4.8 to 21.9 units], respectively [p < 0.001]). PVH is highly associated with the MS. Our results suggest that the MS may predispose patients to develop pulmonary vascular disease.


The role of vitamin D in periodontal health and disease.
Vitamin D plays an essential role in calcium and bone metabolism, immune regulation and possesses profound anti-inflammatory effects. Evidence suggests that low serum vitamin D is associated with increased severity of periodontitis, a chronic inflammatory condition characterised by destruction of the supporting tissues surrounding the tooth, which has several shared risk factors with other chronic non-communicable diseases. The biological functions of vitamin D are mediated by its strong anti-microbial, anti-inflammatory, and host modulatory properties. Experimental periodontitis models involving targeted deletion of 1α-hydroxylase, the enzyme responsible for the conversion of inactive substrate to active 1,25(OH)2 D3 (calcitriol), showed augmented alveolar bone loss and gingival inflammation. Vitamin D receptor (VDR) gene polymorphisms have also been associated with increased severity of periodontitis. Thus, the involvement of vitamin D in the pathogenesis of periodontitis is biological plausible. Clinical studies have consistently demonstrated an inverse relationship between serum 25OHD3 and periodontal disease inflammation. However, due to the paucity of well-designed longitudinal studies, there is less support for the impact of vitamin D status on periodontal disease progression and tooth loss. The evidence emphasises the importance of maintaining vitamin D sufficiency in supporting periodontal health. This review aims to first examine the biological mechanisms by which vitamin D might influence the pathogenesis of periodontal disease and second, discuss the clinical evidence which implicate the role of vitamin D in periodontal disease.


Oral health interventions for older people in residential aged care facilities: a protocol for a realist systematic review.
Poor oral health among older people is a global problem impacting on health and well-being. The economic cost to the health system is significant. An ageing population is intensifying the urgency for action. However, poor oral health, particularly for those in residential aged care facilities, continues to be highly resistant to resolution. The overall aims of this realist review are to: (A) explore and synthesise evidence on oral health interventions for older people in residential aged care facilities, (B) produce a causal theory on how contextual factors and mechanisms interact to produce outcomes, and (C) produce guidelines/policies to inform high-quality oral health interventions to improve older people's oral health in residential aged care facilities. The review is guided by the RAMESES publication standards for realist synthesis. Participants include older people in residential aged care facilities, the aged care workforce, carers and families. Interventions include oral healthcare, oral health education, policy interventions and oral health promotion. The five-step realist review process of Pawson et al will guide the review: clarification of scope and development of initial framework, systematic searches, study appraisal and data extraction, synthesising evidence, drawing conclusions, and dissemination, implementation and evaluation. Expert input with key stakeholders will occur through a blog. Stakeholders will examine consistencies across studies and an explanatory causal theory will be developed to guide policy and practice. Formal ethical approval was granted by the La Trobe University Ethics Committee HREC 20144. The developed theory will guide education, practice and policy decisions about interventions and the factors that impact on implementation. Using an integrated knowledge translation approach, traditional research outputs such as international conference presentations and publications will be supplemented with stakeholder forums, infographics, blogs, social media postings, webinars, podcasts and writing for web-based independent outlets. CRD42021155658.


Developmentally regulated expression of KLF6 in the mouse cornea and lens.
To examine the expression of transcription factor Kruppel-like factor-6 (KLF6) in the cornea and lens of mouse eyes throughout developmental stages. C57BL/6 mice were set up for timed mating. Embryos on embryonic day (E)10.5, E12.5, E15.5, and E18.5 and eyes from mice on postnatal day (P)0, P7, P11, P15, P30, and P60 were collected for immunofluorescence staining. Transcript of KLF6 was detected by in situ hybridization with digoxigenin-labeled RNA probes. Relative quantitative reverse transcription (RT)-PCR was performed to measure the KLF6 transcript level in eyes enucleated at embryonic stages, and the corneas and lenses isolated at postnatal stages. Staining for the KLF6 protein was observed at E10.5 in the lens pit and at E12.5 in the ectoderm, the mesenchyme, and the lens epithelium. Nuclear staining for KLF6 protein was evident at E15.5 in the corneal epithelium and the stroma. The staining was abundant between E18.5 and P60. In the lens epithelium, nuclear staining was detected at P0, P7, and P11. The staining intensity declined subsequently. The KLF6 transcript was found in the lens pit at E10.5 and in the ectoderm and mesenchyme at E12.5. The KLF6 mRNA level in corneal layers remained relatively constant until P60. In the lens epithelium, it was high during embryonic stages but decreased with development. KLF6 is expressed in both the cornea and the lens in mouse eyes. Its expression in the lens is temporally regulated, suggesting that it has a central role in lens development.


Smartphone-Enabled Heart Rate Variability and Acute Mountain Sickness.
The autonomic system and sympathetic activation appears integral in the pathogenesis of acute mountain sickness (AMS) at high altitude (HA), yet a link between heart rate variability (HRV) and AMS has not been convincingly shown. In this study we investigated the utility of the smartphone-derived HRV score to predict and diagnose AMS at HA. Twenty-one healthy adults were investigated at baseline at 1400 m and over 10 days during a trek to 5140 m. HRV was recorded using the ithlete HRV device. Acute mountain sickness occurred in 11 subjects (52.4%) at >2650 m. HRV inversely correlated with AMS Scores (r = -0.26; 95% CI, -0.38 to -0.13: P < 0.001). HRV significantly fell at 3700, 4100, and 5140 m versus low altitude. HRV scores were lower in those with both mild (69.7 ± 14.0) and severe AMS (67.1 ± 13.1) versus those without AMS (77.5 ± 13.1; effect size n = 0.043: P = 0.007). The HRV score was weakly predictive of severe AMS (AUC 0.74; 95% CI, 0.58-0.89: P = 0.006). The change (delta) in the HRV Score (compared with baseline at 1400 m) was a moderate diagnostic marker of severe AMS (AUC 0.80; 95% CI, 0.70-0.90; P = 0.0004). A fall in the HRV score of >5 had a sensitivity of 83% and specificity of 60% to identify severe AMS (likelihood ratio 1.9). Baseline HRV at 1400 m was not predictive of either AMS at higher altitudes. The ithlete HRV score can be used to help in the identification of severe AMS; however, a baseline score is not predictive of future AMS development at HA.


Enhanced switching and familial susceptibility for psychosis.
Working Memory and Task-Switching are essential components of cognitive control, which underlies many symptoms evident across multiple neuropsychiatric disorders, including psychotic and mood disorders. Vulnerability to these disorders has a substantial genetic component, suggesting that clinically unaffected first-degree relatives may carry some vulnerability-related traits. Converging evidence from animal and human studies demonstrates that dopamine transmission, striatal and frontal brain regions, and attention and switching behaviors are essential components of a multilevel circuit involved in salience, and disruptions in that circuit may lead to features of psychosis. Yet, it is possible that unaffected relatives may also possess characteristics that protect against development of illness. We hypothesized that reduced switch cost in a cued task-switching task, may be a behavioral expression of this "resilience" phenotype that will be observable in unaffected relatives. We tested a large community sample (n = 536) via the web, to assess different subcomponents of cognitive control, including task-switching and working memory, as well as risk-taking, among individuals who report having an affected relative with a psychotic or mood disorder. Healthy individuals with suspected genetic risk due to a self-reported familial history of a psychotic disorder demonstrated better task-switching performance compared to healthy people without a psychiatrically ill relative and those with a relative with a mood disorder. This result was specific to illness status and task domain, in that individuals with a personal history of depression or anxiety did not show improved task-switching performance, and this improvement was selective to task-switching and not seen in other putative cognitive control domains (working memory or risk taking). Although this study has limitations and independent replication is needed, these preliminary findings suggest a potential avenue for understanding susceptibility to these disorders by highlighting possible protective as well as vulnerability-related aspects of risk phenotypes.


Current role of pharmacogenomics in cardiovascular medicine.
Pharmacogenomics holds the promise of transforming patient care by allowing providers to tailor therapy to each individual patient based on his or her genetic information. Although no established pharmacogenomic applications in cardiovascular medicine yet exist, there are at least three emerging applications that may ultimately become routine clinical practice; these are related to warfarin, clopidogrel, and statins. Of the three, warfarin pharmacogenomics has been the most rigorously evaluated to date, with several clinical trials either completed or underway. Clopidogrel pharmacogenomics has a growing body of supporting scientific evidence and warrants evaluation in prospective clinical trials. Statin pharmacogenomics remains the least developed application, with controversy surrounding a widely marketed genetic test whose validity has been questioned by recent evidence. Providers are advised to take a "wait and see" approach to pharmacogenomics at the present time, with the expectation that it will be a few years before any cardiovascular pharmacogenomic application is unequivocally proven to be both cost-effective as well as of clinical benefit.


Characterization of mesenchymal progenitor cells in the crown and root pulp of primary teeth.
The existence of progenitor/mesenchymal stem cells (MSCs) was demonstrated previously in human primary/deciduous teeth. In this study, we examined dental pulp cells from root portion (root cells) of primary teeth without discernible root resorption and compared them with pulp cells from the crown portion (crown cells). Root cells and crown cells were characterized and compared to each other based on progenitor/MSC characteristics and on their generation efficiency of induced pluripotent stem (iPS) cells. Root cells and crown cells included cells manifesting typical progenitor/MSC properties such as osteogenic and adipogenic differentiation potential and clonogenicity. Interestingly, root cells showed a higher expression level of embryonic stem cell marker, KLF4, than crown cells. Moreover, the number of colony-forming unit-fibroblast and cell proliferation rate were higher for root cells than crown cells, and the efficiency of generating iPS cells from root cells was approximately four times higher than that from crown cells. Taken together, these results suggest that root cells from primary teeth show the MSC-like properties and thus could be a potent alternative source for iPS cell generation and the subsequent transplantation therapy.


Evidence that SpoIVFB is a novel type of membrane metalloprotease governing intercompartmental communication during Bacillus subtilis sporulation.
Processing of pro-sigma(K) in the mother cell compartment of sporulating Bacillus subtilis involves SpoIVFB and is governed by a signal from the forespore. SpoIVFB has an HEXXH motif characteristic of metalloproteases embedded in one of its transmembrane segments. Several conservative single amino acid changes in the HEXXH motif abolished function. However, changing the glutamic acid residue to aspartic acid, or changing the isoleucine residue that precedes the motif to proline, permitted SpoIVFB function. Only one other putative metalloprotease, site 2 protease has been shown to tolerate aspartic acid rather than glutamic acid in its HEXXH sequence. Site 2 protease and SpoIVFB share a second region of similarity with a family of putative membrane metalloproteases. A conservative change in this region of SpoIVFB abolished function. Interestingly, SpoIVFA increased the accumulation of certain mutant SpoIVFB proteins but was unnecessary for accumulation of wild-type SpoIVFB.


[The right to a good quality of health care].
Quality has a central role in medical care. The satisfaction of the rights of people to medical care, presupposes good quality medical acts. The meaning of quality goes further than a good attention based on scientific evidence and with competent skills. It comprises patient-physician relationship where professional behavior is evaluated, based on the fundamental principles of bioethics. These principles sustain the measures to control quality of medical actions, to comply with the rights of patients to have access to a good professional care.


Relationship between patient, caregiver, and asthma characteristics, responsibility for management, and indicators of asthma control within an urban clinic.
Successful asthma management in children requires an appropriate division of responsibility for management tasks between patient and their family. Non-adherence may result without appropriate assignment or acceptance of responsibility for these tasks. This study explored the relationship between selected child, caregiver, family, and asthma characteristics and responsibility for self-management activities. Child and caregiver perceived responsibility for selected tasks were determined and described via means and mean summary scores. Child, caregiver, family, and asthma characteristics were determined via interview and chart review and described by means or proportions. Pearson's correlation coefficient (r) examined any relationship between these characteristics and perceived levels of responsibility. Multiple regression examined whether the affect of child, caregiver, family, and asthma characteristics influenced perceived levels of responsibility for asthma management. One-hundred and four child and caregiver pairs were enrolled. Mean caregiver scores for all tasks suggest responsibility for each most of the time. The mean child scores for all tasks suggest an unwillingness to assume responsibility most or all of the time. Regression analysis indicated that patient age (r(2) = 0.344), number of hospital admissions (r(2) = 0.052), and PEF (r(2) = 0.106) had the best predictive strength for the patient summary score. Only patient age (r = 0.486) was a significant predictor for the caregiver summary score. We conclude that children and caregivers perceive differently responsibility for asthma management tasks and patient age had the best predictive strength for both patient and caregiver responsibility.


Tetrahydrocurcumin Derivatives Enhanced the Anti-Inflammatory Activity of Curcumin: Synthesis, Biological Evaluation, and Structure-Activity Relationship Analysis.
Tetrahydrocurcumin, the most abundant curcumin transformation product in biological systems, can potentially be a new alternative therapeutic agent with improved anti-inflammatory activity and higher bioavailability than curcumin. In this article, we describe the synthesis and evaluation of the anti-inflammatory activities of tetrahydrocurcumin derivatives. Eleven tetrahydrocurcumin derivatives were synthesized via Steglich esterification on both sides of the phenolic rings of tetrahydrocurcumin with the aim of improving the anti-inflammatory activity of this compound. We showed that tetrahydrocurcumin (2) inhibited TNF-α and IL-6 production but not PGE2 production. Three tetrahydrocurcumin derivatives inhibited TNF-α production, five inhibited IL-6 production, and three inhibited PGE2 production. The structure-activity relationship analysis suggested that two factors could contribute to the biological activities of these compounds: the presence or absence of planarity and their structural differences. Among the tetrahydrocurcumin derivatives, cyclic compound 13 was the most active in terms of TNF-α production, showing even better activity than tetrahydrocurcumin. Acyclic compound 11 was the most effective in terms of IL-6 production and retained the same effect as tetrahydrocurcumin. Moreover, acyclic compound 12 was the most active in terms of PGE2 production, displaying better inhibition than tetrahydrocurcumin. A 3D-QSAR analysis suggested that the anti-inflammatory activities of tetrahydrocurcumin derivatives could be increased by adding bulky groups at the ends of compounds 2, 11, and 12.


Use of betel quid and cigarettes among Bangladeshi patients in an inner-city practice: prevalence and knowledge of health effects.
Betel quid chewing, often combined with tobacco chewing, is a common habit in the Indian subcontinent. It is associated with the development of malignancy of the oral mucosa and foregut. Among Asian communities in the United Kingdom (UK), Bangladeshis are particularly likely to retain this habit. To investigate the prevalence of betel quid chewing, smoking, and knowledge of health hazards associated with these habits among the Bangladeshi population in an east London general practice. A bilingual postal questionnaire to all 306 adults (25 years and over) identified as being of Bangladeshi origin within one practice in east London. The questionnaire response rate was 46%. The prevalence of betel quid chewing was over 80% with no sex difference. Men were more likely to smoke tobacco than women (men = 57%, women = 11%, X2 = 33.3, P < 0.001), but over half the women added tobacco to their quid for chewing. Whereas over 80% of both male and female respondents identified the health risk of smoking, only one third identified oral cancer as a risk. In all, 25% of respondents started chewing in the UK. The low response rate is discussed. The findings indicate that the majority of Bangladeshi respondents are unaware of the health risks of a common social habit, although well informed about smoking risks. A government health warning should be introduced for betel quid sold in the UK.


Prediction of acute-coronary-syndrome using newly-defined R2-CHA2DS2-VASc score among patients with chest pain.
Chest-pain patients with no evidence of acute coronary syndrome might still be at risk for adverse outcomes. Adding renal function to the classic scoring of CHADS and CHA2DS2 VASC may improve risk stratification of chest-pain patients discharged from internal medicine wards after acute coronary syndrome (ACS) rule-out. We accessed medical records of patients admitted to internal medicine wards during 2010-2016 and discharged following ACS rule-out. A R2CHA2DS2-VASc score model that included higher scores as kidney function deteriorated was calculated and compared to CHADS and CHA2DS2 VASC scores. The primary endpoint was the composite of 30-day ACS and mortality. One-year ACS and 1-year mortality were the secondary endpoints. The study included 12,449 patients, stratified into three risk groups according to their R2CHA2DS2-VASc score. Participants were stratified into 3 groups according to R2CHA2DS2-VASc score. R2CHA2DS2-VASc score predicted better the composite outcome of ACS and 30-day and 1-year mortality after discharge (OR: 4, 95%, CI 2.3-7, p < 0.01 and OR: 13.3, 95% CI 7.8-22.7, p < 0.01, respectively). Receiver operating characteristic curve analysis showed better risk stratification of the R2CHA2DS2-VASc compared with both CHADS and CHA2DS2 VASC score. The R2CHA2DS2-VASc score is a better predictor of short- and long-term cardiovascular morbidity and mortality after hospital discharge.


Lyapounov variable: Entropy and measurement in quantum mechanics.
We discuss the question of the dynamical meaning of the second law of thermodynamics in the framework of quantum mechanics. Previous discussion of the problem in the framework of classical dynamics has shown that the second law can be given a dynamical meaning in terms of the existence of so-called Lyapounov variables-i.e., dynamical variables varying monotonically in time without becoming contradictory. It has been found that such variables can exist in an extended framework of classical dynamics, provided that the dynamical motion is suitably unstable. In this paper we begin to extend these results to quantum mechanics. It is found that no dynamical variable with the characteristic properties of nonequilibrium entropy can be defined in the standard formulation of quantum mechanics. However, if the Hamiltonian has certain well-defined spectral properties, such variables can be defined but only as a nonfactorizable superoperator. Necessary nonfactorizability of such entropy operators M has the consequence that they cannot preserve the class of pure states. Physically, this means that the distinguishability between pure states and corresponding mixtures must be lost in the case of a quantal system for which the algebra of observables can be extended to include a new dynamical variable representing nonequilibrium entropy. We discuss how this result leads to a solution of the quantum measurement problem. It is also found that the question of existence of entropy of superoperators M is closely linked to the problem of defining an operator of time in quantum mechanics.


Myostatin decreases with aerobic exercise and associates with insulin resistance.
There is mounting evidence that skeletal muscle produces and secretes biologically active proteins or "myokines" that facilitate metabolic cross talk between organ systems. The increased expression of myostatin, a secreted anabolic inhibitor of muscle growth and development, has been associated with obesity and insulin resistance. Despite these intriguing findings, there have been few studies linking myostatin and insulin resistance. To explore this relationship in more detail, we quantified myostatin protein in muscle and plasma from 10 insulin-resistant, middle-aged (53.1 ± 5.5 yr) men before and after 6 months of moderate aerobic exercise training (1200 kcal·wk−¹ at 40%-55% VO2peak). To establish a cause-effect relationship, we also injected C57/Bl6 male mice with high physiological levels of recombinant myostatin protein. Myostatin protein levels were shown to decrease in muscle (37%, P = 0.042, n = 10) and matching plasma samples (from 28.7 ng·mL−¹ pretraining to 22.8 ng·mL−¹ posttraining, P = 0.003, n = 9) with aerobic exercise. Furthermore, the strong correlation between plasma myostatin levels and insulin sensitivity (R² = 0.82, P < 0.001, n = 9) suggested a cause-effect relationship that was subsequently confirmed by inducing insulin resistance in myostatin-injected mice. A modest increase (44%) in plasma myostatin levels was also associated with significant reductions in the insulin-stimulated phosphorylation of Akt (Thr308) in both muscle and liver of myostatin-treated animals. These findings indicate that both muscle and plasma myostatin protein levels are regulated by aerobic exercise and, furthermore, that myostatin is in the causal pathway of acquired insulin resistance with physical inactivity.


Decoding of the spike timing of primary afferents during voluntary arm movements in monkeys.
Understanding the mechanisms of encoding forelimb kinematics in the activity of peripheral afferents is essential for developing a somatosensory neuroprosthesis. To investigate whether the spike timing of dorsal root ganglion (DRG) neurons could be estimated from the forelimb kinematics of behaving monkeys, we implanted two multi-electrode arrays chronically in the DRGs at the level of the cervical segments in two monkeys. Neuronal activity during voluntary reach-to-grasp movements were recorded simultaneously with the trajectories of hand/arm movements, which were tracked in three-dimensional space using a motion capture system. Sixteen and 13 neurons, including muscle spindles, skin receptors, and tendon organ afferents, were recorded in the two monkeys, respectively. We were able to reconstruct forelimb joint kinematics from the temporal firing pattern of a subset of DRG neurons using sparse linear regression (SLiR) analysis, suggesting that DRG neuronal ensembles encoded information about joint kinematics. Furthermore, we estimated the spike timing of the DRG neuronal ensembles from joint kinematics using an integrate-and-fire model (IF) incorporating the SLiR algorithm. The temporal change of firing frequency of a subpopulation of neurons was reconstructed precisely from forelimb kinematics using the SLiR. The estimated firing pattern of the DRG neuronal ensembles encoded forelimb joint angles and velocities as precisely as the originally recorded neuronal activity. These results suggest that a simple model can be used to generate an accurate estimate of the spike timing of DRG neuronal ensembles from forelimb joint kinematics, and is useful for designing a proprioceptive decoder in a brain machine interface.


Differences in spontaneous breathing pattern and mechanics in patients with severe COPD recovering from acute exacerbation.
The aims of this study were to assess spontaneous breathing patterns in patients with chronic obstructive pulmonary disease (COPD) recovering from acute exacerbation and to assess the relationship between different breathing patterns and clinical and functional parameters of respiratory impairment. Thirty-four COPD patients underwent assessment of lung function tests, arterial blood gases, haemodynamics, breathing pattern (respiratory frequency (fR), tidal volume (VT), inspiratory and expiratory time (tI and tE), duty cycle (tI/ttot), VT/tI) and mechanics (oesophageal pressure (Poes), work of breathing (WOB), pressure-time product and index, and dynamic intrinsic positive end-expiratory pressure (PEEPi,dyn)). According to the presence (group 1) or absence (group 2) of Poes swings during the expiratory phase (premature inspiration), 20 (59%) patients were included in group 1 and 14 (41%) in group 2. Premature inspirations were observed 4.5+/-6.4 times x min(-1) (range 1-31), i.e. 20+/-21% (3.7-100%) of total fR calculated from VT tracings. In group 1 the coefficient of variation in VT, tE, tI/ttot, PEEPi,dyn, Poes and WOB of the eight consecutive breaths immediately preceding the premature inspiration was greater than that of eight consecutive breaths in group 2. There were no significant differences in the assessed parameters between the two groups in the overall population, whereas patients with chronic hypoxaemia in group 1 showed a more severe impairment in clinical conditions, mechanics and lung function than hypoxaemic patients in group 2. In spontaneously breathing patients with chronic obstructive pulmonary disease recovering from an acute exacerbation, detectable activity of inspiratory muscles during expiration was found in more than half of the cases. This phenomenon was not associated with any significant differences in anthropometric, demographic, physiological or clinical characteristics.


CD4+ T cells mediate IFN-gamma-independent control of Mycobacterium tuberculosis infection both in vitro and in vivo.
Although IFN-gamma is necessary for survival of Mycobacterium tuberculosis infection in people and animal models, it may not be sufficient to clear the infection, and IFN-gamma is not a reliable correlate of protection. To determine whether IFN-gamma-independent mechanisms of immunity exist, we developed a murine ex vivo culture system that directly evaluates the ability of splenic or lung lymphocytes to control the growth of M. tuberculosis within infected macrophages, and that models in vivo immunity to tuberculosis. Surprisingly, CD4(+) T cells controlled >90% of intracellular M. tuberculosis growth in the complete absence of IFN-gamma stimulation of macrophages, via a NO-dependent mechanism. Furthermore, bacillus Calmette-Guerin-vaccinated IFN-gamma-deficient mice exhibited significant protection against M. tuberculosis challenge that was lost upon depletion of CD4(+) T cells. These findings demonstrate that CD4(+) T cells possess IFN-gamma-independent mechanisms that can limit the growth of an intracellular pathogen and are dominant in secondary responses to M. tuberculosis.


The history and contributions of the Spanish dermatosurgical school.
The origin of dermatologic surgery in Spain may be traced to the efforts of Professor Felipe de Dulanto, Initially the specialty encompassed only simple direct closure, local flaps, and skin grafts. As the field evolved, distant flaps and other techniques, including dermabrasion, cryosurgery, Mohs' surgery, and laser surgery, were added to the armamentarium. The close, interdepartmental relationships between Dermatology and Otolaryngology, Ophthalmology, Pediatrics, and Gynecology allowed Spanish dermatologic surgery to expand and encompass lymph node dissections, complex reconstructions of the neck, eyelid, vulvar area, breasts, and abdomen.


[Laparoscopic cholecystectomy is the current standard intervention].
In the case of gallstone disease a differentiation is made between uncomplicated symptomatic cholecystolithiasis and acute cholecystitis. In either condition, differentiation may be rendered more complicated by the simultaneous presence of choledocholithiasis. Today, the standard intervention for the removal of the gallbladder is the laparoscopic modality. Early laparoscopic cholecystectomy is now the regular approach, since the former practice (antibiotic therapy and surgery in the inflammation-free interval) led to a considerable delay, which was often accompanied by massive intra-abdominal adhesions and which resulted in an increase in the conversion rate.


Pharmacology of the low-molecular-weight heparins.
Unfractionated heparin (UFH) is widely used to both treat and prevent venous thromboembolism. More recently, UFH has been used to prevent death and myocardial infarction in patients with unstable angina or acute myocardial infarction and acute occlusion in those undergoing percutaneous coronary revascularization. However, its poor bioavailability (when administered in low doses subcutaneously), its mechanism of clearance, and its short half-life make its anticoagulant activity difficult to predict and maintain. To overcome these limitations, low-molecular-weight heparins (LMWHs) have been developed that have greater bioavailability and a longer half-life in plasma. Because LMWHs provide more predictable anticoagulant activity compared with subcutaneous UFH, it is not necessary to monitor the activated partial thromboplastin time during treatment. These newer agents are as effective as UFH in the prophylaxis and treatment of thromboembolic and cardiac disorders and, by allowing shorter hospital stays, are more cost effective. Thus LMWHs offer clear pharmacokinetic advantages over UFH. More studies are needed to determine the extent to which clinically available LMWHs can be used in place of UFH.


Recurrent die-offs of adult coho salmon returning to spawn in Puget Sound lowland urban streams.
Several Seattle-area streams in Puget Sound were the focus of habitat restoration projects in the 1990s. Post-project effectiveness monitoring surveys revealed anomalous behaviors among adult coho salmon returning to spawn in restored reaches. These included erratic surface swimming, gaping, fin splaying, and loss of orientation and equilibrium. Affected fish died within hours, and female carcasses generally showed high rates (>90%) of egg retention. Beginning in the fall of 2002, systematic spawner surveys were conducted to 1) assess the severity of the adult die-offs, 2) compare spawner mortality in urban vs. non-urban streams, and 3) identify water quality and spawner condition factors that might be associated with the recurrent fish kills. The forensic investigation focused on conventional water quality parameters (e.g., dissolved oxygen, temperature, ammonia), fish condition, pathogen exposure and disease status, and exposures to metals, polycyclic aromatic hydrocarbons, and current use pesticides. Daily surveys of a representative urban stream (Longfellow Creek) from 2002-2009 revealed premature spawner mortality rates that ranged from 60-100% of each fall run. The comparable rate in a non-urban stream was <1% (Fortson Creek, surveyed in 2002). Conventional water quality, pesticide exposure, disease, and spawner condition showed no relationship to the syndrome. Coho salmon did show evidence of exposure to metals and petroleum hydrocarbons, both of which commonly originate from motor vehicles in urban landscapes. The weight of evidence suggests that freshwater-transitional coho are particularly vulnerable to an as-yet unidentified toxic contaminant (or contaminant mixture) in urban runoff. Stormwater may therefore place important constraints on efforts to conserve and recover coho populations in urban and urbanizing watersheds throughout the western United States.


Post-traumatic stress disorder and post-traumatic stress symptoms following critical illness in medical intensive care unit patients: assessing the magnitude of the problem.
Post-traumatic stress disorder (PTSD) is a potentially serious psychiatric disorder that has traditionally been associated with traumatic stressors such as participation in combat, violent assault, and survival of natural disasters. Recently, investigators have reported that the experience of critical illness can also lead to PTSD, although details of the association between critical illness and PTSD remain unclear. We conducted keyword searches of MEDLINE and Psych Info and investigations of secondary references for all articles pertaining to PTSD in medical intensive care unit (ICU) survivors. From 78 screened papers, 16 studies (representing 15 cohorts) and approximately 920 medical ICU patients met inclusion criteria. A total of 10 investigations used brief PTSD screening tools exclusively as opposed to more comprehensive diagnostic methods. Reported PTSD prevalence rates varied from 5% to 63%, with the three highest prevalence estimates occurring in studies with fewer than 30 patients. Loss to follow-up rates ranged from 10% to 70%, with average loss to follow-up rates exceeding 30%. Exact PTSD prevalence rates cannot be determined due to methodological limitations such as selection bias, loss to follow-up, and the wide use of screening (as opposed to diagnostic) instruments. In general, the high prevalence rates reported in the literature are likely to be overestimates due to the limitations of the investigations conducted to date. Although PTSD may be a serious problem in some survivors of critical illness, data on the whole population are inconclusive. Because the magnitude of the problem posed by PTSD in survivors of critical illness is unknown, there remains a pressing need for larger and more methodologically rigorous investigations of PTSD in ICU survivors.


The human response to acute enteral and parenteral phosphate loads.
The human response to acute phosphate (PO4) loading is poorly characterized, and it is unknown whether an intestinal phosphate sensor mechanism exists. Here, we characterized the human mineral and endocrine response to parenteral and duodenal acute phosphate loads. Healthy human participants underwent 36 hours of intravenous (IV; 1.15 [low dose] and 2.30 [high dose] mmol of PO4/kg per 24 hours) or duodenal (1.53 mmol of PO4/kg per 24 hours) neutral sodium PO4 loading. Control experiments used equimolar NaCl loads. Maximum PO4 urinary excretory responses occurred between 12 and 24 hours and were similar for low-dose IV and duodenal infusion. Hyperphosphatemic responses were also temporally and quantitatively similar for low-dose IV and duodenal PO4 infusion. Fractional renal PO4 clearance increased approximately 6-fold (high-dose IV group) and 4-fold (low-dose IV and duodenal groups), and significant reductions in plasma PO4 concentrations relative to peak values occurred by 36 hours, despite persistent PO4 loading. After cessation of loading, frank hypophosphatemia occurred. The earliest phosphaturic response occurred after plasma PO4 and parathyroid hormone concentrations increased. Plasma fibroblast growth factor-23 concentration increased after the onset of phosphaturia, followed by a decrease in plasma 1,25(OH)2D levels; α-Klotho levels did not change. Contrary to results in rodents, we found no evidence for intestinal-specific phosphaturic control mechanisms in humans. Complete urinary phosphate recovery in the IV loading groups provides evidence against any important extrarenal response to acute PO4 loads.


Hernia Active Living Trial (HALT): an exercise intervention in people with a parastomal hernia or bulge.
Parastomal hernias are a common consequence of stoma surgery and can occur in up to 50% of patients. They are mangaged either conservatively, through support hosiery, or surgically. A patient feasibility study called the Hernia Active Living Trial (HALT) was designed to examine if a clinical pilates-based exercise programme offers an alternative approach to managing a parastomal hernia or bulge. Adults with an ileostomy or colostomy who perceived they had a bulge around their stoma were included in the study. The intervention included up to 12 online sessions of an exercise booklet and videos with an exercise specialist. Interviews were conducted to explore participants' experiences of the intervention. The interview data were analysed systematically and thematically. Participants were also asked to complete patient diaries every week. Twelve of the 13 participants who completed the intervention agreed to be interviewed. Following analysis, three main themes emerged including managing a hernia/bulge, benefits and barriers. Participants talked about the benefits of this programme including: reduction of the size of their hernia, increased abdominal control, body confidence and posture, as well as increased physical activity levels. The barriers described were generally overcome allowing participants to engage in what was perceived to be a positive and potentially life-changing experience. A clinical pilates-based exercise programme for people with a parastomal hernia can bring both direct and indirect improvements to a patient's hernia management, sense of wellbeing and day-to-day life. Individuals with a hernia should be informed about the need for, and value of, exercise to strengthen core muscles, as part of their non-surgical options for self-management.


HSP90 supports tumor growth and angiogenesis through PRKD2 protein stabilization.
The kinase PRKD2 (protein kinase D) is a crucial regulator of tumor cell-endothelial cell communication in gastrointestinal tumors and glioblastomas, but its mechanistic contributions to malignant development are not understood. Here, we report that the oncogenic chaperone HSP90 binds to and stabilizes PRKD2 in human cancer cells. Pharmacologic inhibition of HSP90 with structurally divergent small molecules currently in clinical development triggered proteasome-dependent degradation of PRKD2, augmenting apoptosis in human cancer cells of various tissue origins. Conversely, ectopic expression of PRKD2 protected cancer cells from the apoptotic effects of HSP90 abrogation, restoring blood vessel formation in two preclinical models of solid tumors. Mechanistic studies revealed that PRKD2 is essential for hypoxia-induced accumulation of hypoxia-inducible factor-1α (HIF1α) and activation of NF-κB in tumor cells. Notably, ectopic expression of PRKD2 was able to partially restore HIF1α and secreted VEGF-A levels in hypoxic cancer cells treated with HSP90 inhibitors. Taken together, our findings indicate that signals from hypoxia and HSP90 pathways are interconnected and funneled by PRKD2 into the NF-κB/VEGF-A signaling axis to promote tumor angiogenesis and tumor growth.


The relationship between specific cognitive domains, fear of falling, and falls in people with multiple sclerosis.
The primary aim was to examine the relationship between seven definite aspects of cognition measured by a computerized cognitive testing tool on the history falls in people with mild to moderate MS (PwMS). Secondary aims focused on whether cognition performance is correlated to fear of falling, walking velocity, and a patient-rated measure of walking ability. One hundred and one PwMS were included in the study analysis. Fifty-two had a history of at least one fall during the past year. Outcome measures included a computerized cognitive test battery designed to evaluate multiple cognitive domains, gait speed, and self-reported questionnaires; 12-item MS walking scale (MSWS-12); and Falls Efficacy Scale International. Significant differences between fallers and nonfallers were exhibited in attention and verbal function, scoring 7.5% (P = 0.013) and 6.2% (P = 0.05), respectively, below the parallel scores of the nonfallers. Attention was the only cognitive component significantly correlated with the MSWS-12 self-reported questionnaire. Fear of falling was significantly correlated with 6 (out of 7) definite cognitive variables. The present findings support the concept that when evaluating and attempting to reduce fall risk, emphasis should be placed not only on traditional fall risk factors like muscle strength and motor function, but also on cognitive function.


Transforming a Mid-infrared Laser Profile from Gaussian to a Top-Hat with a Diffractive Optical Element for Mass Spectrometry Imaging.
Many mass spectrometry imaging (MSI) applications such as infrared matrix-assisted electrospray ionization (IR-MALDESI) employ an infrared (IR) laser with a Gaussian profile where laser irradiance is highest in the center and decreases exponentially. To enable full ablation of a square region of interest, oversampling is often needed, which results in nonuniform ablation and leads to decreased image quality. A diffractive optical element (DOE) was integrated into the optical path to generate homogeneous intensity distributions while maintaining laser energy above the ablation threshold, to enable complete sample removal from laser pulses without oversampling. 2D and 3D imaging with the DOE inserted show clear and sharp ablation patterns with satisfactory biological signals gained. Further improvements will optimize the beam profile and generate a square top-hat laser beam for MSI application at higher spatial resolution.


Diagnosis of human ehrlichiosis by PCR assay of acute-phase serum.
A PCR assay of 43 acute-phase serum samples was evaluated as a method for early detection of human granulocytic ehrlichiosis (HGE) and determination of etiology when serologic testing is inconclusive. Sequence-confirmed products of the HGE agent were amplified from three individuals residing or having exposure history in Minnesota or Wisconsin, and similarly confirmed products from Ehrlichia chaffeensis were amplified from three individuals from Florida or Maryland. Etiology, as determined by PCR and serology, was the same whenever there was a fourfold difference between the maximum titers of antibodies to both antigens, indicating that presumptive determination of etiology may be based on fourfold differences in titers. PCR testing determined that E. chaffeensis was the etiologic agent for one individual who had similar titers of antibodies to both agents. PCR assay of acute-phase serum in the absence of whole blood specimens may be a useful method for early detection of human ehrlichiosis and determination of etiology when serologic testing is inconclusive.


Aberrant MEK5/ERK5 signalling contributes to human colon cancer progression via NF-κB activation.
This study was designed to evaluate MEK5 and ERK5 expression in colon cancer progression and to ascertain the relevance of MEK5/ERK5 signalling in colon cancer. Expression of MEK5 and ERK5 was evaluated in 323 human colon cancer samples. To evaluate the role of MEK5/ERK5 signalling in colon cancer, we developed a stable cell line model with differential MEK5/ERK5 activation. Impact of differential MEK5/ERK5 signalling was evaluated on cell cycle progression by flow cytometry and cell migration was evaluated by wound healing and transwell migration assays. Finally, we used an orthotopic xenograft mouse model of colon cancer to assess tumour growth and progression. Our results demonstrated that MEK5 and ERK5 are overexpressed in human adenomas (P<0.01) and adenocarcinomas (P<0.05), where increased ERK5 expression correlated with the acquisition of more invasive and metastatic potential (P<0.05). Interestingly, we observed a significant correlation between ERK5 expression and NF-κB activation in human adenocarcinomas (P<0.001). We also showed that ERK5 overactivation significantly accelerated cell cycle progression (P<0.05) and increased cell migration (P<0.01). Furthermore, cells with overactivated ERK5 displayed increased NF-κB nuclear translocation and transcriptional activity (P<0.05), together with increased expression of the mesenchymal marker vimentin (P<0.05). We further demonstrated that increased NF-κB activation was associated with increased IκB phosphorylation and degradation (P<0.05). Finally, in the mouse model, lymph node metastasis was exclusively seen in orthotopically implanted tumours with overactivated MEK5/ERK5, and not in tumours with inhibited MEK5/ERK5. Our results suggested that MEK5/ERK5/NF-κB signalling pathway is important for tumour onset, progression and metastasis, possibly representing a novel relevant therapeutic target in colon cancer treatment.


N-acetyl-S-(2-hydroxyethyl)-L-cysteine as a potential tool in biological monitoring studies? A critical evaluation of possibilities and limitations.
In mammalian species, including man, N-acetyl-S-(2-hydroxyethyl)-L-cysteine (2-HEMA) is a common urinary metabolite of a large number of structurally different xenobiotic chemicals. It is a common urinary end product of glutathione pathway metabolism of a variety of chemicals possessing electrophilic properties and, in most cases, also a genotoxic potential. Five different chemically reactive intermediates, with different electrophilic properties, may be involved in the formation of 2-HEMA. An inventory of chemicals known to lead to the formation of 2-HEMA, or based on their chemical structure expected to do so, is presented. Furthermore, an attempt is made to evaluate the possibilities and limitations in terms of the potential use of urinary 2-HEMA as a tool in biomonitoring studies. Two other related, sulfur-containing urinary metabolites, i.e. N-acetyl-(S-carboxymethyl)-L-cysteine and thio-diacetic acid, are proposed as possible alternatives to urinary 2-HEMA. It is suggested that 2-HEMA might be seen as a potentially useful and sensitive signal parameter for the assessment of exposure of animals and man to a variety of electrophilic and therefore potentially toxic xenobiotic chemicals.


Aqp1 expression in erythroleukemia cells: genetic regulation of glucocorticoid and chemical induction.
The aquaporin-1 (AQP1) water channel protein is expressed in multiple mammalian tissues by several different developmental programs; however, the genetic regulation is undefined. The proximal promoter of mouse Aqp1 contains multiple putative cis-acting regulatory elements, and mouse erythroleukemia (MEL) cells are a well-characterized model for erythroid differentiation. Corticosteroid or dimethyl sulfoxide (DMSO) exposure induces AQP1 protein expression in MEL cells, and transcriptional regulation was investigated by transient transfections with Aqp1 promoter-reporter constructs. Dexamethasone induction is abrogated by deletion of two glucocorticoid response elements -0.5 kilobases (kb) from the transcription initiation site. Mutation of the GATA element at -0.62 kb has no effect, whereas mutation of the CACCC site at -37 bp significantly reduces DMSO-induced promoter activity. Hydroxyurea induces expression of AQP1 protein without acting through the proximal promoter. The MEL cell line is a reproducible erythroid model system for studying transcriptional regulation of the Aqp1 gene while determining the consequences on AQP1 protein biosynthesis.


'In vivo' size of knitted Dacron prostheses (Gelseal) used in the thoracic aorta: a computed tomography study.
When replacing the thoracic aorta, gelatin-sealed triaxial knitted Dacron prostheses are used as they have zero porosity and are easy to handle. It is known that knitted prostheses (not triaxially constructed), when implanted in the abdominal aorta or in the peripheral vessels, show a dilatation of 10-20%. The initial in vivo expansion of this prosthesis in the thoracic aorta was assessed using computed tomography scanning in 18 patients. The graft sizes used were 18mm (n = 4). 20mm (n = 5). 22mm (n = 4), 26mm (n = 1), 28mm (n = 2) and 30mm (n = 2). All patients were kept normotensive postoperatively. Computed tomography scan measurement was performed within 4 weeks of operation. using standard computed tomography equipment and no contrast. Two radiologists checked and agreed upon the slice levels and measurements compared with the manufacturer's stated size referring to internal diameter of the crimped prosthesis. The mean(s.d.) 'in vivo' size was 16.2(6)% larger. This 'true size' should be taken as the reference measurement when considering further dilatation over the period of follow-up.


Retention of enteropathogenicity by viable but nonculturable Escherichia coli exposed to seawater and sunlight.
The effect of natural sunlight on culturability and persistence of pathogenicity of Escherichia coli was examined in the field, i.e., in the Morlaix Estuary, France, using an enterotoxigenic strain of Escherichia coli H10407. Results showed that E. coli responds to the estuarine diurnal solar cycle by entering the viable but nonculturable state upon exposure to sunlight. That is, direct counts of viable cells remained stable without significant change, but E. coli cells remained fully culturable only when exposed to seawater in control chambers in the dark, i.e., without solar irradiation. The effect of sunlight on the pathogenicity of E. coli H10407 was studied, using both the rabbit intestinal loop assay and ganglioside-enzyme-linked immunosorbent assay (GM1-ELISA), a sensitive procedure for testing for production of enterotoxin. Results of the GM1-ELISA demonstrated that strains of E. coli, after exposure to sunlight and entering the viable but nonculturable state, as well as culturable E. coli, retained pathogenicity, i.e., produced enterotoxin. The GM1-ELISA is concluded to be more sensitive than the rabbit intestinal loop assay for analysis of enterotoxin in natural water samples.


Oestrogen receptor-related receptor alpha (ERRalpha) and oestrogen receptors (ERalpha and ERbeta) exhibit different gene expression in human colorectal tumour progression.
We have investigated the presence of oestrogen receptor-related (ERR) mRNA in human colorectal tumour tissues and adjacent normal mucosa by reverse transcriptase and nested-polymerase chain reaction. ERRalpha was found in 100% of the patients and ERRgamma in approximately 30% while ERRbeta was not detected at all. The multiplex PCR analysis showed elevated levels of ERRalpha mRNA in tumour tissue compartment as compared to normal mucosa, whereas ERRgamma mRNA was found in lower levels but in both tissue compartments. In contrast, oestrogen receptor (ERalpha and ERbeta) mRNA levels were shown to be decreased in tumour tissues. A positive correlation was observed between ERalpha and ERbeta and between ERalpha and ERRalpha, respectively, in normal mucosa but not in tumour tissue. ERRalpha expression in tumour tissues significantly increased from TNM stages II to IV, whereas both ERs progressively declined. These findings suggest that ERRalpha, as well as the two ERs, might play a critical role in the progression of the colorectal cancer.


Evaluation of Protein Adequacy From Plant-Based Dietary Scenarios in Simulation Studies: A Narrative Review.
Although a diet high in plant foods can provide beneficial nutritional outcomes, unbalanced and restrictive plant-based diets may cause nutrient deficiencies. Protein intake from these diets is widely discussed, but the comparison of animal and plant proteins often disregards amino acid composition and digestibility as measurements of protein quality. Poor provision of high-quality protein may result in adverse outcomes, especially for individuals with increased nutrient requirements. Several dietary modeling studies have examined protein adequacy when animal-sourced proteins are replaced with traditional and novel plant proteins, but no review consolidating these findings are available. This narrative review aimed to summarize the approaches of modeling studies for protein intake and protein quality when animal-sourced proteins are replaced with plant foods in diet simulations and examine how these factors vary across age groups. A total of 23 studies using dietary models to predict protein contribution from plant proteins were consolidated and categorized into the following themes-protein intake, protein quality, novel plant-based alternatives, and plant-based diets in special populations. Protein intake from plant-based diet simulations was lower than from diets with animal-sourced foods but met country-specific nutrient requirements. However, protein adequacy from some plant-sourced foods were not met for simulated diets of children and older adults. Reduced amino acid adequacy was observed with increasing intake of plant foods in some scenarios. Protein adequacy was generally dependent on the choice of substitution with legumes, nuts, and seeds providing greater protein intake and quality than cereals. Complete replacement of animal to plant-sourced foods reduced protein adequacy when compared with baseline diets and partial replacements.


Impact of HIV and chronic kidney disease comorbidities on hepatitis C treatment choices, drug-drug interactions and hepatitis C cure.
Background Human immunodeficiency virus (HIV) co-infection and chronic kidney disease add challenges to hepatitis C virus treatment. Objective To conduct a comparative study of treatment choices, drug-drug interactions and clinical outcomes in hepatitis C mono-infected patients, or those with HIV or chronic kidney disease comorbidities. Setting Hepatitis C treatment centers of West Midlands England, United Kingdom. Method An observational study was conducted analyzing datasets of all hepatitis C patients that were referred to a large tertiary liver unit in the West Midlands, UK between July 2015 and January 2018. Patients aged ≥ 18 years with diagnosis of hepatitis C alone or co-infected with HIV or comorbid with chronic kidney disease were eligible. Main outcome measures The treatment choices, relevant potential drug-drug interactions and sustained virologic response 12 weeks post end of treatment were assessed. Results Out of 313 patients, 154 (49.2%) were hepatitis C mono-infected, 124 (39.6%) hepatitis C/HIV co-infected and 35 (11.2%) were hepatitis C/chronic kidney disease comorbid. There were 151 (98.1%) of hepatitis C mono-infected, 110 (88.7%) of hepatitis C/HIV and 20 (57.1%) of hepatitis C/chronic kidney disease patients treated with 1st line regimens. Significantly more patients who had co-morbidity with either HIV or chronic kidney disease were prescribed 2nd line regimens (8.1% and 37.1% respectively), compared to patients with hepatitis C mono-infection (1.9%) (P value < 0.05). Comorbid patients (12.1% of HIV and 25.8% of chronic kidney disease) were more likely to required drug-drug interactions advice (grade 5) than hepatitis C mono-infected (1.8%). Higher cure rates were observed in hepatitis C mono-infected (95.33%), hepatitis C/HIV (96.1%) compared to hepatitis C/chronic kidney disease patients (90.3%). Conclusion This study shows that treatment pathways permitting access to individual treatment adjustments in accordance with comorbidities and with consideration of drug-drug interaction in a multi-disciplinary team, provides successful outcomes in hepatitis C patients co-morbid with HIV or chronic kidney disease.


Inactivation of Foodborne Viruses by High-Pressure Processing (HPP).
High-pressure processing (HPP) is an innovative non-thermal food preservation method. HPP can inactivate microorganisms, including viruses, with minimal influence on the physicochemical and sensory properties of foods. The most significant foodborne viruses are human norovirus (HuNoV), hepatitis A virus (HAV), human rotavirus (HRV), hepatitis E virus (HEV), human astrovirus (HAstV), human adenovirus (HuAdV), Aichi virus (AiV), sapovirus (SaV), and enterovirus (EV), which have also been implicated in foodborne outbreaks in various countries. The HPP inactivation of foodborne viruses in foods depends on high-pressure processing parameters (pressure, temperature, and duration time) or non-processing parameters such as virus type, food matrix, water activity (aw), and the pH of foods. HPP was found to be effective for the inactivation of foodborne viruses such as HuNoV, HAV, HAstV, and HuAdV in foods. HPP treatments have been found to be effective at eliminating foodborne viruses in high-risk foods such as shellfish and vegetables. The present work reviews the published data on the effect of HPP processing on foodborne viruses in laboratory media and foods.


[Crystallization of biological fluids in a closet cell. Example of saliva].
The informative value of the method of crystallization of biological fluids in a closed cell for analysis of salivary pools from patients with myocardial infarction is assessed. The structural features of the saliva varied not only in health and disease, but depended on the disease severity as well. The method can be used for analysis of oral fluid in various diseases and for screenings.


Eye movements of older and younger readers when reading disappearing text.
Older and younger readers read sentences in which target words were masked 40 to 60 ms after fixation onset. Masking only the target word caused more disruption than did masking each word in the sentence, and this effect was stronger for the younger readers than for the older readers. Although older readers had longer eye fixations than did younger readers, the results indicated that the masking effect was comparable for the 2 groups. However, for both groups, how long the eyes remained in place was strongly influenced by the frequency of the fixated word (even though it had been rapidly replaced by the mask and was no longer there when the eyes did move). This is compelling evidence that for both older and younger readers, cognitive/lexical processing has a very strong influence on when the eyes move in reading.


Filamentous condensation of DNA induced by pegylated poly-L-lysine and transfection efficiency.
In this paper we propose a detailed analysis of structural and morphological properties of two poly-L-lysine (PLL)-based transfection formulations, PLL/DNA and pegylated PLL (PLL-g-PEG)/DNA, by means of atomic force microscopy (AFM) and transmission electron microscopy (TEM). Comparing PLL-g-PEG/DNA with PLL/DNA polyplexes, we demonstrate that, due to the presence of PEG, the particles differ not only in size, shape, and crystalline structure, but also in transfection efficiency. While PLL condensates DNA in large agglomerates, PLL grafted with polyethylene glycol 2000 can condensate DNA in long filaments with diameters of some nanometers (6-20 nm). These structures are dependent on the grafting ratio and are more efficient than compacted ones, showing that DNA uptake and processing by cell is directly related to physicochemical properties of the polyplexes.


D3R Grand Challenge 3: blind prediction of protein-ligand poses and affinity rankings.
The Drug Design Data Resource aims to test and advance the state of the art in protein-ligand modeling by holding community-wide blinded, prediction challenges. Here, we report on our third major round, Grand Challenge 3 (GC3). Held 2017-2018, GC3 centered on the protein Cathepsin S and the kinases VEGFR2, JAK2, p38-α, TIE2, and ABL1, and included both pose-prediction and affinity-ranking components. GC3 was structured much like the prior challenges GC2015 and GC2. First, Stage 1 tested pose prediction and affinity ranking methods; then all available crystal structures were released, and Stage 2 tested only affinity rankings, now in the context of the available structures. Unique to GC3 was the addition of a Stage 1b self-docking subchallenge, in which the protein coordinates from all of the cocrystal structures used in the cross-docking challenge were released, and participants were asked to predict the pose of CatS ligands using these newly released structures. We provide an overview of the outcomes and discuss insights into trends and best-practices.


Outbreak of hepatitis C virus infection in a hemodialysis unit: potential transmission by the hemodialysis machine?
To identify the routes of transmission during an outbreak of infection with hepatitis C virus (HCV) genotype 2a/2c in a hemodialysis unit. A matched case-control study was conducted to identify risk factors for HCV seroconversion. Direct observation and staff interviews were conducted to assess infection control practices. Molecular methods were used in a comparison of HCV infecting isolates from the case-patients and from patients infected with the 2a/2c genotype before admission to the unit. A hemodialysis unit treating an average of 90 patients. A case-patient was defined as a patient receiving hemodialysis with a seroconversion for HCV genotype 2a/2c between January 1994 and July 1997 who had received dialysis in the unit during the 3 months before the onset of disease. For each case-patient, 3 control-patients were randomly selected among all susceptible patients treated in the unit during the presumed contamination period of the case-patient. HCV seroconversion was associated with the number of hemodialysis sessions undergone on a machine shared with (odds ratio [OR] per additional session, 1.3; 95% confidence interval [CI95], 0.9 to 1.8) or in the same room as (OR per additional session, 1.1; CI95, 1.0 to 1.2) a patient who was anti-HCV (genotype 2a/2c) positive. We observed several breaches in infection control procedures. Wetting of transducer protectors in the external pressure tubing sets with patient blood reflux was observed, leading to a potential contamination by blood of the pressure-sensing port of the machine, which is not accessible to routine disinfection. The molecular analysis of HCV infecting isolates identified among the case-patients revealed two groups of identical isolates similar to those of two patients infected before admission to the unit. The results suggest patient-to-patient transmission of HCV by breaches in infection control practices and possible contamination of the machine. No additional cases have occurred since the reinforcement of infection control procedures and the use of a second transducer protector.


Asymmetric Trimeric Ring Structure of the Nucleocapsid Protein of Tospovirus.
Tomato spotted wilt virus (TSWV), belonging to the genus Tospovirus of the family Bunyaviridae, causes significant economic damage to several vegetables and ornamental plants worldwide. Similar to those of all other negative-strand RNA viruses, the nucleocapsid (N) protein plays very important roles in its viral life cycle. N proteins protect genomic RNAs by encapsidation and form a viral ribonucleoprotein complex (vRNP) with some RNA-dependent RNA polymerases. Here we show the crystal structure of the N protein from TSWV. Protomers of TSWV N proteins consist of three parts: the N arm, C arm, and core domain. Unlike N proteins of other negative-strand RNA viruses, the TSWV N protein forms an asymmetric trimeric ring. To form the trimeric ring, the N and C arms of the N protein interact with the core domains of two adjacent N proteins. By solving the crystal structures of the TSWV N protein with nucleic acids, we showed that an inner cleft of the asymmetric trimeric ring is an RNA-binding site. These characteristics are similar to those of N proteins of other viruses of the family Bunyaviridae Based on these observations, we discuss possibilities of a TSWV encapsidation model.IMPORTANCE Tospoviruses cause significant crop losses throughout the world. Particularly, TSWV has an extremely wide host range (>1,000 plant species, including dicots and monocots), and worldwide losses are estimated to be in excess of $1 billion annually. Despite such importance, no proteins of tospoviruses have been elucidated so far. Among TSWV-encoded proteins, the N protein is required for assembling the viral genomic RNA into the viral ribonucleoprotein (vRNP), which is involved in various steps of the life cycle of these viruses, such as RNA replication, virus particle formation, and cell-to-cell movement. This study revealed the structure of the N protein, with or without nucleic acids, of TSWV as the first virus of the genus Tospovirus, so it completed our view of the N proteins of the family Bunyaviridae.


Impaired memory consolidation in rats produced with beta-adrenergic blockade.
Despite abundant evidence that systemic administration of adrenergic drugs and hormones can produce retrograde memory enhancement, the literature contains no clear demonstration that postlearning systemic administration of adrenergic antagonists produces retrograde amnesia. Here we demonstrate retrograde amnesia for a stressful learning task (a spatial water maze) with systemic administration of the beta-adrenergic antagonist propranolol (5 mg/kg). The amnesic effect of the drug depended on the degree of learning in the subjects: Propranolol caused a robust retrograde amnesia in "good learners," but did not significantly affect memory in "poor learners." The findings provide critical additional support for the hypothesis that postlearning adrenergic activation modulates memory consolidation processes after emotionally stressful events and help explain previous failures to detect memory impairment after systemic administration of adrenergic blocking drugs.


Circadian regulation of glutathione levels and biosynthesis in Drosophila melanogaster.
Circadian clocks generate daily rhythms in neuronal, physiological, and metabolic functions. Previous studies in mammals reported daily fluctuations in levels of the major endogenous antioxidant, glutathione (GSH), but the molecular mechanisms that govern such fluctuations remained unknown. To address this question, we used the model species Drosophila, which has a rich arsenal of genetic tools. Previously, we showed that loss of the circadian clock increased oxidative damage and caused neurodegenerative changes in the brain, while enhanced GSH production in neuronal tissue conferred beneficial effects on fly survivorship under normal and stress conditions. In the current study we report that the GSH concentrations in fly heads fluctuate in a circadian clock-dependent manner. We further demonstrate a rhythm in activity of glutamate cysteine ligase (GCL), the rate-limiting enzyme in glutathione biosynthesis. Significant rhythms were also observed for mRNA levels of genes encoding the catalytic (Gclc) and modulatory (Gclm) subunits comprising the GCL holoenzyme. Furthermore, we found that the expression of a glutathione S-transferase, GstD1, which utilizes GSH in cellular detoxification, significantly fluctuated during the circadian day. To directly address the role of the clock in regulating GSH-related rhythms, the expression levels of the GCL subunits and GstD1, as well as GCL activity and GSH production were evaluated in flies with a null mutation in the clock genes cycle and period. The rhythms observed in control flies were not evident in the clock mutants, thus linking glutathione production and utilization to the circadian system. Together, these data suggest that the circadian system modulates pathways involved in production and utilization of glutathione.


Nanomaterials in the environment, human exposure pathway, and health effects: A review.
Nanomaterials (NMs), both natural and synthetic, are produced, transformed, and exported into our environment daily. Natural NMs annual flux to the environment is around 97% of the total and is significantly higher than synthetic NMs. However, synthetic NMs are considered to have a detrimental effect on the environment. The extensive usage of synthetic NMs in different fields, including chemical, engineering, electronics, and medicine, makes them susceptible to be discharged into the atmosphere, various water sources, soil, and landfill waste. As ever-larger quantities of NMs end up in our environment and start interacting with the biota, it is crucial to understand their behavior under various environmental conditions, their exposure pathway, and their health effects on human beings. This review paper comprises a large portion of the latest research on NMs and the environment. The article describes the natural and synthetic NMs, covering both incidental and engineered NMs and their behavior in the natural environment. The review includes a brief discussion on sampling strategies and various analytical tools to study NMs in complex environmental matrices. The interaction of NMs in natural environments and their pathway to human exposure has been summarized. The potential of NMs to impact human health has been elaborated. The nanotoxicological effect of NMs based on their inherent properties concerning to human health is also reviewed. The knowledge gaps and future research needs on NMs are reported. The findings in this paper will be a resource for researchers working on NMs all over the world to understand better the challenges associated with NMs in the natural environment and their human health effects.


Monitoring reactive microencapsulation dynamics using microfluidics.
We use microfluidic polydimethylsiloxane (PDMS) devices to measure the kinetics of reactive encapsulations occurring at the interface of emulsion droplets. The formation of the polymeric shell is inferred from the droplet deformability measured in a series of expansion-constriction chambers along the microfluidic chip. With this tool we quantify the kinetic processes governing the encapsulation at the very early stage of shell formation with a time resolution of the order of the millisecond for overall reactions occurring in less than 0.5 s. We perform a comparison of monomer reactivities used for the encapsulation. We study the formation of polyurea microcapsules (PUMCs); the shell formation proceeds at the water-oil interface by an immediate reaction of amines dissolved in the aqueous phase and isocyanates dissolved in the oil phase. We observe that both monomers contribute differently to the encapsulation kinetics. The kinetics of the shell formation process at the oil-in-water (O/W) experiments significantly differs from the water-in-oil (W/O) systems; the component dissolved in the continuous phase has the largest impact on the kinetics. In addition, we quantified the retarding effect on the encapsulation kinetics by the interface stabilizing agent (surfactant). Our approach is valuable for quantifying in situ reactive encapsulation processes and provides guidelines to generate microcapsules with soft interfaces of tailored and controllable interfacial properties.


Patient Adherence to Dysphagia Recommendations: A Systematic Review.
Patient adherence to treatment recommendations is an important issue for healthcare providers, in a multitude of specialties, and is critical when assessing the efficacy and effectiveness of a particular treatment approach. Patients who have swallowing impairment often require complex and specific interventions requiring altered daily patterns of behavior. Patients with dysphagia who do not follow recommendations or prescribed exercises may not receive maximum benefit of an intervention. Poor adherence also makes it more difficult to evaluate efficacy of a treatment both clinically and in experimental settings. Further, swallow safety can be compromised if certain recommendations are not followed. Our purpose was to systematically review the literature to understand what is known about adherence within the field of dysphagia treatment. We systematically identified 12 studies that tracked and reported patient-specific adherence. In this review, we found that the average adherence rate from these studies ranges between 21.9 and 51.9%. Adherence to prophylactic treatment recommendations for patients with head and neck cancer was the focus in 9/12 studies. The findings of this review identify a large gap in knowledge regarding adherence to dysphagia treatment. Few studies account for adherence within their study designs. When planning dysphagia treatment studies, it is imperative that investigators include information regarding patient adherence to accurately interpret findings. Given the variable adherence rates found in this review, factors influencing patient adherence with dysphagia treatments should be identified to increase adherence in future trials.


Association between 24-hour movement guidelines and physical fitness in children.
Physical fitness levels in Japanese children are lower than those in the 1980s. Twenty-four hour movement guidelines were recently developed to improve both present and future health of children. This study examined whether meeting the 24 h movement guidelines was associated with physical fitness measures in primary school children. Participants were 243 Japanese children (9.4 ± 1.7 years). Moderate-to-vigorous physical activity (MVPA) was evaluated using accelerometry. Sleep duration and screen time were reported. Physical fitness was assessed by grip strength, sit-ups, sitting trunk flexion, and 20 m shuttle run test. Meeting the 24 h movement guidelines was defined as: 9-11 h / night of sleep, ≤2 h/day of screen time, and at least 60 min/day of MVPA. The associations between physical fitness and the recommendations were analyzed using analysis of covariance. Children meeting the MVPA recommendation alone performed better on the 20 m shuttle run and sit-up test compared to those not meeting the recommendation (number of laps: 41 vs 36, P = 0.009 and number of repetitions: 16.3 vs 14.7, P = 0.021). Children meeting the combination of MVPA and sleep recommendation scored significantly higher on the sit-up test compared to those not meeting the recommendations (number of repetitions: 16.5 vs 15.0, P = 0.038) but the effect was similar to that of the MVPA reference only. Meeting all three 24 h movement guidelines was not associated with measures of fitness in this sample. Meeting the MVPA recommendation was associated with greater aerobic fitness and muscle endurance. In order to enhance children's physical fitness, public health recommendations should primarily target MVPA.


Congruence between health professionals' and patients' pain ratings: a review of the literature.
The literature suggests that health professionals have a tendency to underestimate pain when performing clinical assessments. In addition, it appears that the more clinical experience one has, the greater will be the underestimation of pain. Pain assessment is difficult because of the complex interaction between environment, patient and practitioner variables. Although there is a need for further research in this area, there are clinical implications worthy of consideration. Health professionals need to use a variety of valid and reliable measures, use measures of pain behaviour and disability to complement self-report measures and examine how their own biases and values may influence pain judgements.


Class switch recombination and hypermutation require activation-induced cytidine deaminase (AID), a potential RNA editing enzyme.
Induced overexpression of AID in CH12F3-2 B lymphoma cells augmented class switching from IgM to IgA without cytokine stimulation. AID deficiency caused a complete defect in class switching and showed a hyper-IgM phenotype with enlarged germinal centers containing strongly activated B cells before or after immunization. AID-/- spleen cells stimulated in vitro with LPS and cytokines failed to undergo class switch recombination although they expressed germline transcripts. Immunization of AID-/- chimera with 4-hydroxy-3-nitrophenylacetyl (NP) chicken gamma-globulin induced neither accumulation of mutations in the NP-specific variable region gene nor class switching. These results suggest that AID may be involved in regulation or catalysis of the DNA modification step of both class switching and somatic hypermutation.


Artificial intelligence in positioning between mandibular third molar and inferior alveolar nerve on panoramic radiography.
Determining the exact positional relationship between mandibular third molar (M3) and inferior alveolar nerve (IAN) is important for surgical extractions. Panoramic radiography is the most common dental imaging test. The purposes of this study were to develop an artificial intelligence (AI) model to determine two positional relationships (true contact and bucco-lingual position) between M3 and IAN when they were overlapped in panoramic radiographs and compare its performance with that of oral and maxillofacial surgery (OMFS) specialists. A total of 571 panoramic images of M3 from 394 patients was used for this study. Among the images, 202 were classified as true contact, 246 as intimate, 61 as IAN buccal position, and 62 as IAN lingual position. A deep convolutional neural network model with ResNet-50 architecture was trained for each task. We randomly split the dataset into 75% for training and validation and 25% for testing. Model performance was superior in bucco-lingual position determination (accuracy 0.76, precision 0.83, recall 0.67, and F1 score 0.73) to true contact position determination (accuracy 0.63, precision 0.62, recall 0.63, and F1 score 0.61). AI exhibited much higher accuracy in both position determinations compared to OMFS specialists. In determining true contact position, OMFS specialists demonstrated an accuracy of 52.68% to 69.64%, while the AI showed an accuracy of 72.32%. In determining bucco-lingual position, OMFS specialists showed an accuracy of 32.26% to 48.39%, and the AI showed an accuracy of 80.65%. Moreover, Cohen's kappa exhibited a substantial level of agreement for the AI (0.61) and poor agreements for OMFS specialists in bucco-lingual position determination. Determining the position relationship between M3 and IAN is possible using AI, especially in bucco-lingual positioning. The model could be used to support clinicians in the decision-making process for M3 treatment.


A dopamine metabolite stabilizes neurotoxic amyloid-β oligomers.
Aberrant soluble oligomers formed by the amyloid-β peptide (Aβ) are major pathogenic agents in the onset and progression of Alzheimer's disease. A variety of biomolecules can influence the formation of these oligomers in the brain, although their mechanisms of action are still largely unknown. Here, we studied the effects on Aβ aggregation of DOPAL, a reactive catecholaldehyde intermediate of dopamine metabolism. We found that DOPAL is able to stabilize Aβ oligomeric species, including dimers and trimers, that exert toxic effects on human neuroblastoma cells, in particular increasing cytosolic calcium levels and promoting the generation of reactive oxygen species. These results reveal an interplay between Aβ aggregation and key biochemical processes regulating cellular homeostasis in the brain.


A rapid detection of avian oncovirus group-specific antigens in feather pulp by the enzyme-linked immunosorbent assay.
An ELISA procedure for the detection of avian sarcoma-leukosis gs antigen in feather pulp of adult birds is described. The test can be used for identifying gs+ and gs- chickens in leukosis-free populations. The titres of exogenous and endogenous virus-coded gs antigens overlap and the ELISA can be used only for a preliminary screening of unknown chicken populations.


Potentiation of morphine-induced antinociception and locomotion by citalopram is accompanied by anxiolytic-like effects.
Morphine and related opioids are the mainstay of analgesic treatment, especially in patients suffering chronic pain. Besides their antinociceptive effects they may also exhibit anxiolytic-like properties that could contribute to pain relief. The pharmacological manipulation of the serotonergic system may not only modulate pain transmission and processing but also other behavioral effects of opioids. The present study aimed to analyze the effect of the concurrent treatment with citalopram, a selective serotonin reuptake inhibitor, on the antinociceptive, locomotor and anxiety-related effects induced by acute and subchronic administration of morphine in mice. Citalopram (15mg/kg) enhanced the acute antinociceptive effects of morphine when concurrently administered as evidenced by a two-fold increase in the ED50 for the antinociceptive effect of morphine in the hot-plate test. Chronic studies also revealed that concurrent citalopram treatment (15mg/kg) delayed the development of tolerance to the thermal antinociceptive effects of morphine. Additionally, morphine-induced hyperlocomotion was potentiated by citalopram as assessed in the open-field test and in the spontaneous activity recording in the home cage, a behavioral outcome to which tolerance or desensitization was not developed. Interestingly, chronic administration of both drugs promoted an anxiolytic effect as evidenced by the increased central activity in the open field test. Future investigations on this pharmacological interaction, such as the possible translational research in clinics, might have consequences in future strategies for the therapeutic management of pain.


Cyclic Moisture Sorption and its Effects on the Thermomechanical Properties of Epoxy and Epoxy/MWCNT Nanocomposite.
The aim of this work was to reveal the moisture absorption-desorption-resorption characteristics of epoxy and epoxy-based nanocomposites filled with different multiwall carbon nanotubes (MWCNTs) by investigating the reversibility of the moisture effect on their thermomechanical properties. Two types of MWCNTs with average diameters of 9.5 and 140 nm were used. For the neat epoxy and nanocomposite samples, the moisture absorption and resorption tests were performed in atmospheres with 47%, 73%, and 91% relative humidity at room temperature. Dynamic mechanical analysis was employed to evaluate the hygrothermal ageing effect for unconditioned and environmentally "aged" samples. It was found that moisture sorption was not fully reversible, and the extent of the irreversibility on thermomechanical properties was different for the epoxy and the nanocomposite. The addition of both types of MWCNTs to the epoxy resin reduced sorption characteristics for all sorption tests, improved the hygrothermal and reduced the swelling rate after the moisture absorption-desorption.


Validity of maternal report of prenatal alcohol, cocaine, and smoking in relation to neurobehavioral outcome.
Evidence that mothers report higher levels of drinking retrospectively than during pregnancy has led some investigators to suggest that women systematically underreport alcohol antenatally and that alcohol-related deficits may actually reflect heavier prenatal exposure. This study is the first to compare the validity of antenatal and retrospective reports of pregnancy drinking, drug use, and smoking in relation to effects on infant neurobehavioral outcomes. Three hundred fifty-four inner-city mothers were interviewed regarding their alcohol, drug use, and smoking during pregnancy and retrospectively at 13 months' postpartum. Their infants were assessed at 6.5, 12, and 13 months on a large battery of neurobehavioral assessments. Although higher levels of alcohol were reported retrospectively, the correlations of prenatal alcohol exposure with infant outcome were as strong or stronger for the antenatal measures and only the antenatal reports predicted poorer cognitive performance on the Bayley Scales and symbolic play, slower processing speed on the Fagan Test of Infant Intelligence and cross-modal transfer, and slower infant reaction time. Women also reported higher levels of cocaine and marijuana but not cigarette smoking retrospectively. Relations between cocaine use and smoking on birth size and gestational age were as strong for either report. No effects were detected in relation to either report of marijuana use during pregnancy. These findings suggest that antenatal alcohol interviews provide the most valid information and demonstrate the importance of assessing prenatal alcohol use during pregnancy to minimize the risk of failing to detect neurobehavioral deficits. Adverse effects were consistently seen at levels as low as 0.5 oz absolute alcohol/day (the equivalent of 7 drinks per week) based on maternal antenatal report. These data suggest that alcohol-related deficits do not reflect heavier prenatal exposure than that reported during pregnancy and that threshold values derived from antenatal reports are reasonably accurate.


[Diagnostic and therapeutic approach in hepatic echinococcosis complicated by mechanical jaundice].
The article presents the results of the treatment of 43 patients with echinococcosis of the liver the course of which was complicated by mechanical jaundice (MJ). In 11 patients MJ arose as a result of cystic content break into the bile ducts, in 32 patients, due to cystic compression of the lobular bile ducts. An effective scheme of the patients' examination is proposed which involved present-day ultrasound, X-ray and endoscopic methods. The system of objective evaluation of the patients' condition is outlined as designed for planning surgical policy. In non-severe disease the patients are operated after standard preparation within 24 hours after hospitalization. If the disease is more severe, the patients demand preparation including extracorporeal detoxication and cholangiostomy. In serious conditions the operations are made to remove the cyst content and cholestasis. This differentiated diagnostic and therapeutic policy diminished postoperative lethality from 15.2 to 6.9%.


Identifying and Predicting Distinct Patterns of Implementation in a School-Wide Behavior Support Framework.
The purpose of this study was to examine the extent to which distinct patterns of fidelity of implementation emerged for 5331 schools over a 5-year course of implementing school-wide positive behavioral interventions and supports (SWPBIS). We used latent class analysis to classify schools based on their likelihood of implementing SWPBIS with fidelity each year, then assessed school and district predictors of classifications. A four-class solution fit the model well, with two patterns of sustained implementation (Sustainers and Slow Starters) and two patterns of practice abandonment (Late Abandoners and Rapid Abandoners). Significant predictors of group membership included grade levels served, enrollment, proportion of schools implementing SWPBIS in the district ("critical mass"), and size of the implementation cohort ("community of practice"). Elementary schools, larger schools, schools in districts with more schools already implementing SWPBIS, and those starting within a larger initial district cohort were more likely to be in the sustaining classes. Results are discussed in terms of understanding patterns of implementation in schools to enhance sustained implementation of school practices.


Analysis of osseointegration of implants with hydrophilic surfaces in grafted areas: A Preclinical study.
The aim of this study was to evaluate the effect of a hydrophilic surface on the osseointegration in grafted areas with deproteinized bovine bone (DBB) and with biphasic ceramics of hydroxyapatite/β-tricalcium phosphate (HA/TCP). Fifty-six rats were randomly allocated to four groups with 14 animals each: DBB: DBB+Machined surface; HA/TCP: HA/TCP+Machined surface; DBB-H: DBB+Hydrophilic surface; HA/TCP-H: HA/TCP+Hydrophilic surface. The bone defects were performed at the proximal epiphysis of the tibia. Then, the defects were filled with the biomaterials. After 60 days, the implants were placed in the grafted areas. The animals were submitted to euthanasia at periods of 15 and 45 days after the implants' placement. The osseointegration was assessed by biomechanical, microtomographic, and histometric analyses. In addition, the expression of bone morphogenetic protein-2 (BMP-2), alkaline phosphatase (ALP), and osteocalcin (OCN) was evaluated by immunohistochemistry. The HA/TCP-H group presented higher removal torque values and more mineralized tissue in the vicinity of the implants compared with the HA/TCP group. The DBB-H and HA/TCP-H groups presented higher values of bone-implant contact (at 15 and 45 days), of bone between the threads (45 days), and expression of BMP-2 (45 days) than the DBB and HA/TCP groups. Furthermore, the DBB-H group presented a higher expression of ALP than the DBB group (15 days). In conclusion, implants with a hydrophilic surface improve osseointegration in grafted areas compared to implants with machined surfaces in a rat tibia model.


RNAi nanotherapy for fibrosis: highly durable knockdown of CTGF/CCN-2 using siRNA-DegradaBALL (LEM-S401) to treat skin fibrotic diseases.
Skin fibrosis occurs in a variety of human diseases but the current anti-fibrosis treatments are not sufficient. One major cause of fibrotic diseases shared across diverse organ fibrosis is uncontrolled overexpression of the connective tissue growth factor (CTGF, also known as CCN2). Here, we examine the anti-fibrotic activity of RNAi therapy utilizing siRNA against CTGF with a new drug delivery system (DDS), 'DegradaBALL', which is based on porous nanoparticles, for durable CTGF gene silencing. DegradaBALL is a modular DDS having many favorable properties for RNA delivery such as effective intracellular uptake, convenient drug loading, biocompatibility, sustained release profile and biodegradability. DegradaBALL loaded with siCTGF, named 'LEM-S401', showed highly durable and effective CTGF gene-silencing in TGF-β induced lung fibrosis and skin fibrosis model cells, A549 and HaCaT, respectively. In addition, LEM-S401 induced knockdown of collagen types I and III, which are excess extracellular matrix components in fibrotic skin in addition to CTGF in the mouse wound healing model. Most importantly, we showed that LEM-S401 effectively inhibited the formation of hypertrophic scars in wound-associated dermal fibrosis mouse models, during both the epidermis recovery and tissue remodeling process. Our findings suggest that LEM-S401 could be a highly potent therapeutic option for skin fibrotic diseases.


HIV infection with immunodeficiency presenting with subacute cognitive decline: recent illustrative cases.
We describe three recent patients in whom evaluation of subacute, progressive encephalopathy led to the initial diagnosis of human immunodeficiency virus infection. The clinical neurological picture of a predominance of abnormalities of mental function with few elementary neurological deficits, in conjunction with a paucity of systemic symptoms and lack of evidence for prior opportunistic infections preceding the encephalopathy are notable. The cognitive, behavioral, and neuropsychiatric disturbances are described in detail to illustrate the range of manifestations of disordered mental states associated with encephalopathy in individuals with HIV infection. The importance of a comprehensive and broad-minded work-up by brain magnetic resonance imaging, cerebrospinal fluid examination, and specific microbiological tests in delineating the potential multifactorial pathogenesis of the cerebral syndromes in relation to the HIV infection is emphasized. The gratifying long-term clinical improvements in parallel with resolution of neuroimaging and other laboratory abnormalities in response to antiretroviral drug treatment are reported.


Susceptibility of Canadida albicans to miconazole.
A total of 439 clinical isolates of Candida albicans were tested for susceptibility to miconazole by the agar dilution technique. When tests were read at 48 and 24 h, 56 and 84%, respectively, of the strains were completely inhibited by 4.0 mug of miconazole per ml, the estimated upper limit of probable clinical susceptibility.