The effect of multiple reminders on response patterns in a Danish health survey.
Reminders are routinely applied in surveys to increase response rates and reduce the possibility of bias. This study examines the effect of multiple reminders on the response rate, non-response bias, prevalence estimates and exposure-outcome relations in a national self-administered health survey. Data derive from the Danish National Health Survey 2010, in which 298,550 individuals (16 years of age or older) were invited to participate in a cross-sectional survey using a mixed-mode approach (paper and web questionnaires). At least two reminders were sent to non-respondents, and 177,639 individuals completed the questionnaire (59.5%). Response patterns were compared between four groups of individuals (first mailing respondents, second mailing respondents, third mailing respondents and non-respondents). Multiple reminders led to an increase in response rate from 36.7 to 59.5%; however, the inclusion of second and third mailing respondents did not change the overall characteristics of respondents compared with non-respondents. Furthermore, only small changes in prevalence estimates and exposure-outcome relationships were observed when including second and third mailing respondents compared with only first mailing respondents. Multiple reminders were an effective way to increase the response rate in a national Danish health survey. However, when differences do exist between respondents and non-respondents, the results suggest that second and third mailings are unlikely to eliminate these differences. Overall, multiple reminders seemed to have only minor effect on response patterns and study conclusions in the present study.


Adenovirus enterocolitis in human small bowel transplants.
This report describes two cases of pediatric small bowel transplant patients who developed diffuse adenovirus enterocolitis of their allografts. Based upon the presenting symptoms for this complication, in both patients a differential diagnosis of allograft rejection versus viral infection was clinically entertained. The clinical condition in both instances rapidly deteriorated and both patients died shortly after the development of the symptoms of fulminant septicemia. Autopsies were performed and histologic examination revealed extensive denudation of the gastrointestinal mucosa with edema and a marked acute and chronic inflammatory infiltrate involving the entire wall of the grafts. Numerous viral intranuclear and intracytoplasmic inclusions were evident and an immunohistochemical stain specific for adenovirus was strongly positive in the infected cells. In addition, while in the first case the adenovirus appeared confined to the GI tract, the second patient displayed numerous viral inclusions in the lung as well as within multiple liver abscesses. At this point, the incidence of adenovirus as a cause of gastroenteritis in small bowel transplant patients remains to be determined. We believe that the importance of recognizing this particular type of viral infection in this group of patients lies primarily in differentiating it from other viral organisms (e.g., CMV) that require a specific antiviral therapy. Moreover, an identification of this entity could help avoid a misdiagnosis of rejection which could lead to an unnecessary increase in immunosuppressive therapy and a possible exacerbation of the underlying condition.


The adrenergic system and the release and pressor action of vasopressin.
We studied the effect of various adrenergic components on vasopressin in groups of anephric rats. Pharmacological interventions included alpha 1-, alpha 2-, and beta-adrenergic receptor blockade and infusions of sodium nitroprusside to achieve a baseline blood pressure fall similar to that obtained by alpha 1-blockade, followed by hypertonic saline infusion to stimulate vasopressin release and administration of a specific V1 vascular vasopressin inhibitor to test the degree of blood pressure dependency on vasopressin. The combined hypotensive and osmolar stimuli of nitroprusside followed by hypertonic saline led to the highest level of plasma vasopressin (104 +/- 17 pg/ml, p less than 0.01) but only a 7 +/- 1 mm Hg fall in blood pressure in response to the vasopressin inhibitor. Rats subjected to alpha 1-blockade and saline infusion had the largest blood pressure reduction in response to the vasopressin inhibitor (43 +/- 5 mm Hg, p less than 0.001), despite a modest rise in vasopressin levels (18 +/- 2 pg/ml). Other pharmacological maneuvers produced intermediate responses in terms of vasopressin release and blood pressure response to the vasopressin inhibitor. There was no correlation between vasopressin levels achieved by each maneuver and the magnitude of blood pressure reduction in response to the vasopressin inhibitor. We conclude that 1) plasma levels of vasopressin under these conditions do not permit an accurate estimate of the magnitude of its pressor contribution to the maintenance of a given blood pressure level, which can be demonstrated only by the depressor response to a vasopressin inhibitor.(ABSTRACT TRUNCATED AT 250 WORDS)


Construction of natural language sentence acceptors by a supervised-learning technique.
The problem discussed here is to build automatically an acceptor for natural language sentences, a sample of sentences being given. We solve it in the context of computer-assisted instruction and database interrogation. This paper is focused toward the definition of a learning criterion, i.e., a quality measure on the set of the acceptors which are compatible with the sample.


Polyamidoamine dendrimers can improve the pulmonary absorption of insulin and calcitonin in rats.
The absorption-enhancing effects of polyamidoamine (PAMAM) dendrimers with various generations (G0-G3) and concentrations [0.1%-1.0% (w/v)] on the pulmonary absorption of peptide and protein drugs were studied in rats. Insulin and calcitonin were chosen as models of peptide and protein drugs, and their pulmonary absorption with or without PAMAM dendrimers was examined by in vivo pulmonary absorption studies. PAMAM dendrimers significantly increased the pulmonary absorption of insulin and calcitonin in rats, and their absorption-enhancing effects were generation dependent. The rank order of absorption enhancement effect of these PAMAM dendrimers was G3 > G2 > G1 > G0. For the same generation, the absorption-enhancing effects of PAMAM dendrimers were shown to be concentration dependent. The toxicity of these PAMAM dendrimers in the lung tissues was evaluated by measuring the release of protein and the activities of lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF). The PAMAM dendrimers with various generations and concentrations did not significantly increase the release of protein and the activities of LDH in BALF, indicating that these dendrimers did not cause any membrane damage to the lung tissues. The zeta potentials of insulin and calcitonin solutions changed to positive by the addition of PAMAM dendrimers, and the degree of positive charge as determined by the zeta potentials was linearly correlated with the absorption-enhancing effects of the PAMAM dendrimers. This positive charge of the PAMAM dendrimers might be related to their absorption-enhancing mechanisms for improving the pulmonary absorption of insulin and calcitonin in rats. In conclusion, the PAMAM dendrimers are suitable absorption enhancers to improve the pulmonary absorption of insulin and calcitonin without any membrane damage to the respiratory tissues.


Three tests for measuring unjustified disparate impacts in organ transplantation: the problem of "included variable" bias.
Civil rights statutes often prohibit two distinct types of discrimination, referred to as "disparate treatment" and "disparate impact." Disparate treatment is race-contingent decision making. But even decision making that is not affected by people's race may still produce an unjustified disparate impact. For example, a race-neutral transplantation preference for allografts with partial antigen matches might produce an unjustified disparate impact on African Americans with end-stage renal disease. The transplantation preference might make it harder for African Americans to receive a transplant without significantly increasing the chance of transplant survival. Because disparate impact and disparate treatment claims have distinct elements, they require distinct methods of statistical testing. This article analyzes three different ways of testing unjustified disparate impacts in organ transplantation, which I will call the traditional test, the omitted variable test, and the outcome test. Each of these methods of testing for disparate impact are attuned to the problem of "included variable" bias. Controlling statistically for nonracial variables may actually bias the analysis and mask the existence of unjustified disparate impacts.


Continuing intense malaria transmission in northern Uganda.
Recent reports of reductions in malaria transmission in several African countries have resulted in optimism that malaria can be eliminated in parts of Africa where it is currently endemic. It is not known whether these trends are global or whether they are also present in areas where political instability has hindered effective malaria control. We determined malaria parasite carriage and age-dependent antibody responses to Plasmodium falciparum antigens in cross-sectional surveys in Apac, northern Uganda that was affected by political unrest. Under-five parasite prevalence was 55.8% (115/206) by microscopy and 71.9% (41/57) by polymerase chain reaction. Plasmodium ovale alone, or as a co-infection, was detected in 8.6% (12/139) and Plasmodium malariae in 4.3% (6/139) of the infections. Age seroprevalence curves gave no indication of recent changes in malaria transmission intensity. Malaria control remains a tremendous challenge in areas that have not benefited from large-scale interventions, illustrated here by the district of Apac.


New method of assessing visual acuity with pictures.
It is never easy to assess accurately the vision of an illiterate child. Children under the age of 3 who are unable to understand and co-operate with tests using shapes and a key card present an even greater problem. All available subjective tests for this age group may maintain a small child's interest, but the accuracy of the recorded vision is very much in doubt. The new test described below is designed for 2-3-year old children. It combines the well recognised advantages of using pictures to gain the child's attention with the accuracy of a graded test based on Snellen's chart sizing. It is therefore both a practical and more accurate alternative test for this age group.


Systematic analysis of the phosphoproteome and kinase-substrate networks in the mouse testis.
Spermatogenesis is a complex process closely associated with the phosphorylation-orchestrated cell cycle. Elucidating the phosphorylation-based regulations should advance our understanding of the underlying molecular mechanisms. Here we present an integrative study of phosphorylation events in the testis. Large-scale phosphoproteome profiling in the adult mouse testis identified 17,829 phosphorylation sites in 3955 phosphoproteins. Although only approximately half of the phosphorylation sites enriched by IMAC were also captured by TiO2, both the phosphoprotein data sets identified by the two methods significantly enriched the functional annotation of spermatogenesis. Thus, the phosphoproteome profiled in this study is a highly useful snapshot of the phosphorylation events in spermatogenesis. To further understand phosphoregulation in the testis, the site-specific kinase-substrate relations were computationally predicted for reconstructing kinase-substrate phosphorylation networks. A core sub-kinase-substrate phosphorylation networks among the spermatogenesis-related proteins was retrieved and analyzed to explore the phosphoregulation during spermatogenesis. Moreover, network-based analyses demonstrated that a number of protein kinases such as MAPKs, CDK2, and CDC2 with statistically more site-specific kinase-substrate relations might have significantly higher activities and play an essential role in spermatogenesis, and the predictions were consistent with previous studies on the regulatory roles of these kinases. In particular, the analyses proposed that the activities of POLO-like kinases (PLKs) might be dramatically higher, while the prediction was experimentally validated by detecting and comparing the phosphorylation levels of pT210, an indicator of PLK1 activation, in testis and other tissues. Further experiments showed that the inhibition of POLO-like kinases decreases cell proliferation by inducing G2/M cell cycle arrest. Taken together, this systematic study provides a global landscape of phosphoregulation in the testis, and should prove to be of value in future studies of spermatogenesis.


Development of an ELISA for detection of autoantibodies to nuclear matrix protein 2.
Autoantibodies characterizing certain forms of inflammatory myopathy, which are myositis-specific autoantibodies, are useful in the diagnosis and prediction of prognosis in DM/PM. This study aimed to identify a subset of DM patients who have anti-nuclear matrix protein 2 (anti-NXP-2) antibodies by using biotinylated recombinant proteins, and to clarify the clinical features of DM patients with these antibodies. Sera from 170 Japanese patients with CTDs including 106 with DM, 8 with PM, 21 with SLE, 20 with SSc, 15 with myositis overlap syndrome and 20 healthy controls were screened for anti-NXP-2 antibodies by our novel ELISAs. Positive sera were further examined by immunoprecipitation. Sera from 6 of the 170 patients with CTDs were confirmed to be positive for anti-NXP-2 antibodies. These six positives were from female patients, with five of the six sera being from adult DM patients and only one of the six being from 1 of the 12 JDM patients. All these patients had myositis. None of the anti-NXP-2-positive patients had interstitial lung disease, but one patient was complicated with ovarian cancer. Our newly developed ELISA is applicable for the measurement of anti-NXP-2 antibodies. The results show that anti-NXP-2 antibodies, which have been characterized in JDM, exist in adult DM patients. Further studies using large populations are necessary to elucidate the characteristic clinical features and the prognosis of patients with anti-NXP-2 antibodies, especially for adult patients.


Restarted local search algorithms for continuous black box optimization.
Several local search algorithms for real-valued domains (axis parallel line search, Nelder-Mead simplex search, Rosenbrock's algorithm, quasi-Newton method, NEWUOA, and VXQR) are described and thoroughly compared in this article, embedding them in a multi-start method. Their comparison aims (1) to help the researchers from the evolutionary community to choose the right opponent for their algorithm (to choose an opponent that would constitute a hard-to-beat baseline algorithm), (2) to describe individual features of these algorithms and show how they influence the algorithm on different problems, and (3) to provide inspiration for the hybridization of evolutionary algorithms with these local optimizers. The recently proposed Comparing Continuous Optimizers (COCO) methodology was adopted as the basis for the comparison. The results show that in low dimensional spaces, the old method of Nelder and Mead is still the most successful among those compared, while in spaces of higher dimensions, it is better to choose an algorithm based on quadratic modeling, such as NEWUOA or a quasi-Newton method.


Gender differences in individuals at high-risk of psychosis: a comprehensive literature review.
To date, few studies have focused on the characterization of clinical phenomenology regarding gender in population at high-risk of psychosis. This paper is an attempt to summarize the findings found in the scientific literature regarding gender differences in high-risk populations, taking into account parameters studied in populations with schizophrenia and other psychotic disorders, such as incidence, clinical expression, duration of untreated illness (DUI), social functioning, and cognitive impairment prior to full-blown psychosis development. Studies were systematically searched in PubMed. Studies using gender variable as a control variable were excluded. 12 studies met inclusion criteria. Most of the studies found a differential pattern between women and men as regards clinical, social, and cognitive variables in the prodromal phase, with worse performance in men except in cognitive functioning (more severe negative symptoms, worse social functioning, and longer DUI in men). Similar conversion rates over time were found between men and women. Many of the studies analyzed suggest that differences between men and women in the expression of psychosis extend across a continuum, from the subclinical forms of illness to the debut of psychosis. However, the small number of studies and their significant methodological and clinical limitations do not allow for firm conclusions.


Growth mechanism of cubic MgO granule via common ion effect.
MgO is a typical wide bandgap insulator with its excellent thermodynamic stability, low dielectric constant, and low refractive index for growing various thin film materials. For this application, it is worth developing and understanding suitable growth method for MgO nanostructure. In this study, cubic MgCO3 have been successfully prepared via hydrolysis control of magnesium salt and alkaline solution with common ions to form nanoflake assembly. An optimum hydrothermal process and its shape evolution of cubic MgCO3 and MgO granules are analyzed. The physicochemical properties of the obtained samples are characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) and Fourier Transform InfraRed (FT-IR) to show high purity and structural uniformity of magnesium compounds.


A re-examination of antidepressant treatment-emergent mania in bipolar disorders: evidence of gender differences.
To explore the prevalence and clinical profile of males and females who develop antidepressant treatment-emergent mania (ATEM). From an original sample of 754 patients with BD, we identified ATEM+ cases (n = 75) and ATEM- controls (n = 135) that met stringent criteria. We specifically examined the combinations of clinical factors that best classified males and females as ATEM+ cases. Seventy-five individuals were classified as ATEM+; 87% of ATEM events occurred during antidepressant monotherapy. Regression analyses demonstrated that the presence of an alcohol and/or substance use disorder [Odds Ratio (OR) 6.37], a history of one or more suicide attempts (OR 4.19) and higher number of depressive episodes per year of illness (OR 1.71) correctly classified 73% of males. In contrast, 84% of females were correctly classified on the basis of a positive history of thyroid disorder (OR 3.23), a positive family history of BD I (OR 2.68) and depressive onset polarity (OR 2.01). Using stringent definitions of ATEM status to reduce the probability of inclusion of false-positive cases and false-negative controls, we identified for the first time that the risk profiles for the development of an ATEM differ significantly according to gender.


Evolution of budding yeast prion-determinant sequences across diverse fungi.
Prions are transmissible self-replicating alternative states of proteins. Four prions ([PSI+], [URE3], [RNQ+] and [NU+]) can be inherited cytoplasmically in Saccharomyces cerevisiae laboratory strains. In the case of [PSI+], there is increasing evidence that prion formation may engender mechanisms to uncover hidden genetic variation. Here, we have analysed the evolution of the prion-determinant (PD) domains across 21 fungi, focusing on compositional biases, repeats and substitution rates. We find evidence for constraint on all four PD domains, but each domain has its own evolutionary dynamics. For [PSI+], the Q/N bias is maintained in fungal clades that diverged one billion years ago, with purifying selection observed within the Saccharomyces species. The degree of Q/N bias is correlated with the degree of local homology to prion-associated repeats, which occur rarely in other proteins (<1% of sequences for the proteomes studied). The evolutionary conservation of Q/N bias in Sup35p is unusual, with only eight other S. cerevisiae proteins showing similar, phylogenetically deep patterns of bias conservation. The [URE3] PD domain is unique to Hemiascomycota; part of the PD domain shows purifying selection, whereas another part engenders bias changes between clades. Also, like for Sup35p, the [RNQ+] and [NU+] PD domains show purifying selection in Saccharomyces species. Additionally, in each proteome, we observe on average several hundred yeast-prion-like domains, with fewest in fission yeast. Our findings on yeast prion evolution provide further support for the functional significance of these molecules.


Relationship Between Opacity of Cytomegalovirus Retinitis Lesion Borders and Severity of Immunodeficiency Among People With AIDS.
To evaluate risk factors for severity of cytomegalovirus (CMV) retinitis lesion whitening (opacity), using a standardized scoring system. We performed a cross-sectional, observational investigation of all individuals with newly diagnosed AIDS-related CMV retinitis in three randomized clinical trials and one prospective observational study. Opacity was scored by masked readers, using a prospectively defined ordinal 6-point scale. Demographic factors, laboratory data (CD4+, CD8+ T-lymphocyte counts, human immunodeficiency virus [HIV] blood levels), and lesion characteristics (location, size) were compared to the highest opacity score assigned to either eye. Among eyes with active lesions (scores ≥3), factors associated with severe opacity (scores 5, 6) were identified. There were 299 participants (401 eyes with CMV retinitis). In one or more comparisons, increased opacity was associated with lower CD4+ and lower CD8+ T-lymphocyte counts, higher HIV blood level, lack of antiretroviral therapy, male sex, race/ethnicity, and bilateral disease. In eyes with active disease, severe opacity was associated with lower CD4+ T-lymphocyte count, higher HIV blood level, older age, Karnofsky score, lesion size, and bilateral disease. No relationship was identified between opacity and lesion location. Lesion border opacity (resulting from CMV activity) reflects level of immune function; as immunodeficiency becomes worse, CMV activity (and opacity) increases. The positive relationship between opacity and HIV blood level may reflect both immunodeficiency and increased CMV activity caused by transactivation of CMV by HIV. Scoring of opacity may be a useful, standard measure for continued study of CMV retinitis across different settings and populations. (Clinicaltrials.gov number for the HPMPC CMV Retinitis Trial: NCT00000142; Clinicaltrials.gov number for the Monoclonal Antibody CMV Retinitis Trial: NCT00000135; Clinicaltrials.gov number for the Ganciclovir-Cidofovir CMV Retinitis Trial: NCT0000014; Clinicaltrials.gov number for the Longitudinal Study of the Ocular Complications of AIDS: NCT00000168.).


Autonomic control of blood circulation in patients undergoing elective carotid endarterectomy.
Internal carotid artery stenosis (ICAS) is associated with significantly higher risk of stroke. Autonomic function can be impaired in the presence of atheroma in the carotid sinus region. Two parameters of autonomic nervous system (ANS) function e.g. heart rate variability (HRV) and baroreflex sensitivity (BRS) are respected predictors of cardiovascular prognosis. We assessed the effect of elective unilateral carotid endarterectomy (CEA) on cardiovascular autonomic functions as a major prognostic factor for cardiovascular health. Nineteen patients indicated for CEA underwent formal autonomic assessment in the laboratory. Hemodynamic profiles, HRV and BRS were evaluated with the dedicated high-tech device Task Force Monitor before surgery (day-1) and postoperatively (day 3±1). Data were obtained during 5 min orthostatic challenge and subsequent 5 min in a supine position. There were no significant early postoperative changes in evaluated parameters after CEA. There was a mild decrease of blood pressure and therefore only a slight increase in BRS. It was also possible to observe a rise in the value of total power and high frequency power. In the early postoperative period, healing processes are occurring and the sympatho-vagal interaction is probably still unbalanced. Given the considerable clinical potential of BRS and HRV measurement, further short-term and, more importantly, long-term investigations are needed.


Holographic features of spatial coherence wavelets.
The behavior of the marginal power spectrum as a two-channel-multiplexed hologram is analyzed. Its "negative energies" make it quite different from the conventional holograms, i.e., it is not recordable in general and the objects to be reconstructed (the cross-spectral densities at both the aperture and the observation planes) are virtual. The holographic reconstruction results from the superposition of the spatial coherence wavelets that carry the marginal power spectrum. These features make the marginal power spectrum a powerful tool for analysis and synthesis of optical fields, for instance, in optical information processing (signal encryption) and beam shaping for microlithography.


Neural basis of conditional cooperation.
Cooperation among genetically unrelated individuals is a fundamental aspect of society, but it has been a longstanding puzzle in biological and social sciences. Recently, theoretical studies in biology and economics showed that conditional cooperation-cooperating only with those who have exhibited cooperative behavior-can spread over a society. Furthermore, experimental studies in psychology demonstrated that people are actually conditional cooperators. In this study, we used functional magnetic resonance imaging to investigate the neural system underlying conditional cooperation by scanning participants during interaction with cooperative, neutral and non-cooperative opponents in prisoner's dilemma games. The results showed that: (i) participants cooperated more frequently with both cooperative and neutral opponents than with non-cooperative opponents; and (ii) a brain area related to cognitive inhibition of pre-potent responses (right dorsolateral prefrontal cortex) showed greater activation, especially when participants confronted non-cooperative opponents. Consequently, we suggest that cognitive inhibition of the motivation to cooperate with non-cooperators drives the conditional behavior.


New and old tools for abdominal imaging in critically ill patients.
Diagnostic imaging technology has advanced considerably during the past two decades. Different imaging techniques have been proposed for abdominal imaging in critically ill patients like plain radiography, sonography, computed tomography (CT), magnetic resonance and positron emission tomography. Sonography has been proven to be effective to detect free intra-peritoneal fluid and it is considered one of the primary diagnostic modalities for abdominal evaluation for trauma assessment. In our opinion sonography should replace other invasive techniques to rapidly triage blunt trauma patients with unstable vital signs and examine the peritoneal cavity as a site of major haemorrhage to expedite exploratory laparotomy. On the other hand, CT has become the imaging modality of choice in hemodynamically stable patients with multisystem blunt and penetrating trauma. New developments in the quantitative analysis of the CT images will improve our knowledge of pathophysiology, diagnostic and therapeutic management of abdominal pathologies in critically ill patients.


The fucose salvage pathway inhibits invadopodia formation and extracellular matrix degradation in melanoma cells.
The fucose salvage pathway is a two-step process in which mammalian cells transform L-fucose into GDP-L-fucose, a universal fucose donor used by fucosyltransferases to modify glycans. Emerging evidence indicates the fucose salvage pathway and the fucosylation of proteins are altered during melanoma progression and metastasis. However the underlying mechanisms are not completely understood. Here, we report that the fucose salvage pathway inhibits invadopodia formation and extracellular matrix degradation by promoting α-1,2 fucosylation. Chemically or genetically increasing the fucose salvage pathway decreases invadopodium numbers and inhibits the proteolytic activity of invadopodia in WM793 melanoma cells. Inhibiting fucosylation by depleting fucokinase abrogates L-fucose-mediated inhibition of invadopodia, suggesting dependence on the fucose salvage pathway. The inhibition of invadopodium formation by L-fucose or ectopically expressed FUK could be rescued by treatment with α-1,2, but not α-1,3/α-1,4 fucosidase, implicating an α-1,2 fucose linkage-dependent anti-metastatic effect. The expression of FUT1, an α-1,2 fucosyltransferase, is remarkably down-regulated during melanoma progression, and the ectopic expression of FUT1 is sufficient to inhibit invadopodium formation and ECM degradation. Our findings indicate that the fucose salvage pathway can inhibit invadopodium formation, and consequently, invasiveness in melanoma via α-1,2 fucosylation. Re-activation of this pathway in melanoma could be useful for preventing melanoma invasion and metastasis.


Patient-reported impact of symptoms in myotonic dystrophy type 1 (PRISM-1).
To determine the most critical symptoms in a national myotonic dystrophy type 1 (DM1) population and to identify the modifying factors that have the greatest effect on the severity of these symptoms. We performed a cross-sectional study of 278 adult patients with DM1 from the national registry of patients with DM1 between April and August 2010. We assessed the prevalence and relative significance of 221 critical DM1 symptoms and 14 disease themes. These symptoms and themes were chosen for evaluation based on prior interviews with patients with DM1. Responses were categorized by age, CTG repeat length, gender, and duration of symptoms. Participants with DM1 provided symptom rating survey responses to address the relative frequency and importance of each DM1 symptom. The symptomatic themes with the highest prevalence in DM1 were problems with hands or arms (93.5%), fatigue (90.8%), myotonia (90.3%), and impaired sleep or daytime sleepiness (87.9%). Participants identified fatigue and limitations in mobility as the symptomatic themes that have the greatest effect on their lives. We found an association between age and the average prevalence of all themes (p < 0.01) and between CTG repeat length and the average effect of all symptomatic themes on participant lives (p < 0.01). There are a wide range of symptoms that significantly affect the lives of patients with DM1. These symptoms, some previously underrecognized, have varying levels of importance in the DM1 population and are nonlinearly dependent on patient age and CTG repeat length.


Effects of pathological respiratory pattern on heart rate turbulence in sleep apnea.
Obstructive sleep apnea syndrome (OSAS) is characterized by recurrent episodes of partial or complete upper-airway obstruction during sleep. Although cardiac autonomic impairment is involved in the development of cardiovascular disease in OSAS, the mechanism underlying this derangement is rather unknown. It can be assessed by a recently introduced analysis of the heart rate turbulence (HRT). The aim of the paper is to describe the effects of pathological respiratory pattern on HRT in OSAS. HRT has been assessed by turbulence onset (TO) and turbulence slope (TS) indexes in 20 polysomnographic recordings of severe OSAS patients, and separately calculated during both normal (NR) and obstructive apnea (OA) respiratory pattern. Results showed that, although there is an overall depressed HRT for both indexes, while the TO during OA phases is not significantly different from those of NR epochs, the TS during OA phases is very significantly higher than in NR phases. This novel finding shows a previously unknown paradoxical increase of TS during OA episodes, followed by a marked decrease during subsequent NR phases, where OSAS patient show higher sympathetic tone. Such deeper understanding of the integrated autonomic response in different OSAS pathophysiological conditions could be useful to address an overall cardiorespiratory assessment and treatment in sleep-related breathing disorders.


Health systems research and acute respiratory infections: essential focus on the health system.
Health systems research is receiving increasing prominence in the developing world as an aid to decision-making. In acute respiratory infection (ARI), health systems research has focused on alternative means of educating mothers to recognize pneumonia and seek treatment and on improving the case management practices of health workers. While these interventions have demonstrated their effectiveness in reducing ARI mortality in the research setting, on a wider scale the management and control of ARI will depend on a well-functioning health system, with skilled workers, essential drugs and equipment, an operating referral system, adequate supervision and an active monitoring system. The essential focus for health systems research in the reduction of the impact of ARI on public health in Papua New Guinea should be on improving the effectiveness of the health care delivery system. Some potential areas for health systems research are outlined.


[Epizootiology of salmonellosis in wild and zoo animals].
To demonstrate a few characteristic features of zoo animals caused by infections, bacterial examination of material collected in Leipzig Zoo Garden was carried out with respect to the presence of Salmonella. Examination of 7022 organ and faeces samples revealed that 350 salmonella isolates could be cultivated. This established 5% presence of salmonella. Among the 3 most important classes of animals exists quite a reasonable difference: 9.9% of all samples taken from animals of reptile-origin revealed the presence of Salmonella, only 6.0% and 4.1% was registered among birds and mammals respectively. 65.4% of all the Salmonella isolates were of serovar typhimurium whereby a clear difference between the animal classes was noted. Among birds 84.2% of the isolates were S. typhimurium, among mammals 62.6%, among reptiles only 26.8%.


Circulating immune complexes in bacillary and amebic dysentery.
In order to study the relationship between the presence of circulating immune complexes (CIC) and the severity and duration of acute dysentery, we studied 11 adults and 45 children in Bangladesh with bacillary and amebic dysentery, using the Raji cell and solid-phase C1q (C1q-SPA) assays. CIC were found in 70% of patients with shigellosis and in all eight cases of amebic dysentery. Mild shigellosis was associated with positive samples in the first week of clinical illness, whereas severe cases, including those with the hemolytic-uremic syndrome, had negative admission assays but positive convalescent assays. Samples positive in the first two weeks of illness were more likely positive by the Raji cell assay alone whereas samples in the third and fourth weeks of illness were positive more often by the C1q-SPA assay. Only one shigellosis sample was positive by both assays. In amebiasis 11 of 13 samples were positive by the Raji assay alone. In dysenteric disease circulating immune complexes probably represents the failure of the inflamed mucosa to exclude microbial and dietary antigens, and suggests that the presence of CIC in any intestinal disease must be interpreted with caution.


Cell surface physiology and outer cell envelope impermeability for hydrophobic substances in Burkholderia multivorans.
The purpose of the present study was to obtain a better understanding of the relationship between cell surface physiology and outer cellular envelope permeability for hydrophobic substances in mucoid and non-mucoid B. multivorans strains, as well as in two capsule-deficient derivatives of a mucoid parental strain. Cell surface hydrophobicity properties were determined using the hydrocarbon adherence method, while outer cell envelope accessibility and permeability for non-polar compounds were measured using hydrophobic antimicrobial agent susceptibility and fluorescent probe assays. Extracellular polysaccharide (EPS) production was assessed by cultivating strains of disparate origin on yeast extract agar (YEA) containing different sugars, while the resultant colonial and cellular morphological parameters were assessed macro- and microscopically, respectively.Results/Key findings. The cell surfaces of all the strains were hydrophilic, impermeable to mechanistically disparate hydrophobic antibacterial agents and inaccessible to the hydrophobic probe N-phenyl-1-napthylamine, regardless of EPS phenotype. Supplementation of basal YEA with eight different sugars enhanced macroscopic EPS expression for all but one non-mucoid strain, with mannose potentiating the greatest effect. Despite acquisition of the mucoid phenotype, non-mucoid strains remained non-capsulated and capsulation of a hyper-mucoid strain and its two non-mucoid derivative strains was unaffected, as judged by microscopic observation. These data support the conclusion that EPS expression and the consistent mucoid phenotype are not necessarily associated with the ability of the outer cell surface to associate with non-polar substances or cellular capsulation.


Semi-quantitative analysis of a specific database on priority and emerging substances in wastewater and sludge.
The Water Framework Directive (WFD) has drawn attention to a series of metals and organic compounds because of their demonstrated or potential harmfulness for aquatic environments. The aim of our work was to build and to process a "practical" database focused on the role of wastewater treatment plants for the removal of the 37 priority compounds that have to be reduced or stopped by 2015, and of 34 additional relevant contaminants. About 11,000 concentration values in raw and treated wastewater and sludge, from more than 100 peer-reviewed articles and six French national screening programs, were integrated. A systematic approach showed the global low quality of data for most of the compounds, with missing information about the treatment process, sampling and analysis, leading to 10% of the data available for removal efficiency calculations. A semi-quantitative analysis allowed the identification of 20 priority and 10 additional relevant substances more frequently quantified at significant concentrations in raw wastewater and treated wastewater. Conventional activated sludge was able to remove more than 70% of half of the studied compounds, leaving only 10% of them with less than 50% removal. Physical-chemical treatments appeared to be about 30% less efficient than biological treatments. In addition, very few data are available concerning some compounds and some processes, especially sludge treatment and tertiary wastewater treatment processes. Therefore, complementary on-site measurements and modeling are required to propose adapted solutions for the treatment of priority and emerging substances in wastewater treatment plants.


Hippocampal dose from stereotactic radiosurgery for 4 to 10 brain metastases: Risk factors, feasibility of dose reduction via re-optimization, and patient outcomes.
This study aimed to report hippocampal dose from single-fraction stereotactic radiosurgery (SRS) for 4 to 10 brain metastases and determine feasibility of hippocampal-sparing SRS. Patients with 4 to 10 brain metastases receiving single-isocenter, multi-target single-fraction SRS were identified. Hippocampi were contoured using the Radiation Therapy Oncology Group (RTOG) 0933 atlas. RTOG 0933 dose constraints were converted to a biologically effective dose using an alpha/beta of 2 (D100 421 cGy, Dmax 665 cGy). Number of metastases, total target volume, prescribed dose, and distance of nearest metastasis (dmin) were analyzed as risk factors for exceeding hippocampal constraints. If hippocampi exceeded constraints, the SRS plan was re-optimized. Key dosimetric parameters were compared between original and re-optimized plans. To determine if a single target can exceed constraints, all targets but the closest metastasis were removed from the plan, and dosimetry was compared. Forty plans were identified. Fifteen hippocampi (19%) exceeded constraints in 12 SRS plans. Hippocampal sparing was achieved in 10 of 12 replanned cases (83%). Risk factors associated with exceeding hippocampal constraints were decreasing dmin (24.0 vs 8.0 mm, p = 0.002; odds ratio [OR] 1.14, 95% confidence interval [CI] 1.04 to 1.26) and total target volume (5.46 cm3vs 1.98 cm3, p = 0.03; OR 1.14, 95% CI 1.00 to 1.32). There was no difference in exceeding constraints for 4 to 5 vs 6 to 10 metastases (27% vs 21%, p = 0.409) or prescribed dose (18 Gy, p = 0.58). For re-optimized plans, there were no significant differences in planning target volume (PTV) coverage (99.6% vs 99.0%, p = 0.17) or conformality index (1.47 vs 1.4, p = 0.78). Six (50%) plans exceeded constraints with a single target. A substantial minority of hippocampi receive high radiation dose from SRS for 4 to 10 brain metastases. Decreasing distance of the closest metastasis and total target volume are associated with exceeding hippocampal constraints. Re-optimizing these plans yielded hippocampal-sparing SRS plans with acceptable dosimetry. Prospective evaluation of the impact of hippocampal dose from SRS on neurocognition merits consideration.


Tracking and inferring spatial rotation by children and great apes.
Finding hidden objects in space is a fundamental ability that has received considerable research attention from both a developmental and a comparative perspective. Tracking the rotational displacements of containers and hidden objects is a particularly challenging task. This study investigated the ability of 3-, 5-, 7-, and 9-year-old children and great apes (chimpanzees, bonobos, gorillas, and orangutans) to (a) visually track rotational displacements of a baited container on a platform and (b) infer its displacements by using the changes of position or orientation of 3 landmarks: an object on a container, the color of the containers, and the color of the platform on which the containers rested. Great apes and 5-year-old and older children successfully tracked visible rotations, but only children were able to infer the location of a correct cup (with the help of landmarks) after invisible rotations. The ability to use landmarks changed with age so that younger children solved this task only with the most explicit marker on the baited container, whereas older children, particularly 9-year-olds, were able to use landmark orientation to infer correct locations.


Detection of Clostridium tyrobutyricum in milk to prevent late blowing in cheese by automated ribosomal intergenic spacer analysis.
Clostridium tyrobutyricum has been identified as the main causal agent of the late blowing defect in cheese, with major effects on quality and commercial value. In this work, for the first time, we applied automated ribosomal intergenic spacer analysis (ARISA) approach to diagnose the presence of C. tyrobutyricum in raw milk before cheesemaking. A species-specific primer set was designed and used for this original application of the ARISA. Sensitivity of detection, reproducibility of the fluorescent PCR assay, and repeatability of the capillary electrophoretic analysis of amplicons were evaluated using DNA extracted from milk added with known amounts of C. tyrobutyricum genome copies, ranging from 3 × 10(6) to 3. Results indicated that the sensitivity of the technique permits to detect the bacterium in all the samples. The reproducibility, evaluated by analyzing 3 sets of serial dilutions, resulted satisfactory, with little deviation within PCR reactions amplifying the same starting amount of template (standard deviations ≤ 0.1, coefficients of variation ≤ 3%). The peaks' fluorescence displayed an evident correspondence with the number of genome copies contained in each dilution. The capillary electrophoretic analysis, tested by running a single PCR product per dilution point in 10 repeats, resulted efficient and highly repeatable, with excellent coefficients of variation ≤ 2% and standard deviations ≤ 0.1 in all the sample sets. This application of ARISA gives good estimates of the total C. tyrobutyricum DNA content allowing a specific, fine-scale resolution of this pollutant species in a complex system as milk. A further advantage linked to the automatization of the process.


Cross-species global and subset gene expression profiling identifies genes involved in prostate cancer response to selenium.
Gene expression technologies have the ability to generate vast amounts of data, yet there often resides only limited resources for subsequent validation studies. This necessitates the ability to perform sorting and prioritization of the output data. Previously described methodologies have used functional pathways or transcriptional regulatory grouping to sort genes for further study. In this paper we demonstrate a comparative genomics based method to leverage data from animal models to prioritize genes for validation. This approach allows one to develop a disease-based focus for the prioritization of gene data, a process that is essential for systems that lack significant functional pathway data yet have defined animal models. This method is made possible through the use of highly controlled spotted cDNA slide production and the use of comparative bioinformatics databases without the use of cross-species slide hybridizations. Using gene expression profiling we have demonstrated a similar whole transcriptome gene expression patterns in prostate cancer cells from human and rat prostate cancer cell lines both at baseline expression levels and after treatment with physiologic concentrations of the proposed chemopreventive agent Selenium. Using both the human PC3 and rat PAII prostate cancer cell lines have gone on to identify a subset of one hundred and fifty-four genes that demonstrate a similar level of differential expression to Selenium treatment in both species. Further analysis and data mining for two genes, the Insulin like Growth Factor Binding protein 3, and Retinoic X Receptor alpha, demonstrates an association with prostate cancer, functional pathway links, and protein-protein interactions that make these genes prime candidates for explaining the mechanism of Selenium's chemopreventive effect in prostate cancer. These genes are subsequently validated by western blots showing Selenium based induction and using tissue microarrays to demonstrate a significant association between downregulated protein expression and tumorigenesis, a process that is the reverse of what is seen in the presence of Selenium. Thus the outlined process demonstrates similar baseline and selenium induced gene expression profiles between rat and human prostate cancers, and provides a method for identifying testable functional pathways for the action of Selenium's chemopreventive properties in prostate cancer.


Dilemmas for guardians of advanced dementia patients regarding tube feeding.
advanced dementia is an incurable illness, its last stage marked by inability to eat. Tube feeding was deemed a helpful solution at this stage, but in recent years its inefficiency has been proved, and it is no longer practiced in many countries around the world. In Israel, however, the procedure is still accepted. In the gastroenterology department at the Bnai Zion Medical Center, a serious interaction is ongoing with patients' legal guardians, where detailed information is given about the inefficiency of the tube procedure. Nevertheless, the great majority of guardians choose to have it performed. to probe the considerations underlying the decision for gastrostomy, despite the data and the recommendations. qualitative research, including participant observation at the clinic and in-depth interviews with guardians. the families of most patients did not discuss end-of-life issues with them. The overwhelming preference for using the technology was interpreted as life-saving, in contrast to comfort feeding, which was deemed euthanasia. The reasons given for the decision to tube feed were drawn from a range of outlooks: religion, the patient's earlier survival capacity, and pragmatic considerations involving relations with nursing home staff. study of the decision-making process of advanced dementia patients' guardians sheds light on the layers of meaning of the Israeli discourse regarding end-of-life issues.


Clearance of benzo(a)pyrene from the respiratory tract of hamsters following its intratracheal instillation with or without ferric oxide.
A comparative study was carried out on the clearance of benzo(a)pyrene (BP) from the respiratory tract of Syrian golden hamsters following intratracheal instillation of either BP alone or BP attached to ferric oxide particles. Eight series of 18 hamsters each, received a single intratracheal instillation of 0.5 or 1.0 mg BP suspended in 0.9% NaCl solution. In addition, three comparable series of hamsters received in the same way a mixture, of 1.0 mg BP + 1.0 mg ferric oxide suspended in 0.9% NaCl solution. In each of the series the BP content of the respiratory tract was determined at six different points of time viz. immediately after administration of BP or BP + ferric oxide, and three, six and 24 hours, and three and seven days after an instillation. The clearance of BP from the respiratory tract did not appear to be significantly influenced by the presence of ferric oxide. It was concluded that the present study produced no evidence of ferric oxide particles being capable of enhancing the retention of BP in the respiratory tract.


Ameloplasty is counterproductive in reducing microleakage around Resin Modified Glass Ionomer and Resin based fissure sealants.
To compare the microleakage around resin modified glass ionomer cement (RMGIC) based sealants and flowable resin based sealants placed with or without ameloplasty in extracted human teeth. This in-vitro experimental study was conducted at the Operative Dentistry Department, Dow University of Health Sciences, Karachi, Pakistan from June 2017 to December 2018. Sixty extracted human molars and premolars were assigned to four groups (n=15) each, according to the type of fissure sealant (flowable resin based sealant or resin modified glass ionomer based sealant) used and either placed with or without ameloplasty. Specimens were thermocycled and then immersed in 1% methylene blue for 24 hours. Specimens were then sectioned and examined using stereo-microscope (50X) for microleakage that was scored on an ordinal scale. Mann-Whitney U test and Ordinal regression were applied. Level of significance kept at 0.05. There was a statistically significant difference (p-value <0.001) between the two sealant types for the microleakage scores. Sealants placed with ameloplasty demonstrated significantly higher microleakage values (p-value <0.001). Microleakage was found to be more pronounced in RMGIC based sealants compared to the resin based sealants. Ameloplasty resulted in higher leakage around the sealants irrespective of the chemistry of material.


Disorder effect in the transmission spectra of a noncompact single layer of dielectric spheres derived from microwave spectroscopy.
Single layers of dielectric spheres are an interesting system to study from the fundamental and applied points of view. In this paper we present a systematic study of the influence of structural disorder on the transmission spectra of arrangements of spheres of different compactness. Glass sphere (ε=7) planes were built and their transmission spectra in the microwave range measured. Transmission behavior of this system is highly tolerant to disorder. Even in completely disordered arrangements, there is a highly rejected band with the dips of the spectrum observable. These results suggest that the collective modes of the sphere planes are formed by weakly coupled Mie modes of the individual spheres, and this coupling is governed by the average distance among the spheres. Disorder tolerance allows simpler fabrication procedures where the position of the spheres does not need to be precisely controlled.


A Pseudomonas aeruginosa EF-hand protein, EfhP (PA4107), modulates stress responses and virulence at high calcium concentration.
Pseudomonas aeruginosa is a facultative human pathogen, and a major cause of nosocomial infections and severe chronic infections in endocarditis and in cystic fibrosis (CF) patients. Calcium (Ca2+) accumulates in pulmonary fluids of CF patients, and plays a role in the hyperinflammatory response to bacterial infection. Earlier we showed that P. aeruginosa responds to increased Ca2+ levels, primarily through the increased production of secreted virulence factors. Here we describe the role of putative Ca2+-binding protein, with an EF-hand domain, PA4107 (EfhP), in this response. Deletion mutations of efhP were generated in P. aeruginosa strain PAO1 and CF pulmonary isolate, strain FRD1. The lack of EfhP abolished the ability of P. aeruginosa PAO1 to maintain intracellular Ca2+ homeostasis. Quantitative high-resolution 2D-PAGE showed that the efhP deletion also affected the proteomes of both strains during growth with added Ca2+. The greatest proteome effects occurred when the pulmonary isolate was cultured in biofilms. Among the proteins that were significantly less abundant or absent in the mutant strains were proteins involved in iron acquisition, biosynthesis of pyocyanin, proteases, and stress response proteins. In support, the phenotypic responses of FRD1 ΔefhP showed that the mutant strain lost its ability to produce pyocyanin, developed less biofilm, and had decreased resistance to oxidative stress (H2O2) when cultured at high [Ca2+]. Furthermore, the mutant strain was unable to produce alginate when grown at high [Ca2+] and no iron. The effect of the ΔefhP mutations on virulence was determined in a lettuce model of infection. Growth of wild-type P. aeruginosa strains at high [Ca2+] causes an increased area of disease. In contrast, the lack of efhP prevented this Ca2+-induced increase in the diseased zone. The results indicate that EfhP is important for Ca2+ homeostasis and virulence of P. aeruginosa when it encounters host environments with high [Ca2+].


Behavioral effects of chronic exposure to low concentrations of halothane during development in rats.
Long-term behavioral effects of chronic exposure to low concentrations of halothane were evaluated in rats exposed to low (12.5 ppm) concentrations from day 2 of conception until either 30 (halothane-30) or 60 (halothane-60) days after birth. Rats similarly treated but not exposed to halothane served as controls. When these rats were tested for radial arm maze exploration as adults (1 yr old) both exposure groups showed significant deficits compared with controls. The halothane-treated rats entered significantly fewer arms before reentering an arm (entries-to-repeat). At 55 days of age, in the spontaneous alternation test, response speed was significantly slower than controls in both halothane-30 and halothane-60 rats. This effect was not seen in rats more than 55 days old. Replicating previous results, the halothane-60 rats showed deficits in learning a light-dark discrimination. This deficit was not seen with halothane-30 rats, indicating that continued halothane exposure during the 30- through 60-day period was necessary for inducing a noticeable long-term learning deficit. The results show that chronic exposure of rats to low concentrations of halothane during development results in subsequent behavioral alteration, and that termination of halothane exposure at 30 days of age rather than at 60 days of age avoids some of the signs of behavioral impairment.


Identification of amino acids that account for long-range interactions in two triosephosphate isomerases from pathogenic trypanosomes.
For a better comprehension of the structure-function relationship in proteins it is necessary to identify the amino acids that are relevant for measurable protein functions. Because of the numerous contacts that amino acids establish within proteins and the cooperative nature of their interactions, it is difficult to achieve this goal. Thus, the study of protein-ligand interactions is usually focused on local environmental structural differences. Here, using a pair of triosephosphate isomerase enzymes with extremely high homology from two different organisms, we demonstrate that the control of a seventy-fold difference in reactivity of the interface cysteine is located in several amino acids from two structurally unrelated regions that do not contact the cysteine sensitive to the sulfhydryl reagent methylmethane sulfonate, nor the residues in its immediate vicinity. The change in reactivity is due to an increase in the apparent pKa of the interface cysteine produced by the mutated residues. Our work, which involved grafting systematically portions of one protein into the other protein, revealed unsuspected and multisite long-range interactions that modulate the properties of the interface cysteines and has general implications for future studies on protein structure-function relationships.


Long-term calorie restriction reduces proton leak and hydrogen peroxide production in liver mitochondria.
Calorie restriction (CR) without malnutrition increases maximal life span in diverse species. It has been proposed that reduction in energy expenditure and reactive oxygen species (ROS) production could be a mechanism for life span extension with CR. As a step toward testing this theory, mitochondrial proton leak, H2O2 production, and markers of oxidative stress were measured in liver from FBNF1 rats fed control or 40% CR diets for 12 or 18 mo. CR was initiated at 6 mo of age. Proton leak kinetics curves, generated from simultaneous measures of oxygen consumption and membrane potential, indicated a decrease in proton leak after 18 mo of CR, while only a trend toward a proton leak decrease was observed after 12 mo. Significant shifts in phosphorylation and substrate oxidation curves also occurred with CR; however, these changes occurred in concert with the proton leak changes. Metabolic control analysis indicated no difference in the overall pattern of control of the oxidative phosphorylation system between control and CR animals. At 12 mo, no significant differences were observed between groups for H2O2 production or markers of oxidative stress. However, at 18 mo, protein carbonyl content was lower in CR animals, as was H2O2 production when mitochondria were respiring on either succinate alone or pyruvate plus malate in the presence of rotenone. These results indicate that long-term CR lowers mitochondrial proton leak and H2O2 production, and this is consistent with the idea that CR may act by decreasing energy expenditure and ROS production.


Evaluation of the paraskeletal clamp system (Mennen plate) in treatment of mandibular fractures.
In this study, we used the relatively recent Paraskeletal clamp system (Mennen plate) to evaluate its effectiveness in the treatment of mandibular fractures. This study was conducted on eight patients with mandibular fractures selected from the out patient clinic, Oral Surgery Department, Faculty of Oral and Dental Medicine, Cairo University. Patient sample consisted of six males and two females, four patients were children below the age of 11 years, while the other four were edentulous above the age of 58. Each patient was thoroughly examined both clinically and radiographically. Data collected from each patient were recorded in a special examination chart. Under general anesthesia, the fracture was exposed using a submandibular approach. The fractured segments were reduced and fixed using micro-5 Mennen plates. All patients were followed up both clinically and radiographically for six months postoperatively. Results obtained from this study showed uneventful healing of all patients with no cases of non-union, bony infection or osteomyelitis as proven both clinically and radiographically. All the patients presented normal functioning occlusion and facial symmetry. No bony step deformities were detected.


Patterns of unit activity in the rostral thalamus of cats related to short-latency discrimination between different auditory stimuli.
Short-latency auditory-responsive units were found in the rostral thalamus of cats during performance of conditioned eyeblink responses (CRs) elicited discriminatively by a forward-paired, 70-dB-click conditioned stimulus (CS) as opposed to a backward-paired, 70-dB-hiss discriminative stimulus (DS). Discharges in response to the CS or DS were found in 57% of 138 units tested. Forty-one percent of units responding to the CS did so at latencies of less than 40 msec. After conditioning a discriminative CR to click CS, an increase in the ratio of CS-evoked activity to baseline activity was found relative to that before conditioning. This increase was attributable, in part, to a decrease in baseline activity and, in part, to an increase in the magnitude of response to the CS. These responses preceded early components of the electromyographically measured motor responses with latencies sufficient to contribute to initiation of the movement. After acquisition of the CR, the proportion of CS responsive units also increased. We conclude that this area of the thalamus, a region thought to support thalamocortical reverberatory activity, also functions to transmit short-latency auditory signals. Our evidence further suggests that this region may participate in the elicitation of conditioned responses by specific auditory stimuli and in discrimination between auditory stimuli of different significance.


Processed EEG monitoring for anesthesia and intensive care practice.
Individual response to sedatives and hypnotics is characterized by high variability and the identification of a personalized dose during anesthesia in the operating room and during sedation in the intensive care unit may have beneficial effects. Although the brain is the main target of general intravenous and inhaled anesthetic agents, electroencephalography (EEG) is not routinely utilized to explore cerebral response to sedation and anesthesia probably because EEG trace reading is complex and requires encephalographers' skills. Automated processing algorithms (processed EEG, pEEG) of raw EEG traces provide easy-to-use indices that can be utilized to optimize anesthetic management. A large number of high-quality studies and the recommendations of international scientific societies have confirmed the deleterious consequences of inadequate or excessively deep anesthesia (and sedation) level. In this context, anesthesia in the operating rooms and moderate/deep sedation in intensive care units driven by pEEG monitors could become a standard practice in the near future. The aim of the present review was to provide an overview of current knowledge and debate on available technologies for pEEG monitoring and their role in clinical practice for anesthesia and sedation.


[Amine oxidase activity and blood serotonin levels in cancer of the gastro-intestinal tract and lung].
Activity of amine oxidase less than using serotonin as a substrate greater than and content of serotonin were studied in blood of healthy persons and in patients with carcinoma of stomach, intestine and lung at the III-IV steps of the disease. In the patients with carcinoma of gastrointestinal tract the amine oxidase activity was decreased 2-fold and in the patients with carcinoma of lung it was decreased 4-fold as compared with controls. At the same time, content of serotonin was increased both in blood plasma and in blood platelets of the patients. The increase in content of serotonin depends on localization of the tumors.


Induced pluripotent stem cells derived from rabbits exhibit some characteristics of naïve pluripotency.
Not much is known about the molecular and functional features of pluripotent stem cells (PSCs) in rabbits. To address this, we derived and characterized 2 types of rabbit PSCs from the same breed of New Zealand White rabbits: 4 lines of embryonic stem cells (rbESCs), and 3 lines of induced PSCs (rbiPSCs) that were obtained by reprogramming adult skin fibroblasts. All cell lines required fibroblast growth factor 2 for their growth and proliferation. All rbESC lines showed molecular and functional properties typically associated with primed pluripotency. The cell cycle of rbESCs had a prolonged G1 phase and a DNA damage checkpoint before entry into the S phase, which are the 2 features typically associated with the somatic cell cycle. In contrast, the rbiPSC lines exhibited some characteristics of naïve pluripotency, including resistance to single-cell dissociation by trypsin, robust activity of the distal enhancer of the mouse Oct4 gene, and expression of naïve pluripotency-specific genes, as defined in rodents. According to gene expression profiles, rbiPSCs were closer to the rabbit inner cell mass (ICM) than rbESCs. Furthermore, rbiPSCs were capable of colonizing the ICM after aggregation with morulas. Therefore, we propose that rbiPSCs self-renew in an intermediate state between naïve and primed pluripotency, which represents a key step toward the generation of bona fide naïve PSC lines in rabbits.


The study of leukocyte phagocytic activity in the presence of herpetic infection and stroke.
Inrtoduction: Post-stroke complications are one of the urgent and insufficiently resolved problems. According to different literature data 23% to 65% of patients suffer from the post-stroke development of an infectious process. Herpes simplex virus type 1 and 2 can also be etiological factors of stroke development, however their reactivation is seldom mentioned in clinical observations. The development of immune suppression is considered to be the cause of these complications. The aim: The current study aims at determining post-stroke changes in leukocyte component of the immunity and in the presence of concomitant herpetic infection as well as at finding changes in phagocytosis parameters during antiviral treatment. Materials and methods: The experiments were carried out on mice of the Balb/с line. The animals were infected with the herpes simplex virus type I, and 30 days later hemorrhagic stroke was simulated by administering 0.1 ml of autoblood into the right hemisphere. Following the acute stroke some animals were given acyclovir, proteflazid or altabor. From the animals' blood leukocytes were obtained and phagocytic activity and production of reactive oxygen species of granulocytes and agranulocytes in relation to fluorescent E.coli bacteria were studied by flow cytometry. Results: The experiment revealed significant changes in the redistribution between two major types of leukocytes in mice with stroke (an increased number of agranulocytes by 19.9%) and decreased phagocytosis activity, in the animals infected with herpes simplex virus type І in particular. Ischemic brain damage had an immunosuppressive effect on blood leukocytes. For comparison a significant increase in phagocyte count in leukocytes was found in the case of viral infection. The use of drugs with antiviral effects did not affect the activity of granulocytes / agranulocytes. Conclusion: Stroke can be the cause of latent herpes virus infection reactivation and has essential negative effect on immune characteristics of leukocytes that remain unchanged with the use of antiviral agents.


Selectivity of the cimetidine-induced alterations in the renal handling of organic substrates in humans. Studies with anionic, cationic and zwitterionic drugs.
Cimetidine reduces the renal clearances of the organic cations procainamide and n-acetylprocainamide in humans and in vitro preparations by inhibition of renal cationic proximal tubular secretion. The aim of this study was to investigate in humans the selectivity of cimetidine in altering the renal handling of three different organic ions as drug substances: anion (cephalothin), cation (ranitidine) and zwitterion (cephalexin). The study was conducted in six healthy subjects who received the above drugs as single doses with and without chronic cimetidine administration. Cimetidine had no statistically significant (P greater than .05) effect on cephalothin disposition including renal clearance, but significantly reduced the renal clearance of ranitidine by over 40% between 4 and 12 hr after administration, with a concomitant increase in ranitidine plasma concentrations and elimination half-life prolongation. In addition, the renal clearance of cephalexin was reduced by cimetidine by 27% between 1 and 2 hr, but there was no change in cephalexin plasma concentrations and elimination half-life. These findings confirmed the hypothesis that cimetidine-mediated inhibition of renal drug clearance in humans is selective for a common cationic secretory transport mechanism in the proximal tubule of the kidney, rather than a nonspecific action on renal function.


Copper-catalyzed azide-alkyne cycloaddition (click chemistry)-based detection of global pathogen-host AMPylation on self-assembled human protein microarrays.
AMPylation (adenylylation) is a recently discovered mechanism employed by infectious bacteria to regulate host cell signaling. However, despite significant effort, only a few host targets have been identified, limiting our understanding of how these pathogens exploit this mechanism to control host cells. Accordingly, we developed a novel nonradioactive AMPylation screening platform using high-density cell-free protein microarrays displaying human proteins produced by human translational machinery. We screened 10,000 unique human proteins with Vibrio parahaemolyticus VopS and Histophilus somni IbpAFic2, and identified many new AMPylation substrates. Two of these, Rac2, and Rac3, were confirmed in vivo as bona fide substrates during infection with Vibrio parahaemolyticus. We also mapped the site of AMPylation of a non-GTPase substrate, LyGDI, to threonine 51, in a region regulated by Src kinase, and demonstrated that AMPylation prevented its phosphorylation by Src. Our results greatly expanded the repertoire of potential host substrates for bacterial AMPylators, determined their recognition motif, and revealed the first pathogen-host interaction AMPylation network. This approach can be extended to identify novel substrates of AMPylators with different domains or in different species and readily adapted for other post-translational modifications.


Caregivers of hip fracture patients: The forgotten victims?
The burden that family and friends assume when caring for hip fracture patients can negatively impact the caregiver's quality of life, relationships, and the decision to place the patient in a care facility. The purpose of this study was to evaluate the burden of caregiving for intertrochanteric hip fractures to better counsel patients and caregivers in order to prevent delayed admission to a care facility. A retrospective analysis of a prospectively gathered elderly hip fracture database identified 29 patients and their caregivers with complete 6 month follow-up. Caregiver burden and depression scales were administered to the primary caregiver in the immediate perioperative period (baseline), at 3 month follow-up, and at 6 month follow-up. At each time point caregivers reported the effects of caregiving on their finances, work hours, relationships, and their willingness to admit the patient to a long-term care facility. At 6 month follow-up, <30% of caregivers reported negative effects on their finances, relationships, work hours, or intent to place the patient in care facility, while 77% endorsed cherishing their time spent as a caregiver. The number of caregivers with a high caregiver burden remained stable at 20% over the 6 month follow-up; these caregivers were more likely to have a depressed mood (p < 0.01), to consider placement of the patient into a long-term care facility (p < 0.01), and to have negatively affected finances (p = 0.03) and relationships (p < 0.01). High degrees of burden were experienced by 20% of caregivers of hip fracture patients. Caregivers with high caregiver burdens were more likely to consider placement of the patient into a long-term care facility. Risk factors for high caregiver burdens should be identified to optimize the quality of caregiving after discharge and to prevent delayed admission to a long-term care facility. Level IV, case series.


Activation of single lateral geniculate cells by stimulation of either optic nerve.
The lateral geniculate nucleus is organized in such a way that, initially at least, information from the one eye is almost exclusively segregated from that from the other eye. Single-unit recording, however, confirms the histological evidence that bilateral integration does take place. A small number of cells (< 8.5 percent) receive afferents directly from both optic nerves and are discharged by stimulating either nerve (direct interaction). More common is delayed interaction, where the cells are discharged independently by either optic nerve but only after a relatively long latency. Indirect interaction effects also occur.


Combining perio-restorative protocols to maximize function.
This article describes a team approach for periodontal and restorative treatment intended to produce a predictable, biologically sound outcome that preserves more supporting bone and restores carious and broken down teeth. The goal of periodontal treatment, when performed in conjunction with restorative dentistry, is to provide restorative dentists with a high percentage of tooth structure that allows for a supragingival margin. An equally important goal is to ensure that an adequate thickness of connective tissue exists to create an environment more resistant to trauma and inflammation. The team approach consists of a restorative phase and a surgical phase. The restorative phase involves preparation with complete caries removal, adhesive core buildups, and provisionalization. The surgical phase involves biologic shaping of the roots and judicious osseous resection. Case studies are used to demonstrate the team approach.


A new approach for seasonal pattern: is it related to bipolarity dimension? Findings from an Italian multicenter study.
The aims of this study were to assess the impact of seasonal pattern on several clinical dimensions in inpatients with a current major depressive episode and to evaluate clinical differences between unipolar and bipolar depression according to seasonal pattern. Study participants were 300 patients affected by major depressive disorder (MDD) or bipolar disorder (BD) currently experiencing a major depressive episode (MDE) and were recruited at three University Medical Centres in Italy. All study subjects completed several evaluation scales for depressive and hypomanic symptoms, quality of life and functioning, impulsiveness, and seasonal pattern. Several differences between BD with and without seasonal pattern, MDD with and without seasonal pattern but in particular between BD and MDD with seasonal pattern were found. Patients with MDE with seasonal pattern had more frequently received a longitudinal diagnosis of BD. A large number of patients with BD and seasonal pattern, but also a considerable number of patients with MDD and seasonal pattern, endorsed manic items during a current MDE. Seasonal pattern should be associated with a concept of bipolarity in mood disorders and not only related to bipolar disorder. A correct identification of seasonal patterns may lead to the implementation of personalised pharmacological treatment approaches.KEY POINTSHigh prevalence of mixed features in mood disorders with seasonal pattern, supporting the need for a dimensional approach to major depressive disorder and bipolar disorder.Significant percentage of patients with a primary diagnosis of major depressive disorder had seasonal pattern.Significant percentage of patients with a primary diagnosis of major depressive disorder reported (hypo)manic symptomatology.


Reproductive health for refugees by refugees in Guinea III: maternal health.
Maternal mortality can be particularly high in conflict and chronic emergency settings, partly due to inaccessible maternal care. This paper examines associations of refugee-led health education, formal education, age, and parity on maternal knowledge, attitudes, and practices among reproductive-age women in refugee camps in Guinea. Data comes from a 1999 cross-sectional survey of 444 female refugees in 23 camps. Associations of reported maternal health outcomes with exposure to health education (exposed versus unexposed), formal education (none versus some), age (adolescent versus adult), or parity (nulliparous, parous, grand multiparous), were analysed using logistic regression. No significant differences were found in maternal knowledge or attitudes. Virtually all respondents said pregnant women should attend antenatal care and knew the importance of tetanus vaccination. Most recognised abdominal pain (75%) and headaches (24%) as maternal danger signs and recommended facility attendance for danger signs. Most had last delivered at a facility (67%), mainly for safety reasons (99%). Higher odds of facility delivery were found for those exposed to RHG health education (adjusted odds ratio 2.03, 95%CI 1.23-3.01), formally educated (adjusted OR 1.93, 95%CI 1.05-3.92), or grand multipara (adjusted OR 2.13, 95%CI 1.21-3.75). Main reasons for delivering at home were distance to a facility (94%) and privacy (55%). Refugee-led maternal health education appeared to increase facility delivery for these refugee women. Improved knowledge of danger signs and the importance of skilled birth attendance, while vital, may be less important in chronic emergency settings than improving facility access where quality of care is acceptable.


Does posttreatment thymoquinone reverse high-dose atorvastatin-induced hepatic oxidative injury in rats?
Atorvastatin (ATO) was commonly used to lower blood cholesterol, but it caused harmful effects to organs, including the liver. Thymoquinone (TQ), a prominent constituent of Nigella sativa, has antioxidant, antiinflammatory, antiapoptotic, antimicrobial, and anticancer activity. The current study investigated the mechanism of ATO-induced hepatotoxicity, whether posttreatment TQ could reverse ATO-induced hepatic injury, and the mechanism of action of TQ as a hepatoprotective agent. Forty adult male Sprague Dawley rats were divided into four equal groups: control, TQ-treated, ATO-treated, and combined ATO/TQ-treated. Rats were treated for 8 weeks and 10 days and euthanized by cervical dislocation 3 days after the last treatment. Blood samples and livers were tested for liver enzymes, oxidative stress, and apoptosis markers and used for histopathological and ultrastructural examination. The ATO-treated group showed an increase in liver enzymes, decreases in reduced glutathione and catalase, and increases in the malondialdehyde lipid peroxidation marker, protein carbonylation, and caspase 3 activity. Posttreatment TQ in the ATO/TQ-treated group seemed to reverse these changes. Histopathological and ultrastructural examination supported these data. Results from the current study suggested that posttreatment TQ may reverse oxidative stress injury in rat liver produced by ATO, suggesting a potential clinical application of using TQ to prevent ATO-induced hepatic injury.


Prognostic factors in early-stage ovarian cancer.
The purpose of this study was to identify the main prognostic factors in patients with early-stage epithelial ovarian cancer. Data were extracted from 222 patients with initial stage (I-IIA) invasive epithelial ovarian cancer treated with primary surgery followed or not followed by adjuvant therapy, from 1 January 1980 to 31 December 2008, at the Division of Obstetrics and Gynecology, Spedali Civili, Brescia, Italy; the median follow-up was 79 months (SD ± 35,945, range 20-250 months). The negative prognostic factors that were statistically significant (p<0.050) in univariate analysis were grade 2, 3, and X (clear cell in our study); stage IB, IC, IIA; positive peritoneal cytology, age equal to/greater than 54; dense adhesions; capsule rupture (pre-operative or intra-operative) and endometrioid histotype (only for disease-free survival (DFS)). Positive cytology was strongly associated with peritoneal relapses, while adhesions were associated with pelvic relapses. A positive prognosis was associated with the mucinous histotype. Conservative treatment had been carried out in 52% of patients under 40 years of age, and we detected only two relapses and three completions of surgery after a few weeks among 31 women in total. Our study indicated a possible execution in patients with patients with cancer stage IA G1-G2 (p=0.030) or IC G1 (p=0.050), provided well staged. Adjuvant chemotherapy improved the survival of cancers that were not IA G1. The positive prognostic role of taxanes must be emphasised, when used in combination with platino.


Osseointegrated implants for auricular defects: operative techniques and complication management.
Auricular defects are challenging to reconstruct with native tissue. We describe operative techniques and complication management for patients undergoing osseointegrated implants for auriculectomy defects and microtia. Tertiary referral center. All patients at Duke University Medical Center with auricular defects treated with osseointegrated implants for prosthetic (OIP) auricles from January 1, 2010, until September 16, 2013. Osseointegrated implantation for auricular defects. Description of operative techniques, complications, and complication management. Sixteen patients met inclusion criteria. Five patients had microtia and atresia. Two of these patients had bilateral microtia and atresia and underwent bilateral simultaneous implantation of both OIP and osseointegrated hearing implants (OHIs). Two other microtia/atresia patients underwent simultaneous unilateral OIP and OHI. Eleven patients had unilateral defects from either trauma or skin cancer resection. Three patients received adjuvant radiation before implantation. Complications included tissue overgrowth requiring revision surgery (two patients), inadequate bone stock requiring split calvarial bone graft and later implantation, loss of implant secondary to osteoradionecrosis requiring hyperbaric oxygen therapy, and skin infection requiring antibiotic therapy. Reconstruction of auriculectomy defects and microtia is difficult to accomplish using native tissue. Complications are common, and these complications can have devastating consequences on the final result. Osseointegrated implantation offers an outstanding alternative for reconstructing these defects. We describe our multidisciplinary team approach, examine operative techniques, and focus on the unique challenges of simultaneous and bilateral simultaneous OIP and OHI implantation.


Genome-Wide DNA Methylation Enhances Stemness in the Mechanical Selection of Tumor-Repopulating Cells.
DNA methylation plays essential roles in tumor occurrence and stemness maintenance. Tumor-repopulating cells (TRCs) are cancer stem cell (CSC)-like cells with highly tumorigenic and self-renewing abilities, which were selected from tumor cells in soft three-dimensional (3D) fibrin gels. Here, we presented a genome-wide map of methylated cytosines for time-series samples in TRC selection, in a 3D culture using whole-genome bisulfite sequencing (WGBS). A comparative analysis revealed that the methylation degrees of many differentially methylated genes (DMGs) were increased by the mechanical environment and changed from 2D rigid to 3D soft. DMGs were significantly enriched in stemness-related terms. In 1-day, TRCs had the highest non-CG methylation rate indicating its strong stemness. We found that genes with continuously increasing or decreasing methylation like CREB5/ADAMTS6/LMX1A may also affect the TRC screening process. Furthermore, results showed that stage-specific/common CSCs markers were biased toward changing their methylation in non-CG (CHG and CHH, where H corresponds to A, T, or C) methylation and enriched in gene body region. WGBS provides DNA methylome in TRC screening. It was confirmed that non-CG DNA methylation plays an important role in TRC selection, which indicates that it is more sensitive to mechanical microenvironments and affects TRCs by regulating the expression of stemness genes in tumor cells.


Positive experience of intraperitoneal chemotherapy followed by intravenous chemotherapy in heavily pretreated patients with suboptimal residual ovarian cancer and primary peritoneal cancer.
To assess feasibility and toxicity of intraperitoneal administration of cisplatin and paclitaxel, followed by intravenous chemotherapy in pretreated patients with suboptimal ovarian cancer (residuum >1 cm) or primary peritoneal tumor, and suffering from ascites and/or intestinal obstruction. Fourteen relapsed ovarian cancer patients, 5 of whom were platinum sensitive (platinum-free interval >6 mo), 7 platinum-resistant (platinum-free interval <6 mo), and 2 platinum-refractory, received one cycle of intraperitoneal cisplatin, 100 mg/m2 on day 1, and two cycles of intraperitoneal paclitaxel, 120 mg/m2 on days 8 and 14. Intravenous chemotherapy was administrated 4 weeks following the last intraperitoneal paclitaxel instillation. Blood and peritoneal fluid samples were harvested at 0, 1, 4 and 24 h after ending paclitaxel delivery to guarantee proper tumor exposure and patient safety. Intraperitoneal cisplatin determined 6 cases of vomiting grade 1-2 (40% of the morbidity). Intraperitoneal paclitaxel was associated with 6 events of grade 1-2 abdominal pain; the only grade 4 toxicity was one case of neutropenia and one of mucositis. Ascites decreased in 11 patients: the median time to first need for paracentesis was 5 months, compared to a median baseline paracentesis of 4 weeks. Three intestinal normalizations were obtained. The median overall survival was 10 months for our cohort of patients. Intraperitoneal paclitaxel clearance was significantly higher in patients with suboptimal tumor and symptomatic disease than in patients with smaller residual masses and without ascites (P = 0.004). Intraperitoneal treatment was feasible, and enhanced response to the following intravenous chemotherapy was seen in these patients.


Treatment of psoriasis with anti-TNF drugs during pregnancy: case report and review of the literature.
Published experiences of TNF-alpha inhibition during pregnancy consist of a limited number of case reports, series and ongoing registry data in patients with arthritis and inflammatory bowel disease. A 28-year-old woman - with psoriasis vulgaris since she was 8 years of age and generalized pustular psoriasis during her first pregnancy (partially controlled with ciclosporin, oral prednisone and topical corticosteroids, when lupus anticoagulant was detected at another hospital) - presented 4 months after delivery with severe psoriasis (PASI = 15.4) that did not respond to ciclosporin (3 mg/kg/day). Ten days after the first infusion of infliximab (5 mg/kg), when the patient became aware that she was pregnant again, there was PASI75 response, and the patient wished to continue this treatment after being fully informed. Complete blanching was achieved by week 6 of treatment, and was maintained thereafter until the moment of writing (19 months after the start of treatment). She gave birth by caesarean delivery to a healthy female baby, who was breastfed for 1 month and has developed normally. The current report extends the available evidence on successful infliximab treatment in pregnant women, with the first case of a patient with psoriasis who presented impetigo herpetiformis during her previous pregnancy. No detectable adverse effects were detected in the neonate, despite potential exposure to infliximab throughout gestation and breastfeeding. Even though absolute safety is difficult to prove, available data suggest that women who become pregnant while taking infliximab or other anti-TNFalpha agents can be reassured regarding the continuation of pregnancy.


Quantifying the evidence for ecological synergies.
There is increasing concern that multiple drivers of ecological change will interact synergistically to accelerate biodiversity loss. However, the prevalence and magnitude of these interactions remain one of the largest uncertainties in projections of future ecological change. We address this uncertainty by performing a meta-analysis of 112 published factorial experiments that evaluated the impacts of multiple stressors on animal mortality in freshwater, marine and terrestrial communities. We found that, on average, mortalities from the combined action of two stressors were not synergistic and this result was consistent across studies investigating different stressors, study organisms and life-history stages. Furthermore, only one-third of relevant experiments displayed truly synergistic effects, which does not support the prevailing ecological paradigm that synergies are rampant. However, in more than three-quarters of relevant experiments, the outcome of multiple stressor interactions was non-additive (i.e. synergies or antagonisms), suggesting that ecological surprises may be more common than simple additive effects.


Chemical, mechanical and morphological properties of hypomineralized enamel of permanent first molars.
The microstructure of hypomineralized enamel in permanent teeth has been described in several studies as less distinct prism sheaths and disorganized enamel with lack of organization of the enamel crystals. The mechanical properties, hardness and modulus of elasticity of the hypomineralized enamel have lower values compared with normal. The aim of this study was to examine normal and hypomineralized enamel using scanning electron microscopy (SEM), hardness measurements and X-ray microanalysis (XRMA). Four extracted hypomineralized permanent first molars, sectioned and cut in half, were analyzed with SEM, XRMA and hardness measurements. An inverse relation was found between the micro hardness and the Ca:C ratio in hypomineralized and normal enamel. The acid-etched hypomineralized enamel appeared on SEM to be covered with a structureless layer and the prisms appeared disorganized, with thick prism sheaths and loosely packed crystallites. Furthermore, bacteria were found deep in porous hypomineralized enamel close to the enamel-dentin junction. Teeth diagnosed with molar incisor hypomineralization have significantly lower hardness values in the hypomineralized enamel compared with normal enamel. The hardness values vary according to the morphological and chemical properties.


Time after feeding and dietary arginine deficiency alter splanchnic and hepatic amino acid flux in rats.
The effect of an arginine-deficient diet containing 3.4% glutamate on net flux of amino acids across the portal-drained viscera and liver was studied in rats at 0, 1 or 2 h after a meal and compared with that in arginine-fed controls. Net portal-drained viscera flux for most amino acids was greater in the fed state compared with the postabsorptive state except for glycine and cystine, which did not change, and methionine, which declined. Net amino acid recovery in portal blood 2 h after feeding compared with amounts consumed was highest for alanine (17.3%); recovery of other amino acids ranged from 5.6 to 15.3%. No net portal-drained viscera recovery of consumed cystine was observed. For the branched-chain and aromatic amino acids, methionine, threonine, histidine and lysine, net hepatic uptake was nearly equal to net portal-drained viscera absorption (range 77-127% of portal-drained viscera flux). Correlation coefficients between net hepatic and portal-drained viscera fluxes for leucine, valine, isoleucine, methionine and phenylalanine were 0.84 to 0.93. Postabsorptive hepatic extraction for most amino acids was zero, but after a meal, ranged from 13.3 to 22.9% for the branched-chain and aromatic amino acids. Net hepatic production of ornithine and proline occurred in arginine-fed control rats. This value was near zero for ornithine in rats fed the arginine-deficient diet. Models of interorgan amino acid metabolism in the food-deprived and fed state are presented.


[Laughter therapy for chronic skeletal muscular pain].
The authors explain the effects introducing workshops for laughter therapy and relaxation to a unit dedicated to therapeutic education and functional rehabilitation; the authors test to see if the application of this therapy helps to decrease pain, to improve mobility and to reduce an altered emotional state, such as anxiety-depression, common among chronic pain patients.


CD4 dynamics over a 15 year-period among HIV controllers enrolled in the ANRS French observatory.
There are few large published studies of HIV controllers with long-term undetectable viral load (VL). We describe the characteristics and outcomes of 81 French HIV controllers. HIV controllers were defined as asymptomatic, antiretroviral-naïve persons infected ≥10 years previously, with HIV-RNA <400 copies/mL in >90% of plasma samples. All available CD4 and VL values were collected at enrolment. Mixed-effect linear models were used to analyze CD4 cell count slopes since diagnosis. HIV controllers represented 0.31% of all patients managed in French hospitals. Patients infected through intravenous drug use were overrepresented (31%) and homosexual men were underrepresented (26% of men) relative to the ANRS SEROCO cohort of subjects diagnosed during the same period. HIV controllers whose VL values were always below the detection limit of the assays were compared with those who had rare "blips" (<50% of VL values above the detection limit) or frequent blips (>50% of VL values above the detection limit). Estimated CD4 cell counts at HIV diagnosis were similar in the three groups. CD4 cell counts remained stable after HIV diagnosis in the "no blip" group, while they fell significantly in the two other groups (-0.26√CD4 and -0.28√CD4/mm(3)/year in the rare and frequent blip groups, respectively). No clinical, immunological or virological progression was observed in the no blip group, while 3 immunological and/or virological events and 4 cancers were observed in the blip subgroups. Viral blips in HIV controllers are associated with a significant decline in CD4 T cells and may be associated with an increased risk of pathological events, possibly owing to chronic inflammation/immune activation.


Occurrence, Source and Dietary Exposure of Toxic and Essential Elements in the Indian Food Basket.
In this study, representative urban and peri-urban Indian food baskets have been studied for the presence of toxic and essential elements. The concentration of target toxic and essential elements was used to estimate dietary intakes (EDIs) and health risks. Across all food matrices, toxic elements like Cd and Pb were dominant. The highest concentrations of the target elements were found in vegetables, with Cd, Pb, and Ni being beyond permissible limits of the Food and Agriculture Organization of the United Nations and the World Health organization (0.05 mg/kg, 0.1 mg/kg, and 1.5 mg/kg, respectively) in okra, spinach, and cauliflower. The sum of concentrations of the toxic elements (As, Ni, Hg, Cr, Cd, Pb) in vegetables had a range of 0.54-12.08 mg/kg, the highest sum was found in spinach (median 12.08 mg/kg), followed by okra (median 1.68 mg/kg). The EDI was observed for vegetables with a contribution as high as 92% for Cd. Dairy products were found with the highest loading for Ni with a dietary intake of 3.1 mg/kg/day for adults and twice as much for children. Carcinogenic risk for Ni was the highest and found above the threshold for all food categories, as was the case with As. Cumulative carcinogenic and non-carcinogenic risks were mostly contributed by milk and vegetables, in particular, spinach.


Self-reflection for Activist Engineering.
Many blame politicians, governments, and markets for the technically-driven problems the world faces (think war, climate change, surveillance, disinformation, and so on). But why is it that there are almost always engineers and corporations willing to design and build the technologies that cause those problems, many times in spite of knowing about the negative consequences of those technologies? I offer in this paper practical guidance on how to engage in activist engineering, the goal of which is to get engineers to step back from their work and be able to ask and have a conversation about the question, "What is the real problem, and does this problem 'require' an engineering solution?" Building on research in the history and philosophy of engineering, and engineering ethics and education, as well as current events-all of which highlight important issues of debate within engineering practice-I provide a list of questions that engineers can start with for self-reflection to better understand their motivations for doing engineering work, and to better understand the implications of their work. The questions relate to considerations engineers must make regarding the social, environmental, economic, and peace implications of their work, and relate to alternative and non-technical interventions to the problem at hand. I believe that each engineer should, in the end, be able to answer the questions: Why am I an engineer? For whose benefit do I work? What is the full measure of my moral and social responsibility?


Identification of exosite-targeting inhibitors of anthrax lethal factor by high-throughput screening.
Protease inhibitor discovery has focused almost exclusively on compounds that bind to the active site. Inhibitors targeting protease exosites, regions outside of the active site that influence catalysis, offer potential advantages of increased specificity but are difficult to systematically discover. Here, we describe an assay suitable for detecting exosite-targeting inhibitors of the metalloproteinase anthrax lethal factor (LF) based on cleavage of a full-length mitogen-activated protein kinase kinase (MKK) substrate. We used this assay to screen a small-molecule library and then subjected hits to a secondary screen to exclude compounds that efficiently blocked cleavage of a peptide substrate. We identified a compound that preferentially inhibited cleavage of MKKs compared with peptide substrates and could suppress LF-induced macrophage cytolysis. This approach should be generally applicable to the discovery of exosite-targeting inhibitors of many additional proteases.