Strength of predicted information content in the brain biases decision behavior.
Prediction-for-perception theories suggest that the brain predicts incoming stimuli to facilitate their categorization.1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17 However, it remains unknown what the information contents of these predictions are, which hinders mechanistic explanations. This is because typical approaches cast predictions as an underconstrained contrast between two categories18,19,20,21,22,23,24-e.g., faces versus cars, which could lead to predictions of features specific to faces or cars, or features from both categories. Here, to pinpoint the information contents of predictions and thus their mechanistic processing in the brain, we identified the features that enable two different categorical perceptions of the same stimuli. We then trained multivariate classifiers to discern, from dynamic MEG brain responses, the features tied to each perception. With an auditory cueing design, we reveal where, when, and how the brain reactivates visual category features (versus the typical category contrast) before the stimulus is shown. We demonstrate that the predictions of category features have a more direct influence (bias) on subsequent decision behavior in participants than the typical category contrast. Specifically, these predictions are more precisely localized in the brain (lateralized), are more specifically driven by the auditory cues, and their reactivation strength before a stimulus presentation exerts a greater bias on how the individual participant later categorizes this stimulus. By characterizing the specific information contents that the brain predicts and then processes, our findings provide new insights into the brain's mechanisms of prediction for perception.


Motor learning affects visual movement perception.
In the present study we investigated whether imitation of artificial movement trajectories of meaningless objects has an effect on how these trajectories are later perceptually processed within the human brain. During observation of a sequence of artificial object movements 10 participants (experimental group) actively imitated the trajectories during motor training and 10 participants (control group) solved a working memory task without motor training. The haemodynamic responses were recorded before and after the intervention while participants observed the movements and either had to detect colour changes of one of the objects (colour task, motor-irrelevant) or had to judge whether the movement pattern could be imitated with the hands (simulation judgement task, motor-relevant). The between-group comparison of the post-intervention haemodynamic responses revealed stronger activity for the motor training than for the control group during the simulation judgement task. This activity appeared in motor-related areas (supplementary motor area and inferior parietal lobe) and in the occipito-temporal area. During the colour task, the motor training group showed stronger activity in the occipital lobe. The control group did not reveal any stronger activity than the motor training group for either task. The results suggest that motor training has task-specific effects on neural processes that are involved in perception of movements. Furthermore, they indicate that motor-related areas are triggered by observed artificial object movements, but only if a motor-relevant task is pursued.


Spectral analysis of circadian rhythms in heart rate variability of dogs.
To determine characteristics of power spectral analysis of heart rate variability (HRV) during a 24-hour period in dogs and to evaluate the effects of vagal and sympathetic tone on HRV ANIMALS: 16 healthy adult Beagles. Power spectral analysis of HRV was conducted, using 24-hour ambulatory ECG recordings. Circadian rhythms were evaluated in terms of absolute units of low-frequency (LF) and high-frequency (HF) powers, their ratio (LF:HF), and their adjusted (normalized) units (LF[norm] and HF[norm]). Three or 4 dogs were used for simultaneous measurement of heart rate and respiratory waveform as well as to evaluate treatment (propranolol, atropine, or both) administered to cause blockade of the autonomic nervous system. Values for LF and HF powers, LF:HF, LF(norm), and HF(norm) had obvious rhythmicity in clinically normal dogs. The HF power of HRV in dogs was extremely high, compared with that of other species, and HF peaks corresponded to peaks obtained from respiratory waveforms. Blockade of the autonomic nervous system documented that HRV in dogs was mostly attributable to vagal activity. We determined characteristics of power spectral analysis of HRV in dogs, including circadian rhythm of the autonomic nervous system. Power spectral analysis of HRV may provide a useful noninvasive technique for assessing the effect of drugs on activity of the autonomic nervous system in dogs.


Assessing the Efficacy of Different Bead-Based Assays in Capturing Hepatitis E Virus.
Hepatitis E virus (HEV) generally causes acute liver infection in humans and its transmission could be waterborne, foodborne, bloodborne, or zoonotic. To date, there is no standard method for the detection of HEV from food and environmental samples. Herein, we explored the possibility of using magnetic beads for the capture and detection of HEV. For this purpose, we employed Dynabeads M-270 Epoxy magnetic beads, coated with different monoclonal antibodies (mAbs) against HEV capsid protein, and the Nanotrap Microbiome A Particle magnetic beads, which are coated with chemical affinity baits, to capture HEV-3 particles in suspension. Viral RNA was extracted by heat-shock or QIAamp viral RNA kit and subjected to quantification using digital-droplet RT-PCR (ddRT-PCR). We demonstrated that the mAb-coupled Dynabeads and the Nanotrap particles, both were able to successfully capture HEV-3. The latter, however had lower limit of detection (<140gc compared with <1400 gc) and significantly higher extraction efficiency in comparison to the mAb-coupled Dynabeads (41.1% vs 8.8%). We have also observed that viral RNA extraction by heat-shock is less efficient compared to using highly denaturing reagents in QIAmp viral RNA extraction kit. As such, magnetic beads have the potential to be used to capture HEV virions for research and surveillance purposes.


Magnetic-enhanced modulation transfer spectroscopy and laser locking for 87Rb repump transition.
Locking of a laser frequency to an atomic or molecular resonance line is a key technique in applications of laser spectroscopy and atomic metrology. Modulation transfer spectroscopy (MTS) provides an accurate and stable laser locking method which has been widely used. Normally, the frequency of the MTS signal would drift due to Zeeman shift of the atomic levels and rigorous shielding of stray magnetic field around the vapor cell is required for the accuracy and stability of laser locking. Here on the contrary, by applying a transverse bias magnetic field, we report for the first time observation of a magnetic-enhanced MTS signal on the transition of 87Rb D2-line Fg = 1→ Fe = 0 (close to the repump transition of Fg = 1→ Fe = 2), with signal to noise ratio larger than 100:1. The error signal is immune to the external magnetic fluctuation. Compared to the ordinary MTS scheme, it provides a robust and accurate laser locking approach with more stable long-term performance. This technique can be conveniently applied in areas of laser frequency stabilization, laser manipulation of atoms and precision measurement.


Androgen deprivation therapy complications.
Androgen deprivation therapy (ADT) is increasingly used to treat advanced prostate cancer and is also utilised as adjuvant or neo-adjuvant treatment for high-risk disease. The resulting suppression of endogenous testosterone production has deleterious effects on quality of life, including hot flushes, reduced mood and cognition and diminished sexual function. Cross-sectional and longitudinal studies show that ADT has adverse bone and cardio-metabolic effects. The rate of bone loss is accelerated, increasing the risk of osteoporosis and subsequent fracture. Fat mass is increased and lean mass reduced, and adverse effects on lipid levels and insulin resistance are observed, the latter increasing the risk of developing type 2 diabetes. ADT also appears to increase the risk of incident cardiovascular events, although whether it increases cardiovascular mortality is not certain from the observational evidence published to date. Until high-quality evidence is available to guide management, it is reasonable to consider men undergoing ADT to be at a higher risk of psychosexual dysfunction, osteoporotic fracture, diabetes and cardiovascular disease, especially when treated for extended periods of time and therefore subjected to profound and prolonged hypoandrogenism. Health professionals caring for men undergoing treatment for prostate cancer should be aware of the potential risks of ADT and ensure appropriate monitoring and clinical management.


Effects of Echium plantagineum L. bee pollen on basophil degranulation: relationship with metabolic profile.
This study aimed to evaluate the anti-allergic potential of Echium plantagineum L. bee pollen and to characterize its primary metabolites. The activity of E. plantagineum hydromethanolic extract, devoid of alkaloids, was tested against β-hexosaminidase release in rat basophilic leukemic cells (RBL-2H3). Two different stimuli were used: calcium ionophore A23187 and IgE/antigen. Lipoxygenase inhibitory activity was evaluated in a cell-free system using soybean lipoxygenase. Additionally, the extract was analysed by HPLC-UV for organic acids and by GC-IT/MS for fatty acids. In RBL-2H3 cells stimulated either with calcium ionophore or IgE/antigen, the hydromethanolic extract significantly decreased β-hexosaminidase release until the concentration of 2.08 mg/mL, without compromising cellular viability. No effect was found on lipoxygenase. Concerning extract composition, eight organic acids and five fatty acids were determined for the first time. Malonic acid (80%) and α-linolenic acid (27%) were the main compounds in each class. Overall, this study shows promising results, substantiating for the first time the utility of intake of E. plantagineum bee pollen to prevent allergy and ameliorate allergy symptoms, although a potentiation of an allergic response can occur, depending on the dose used.


Prenatal pet keeping and caregiver-reported attention deficit hyperactivity disorder through preadolescence in a United States birth cohort.
While the keeping of pets has been shown to protect against childhood allergic disease and obesity, less is known regarding potential associations of prenatal pet keeping and attention deficit hyperactivity disorder (ADHD). We sought to examine the associations between prenatal dog or cat keeping with caregiver-reported ADHD in preadolescents in the Wayne County Health, Environment, Allergy and Asthma Longitudinal Study (WHEALS) birth cohort (N = 1258). At an interview with the caregiver at child age 10-12 years, caregivers reported if the WHEALS child had ever been diagnosed with ADHD. Similarly, during an interview with the mother prenatally, pet keeping (defined as dog or cat kept inside ≥1 h/day) was ascertained. Logistic regression models were fit to examine the association of prenatal pet keeping (dog keeping and cat keeping, separately) with ADHD. A subset of 627 children were included in the analyses: 93 who had ADHD and 534 with neurotypical development. After accounting for confounders and loss to follow-up, maternal prenatal dog exposure was associated with 2.23 times (95% CI: 1.15, 4.31; p = 0.017) greater odds of ADHD among boys. Prenatal dog keeping was not statistically significantly associated with ADHD in girls (odds ratio = 0.27, 95% CI: 0.06, 1.12; p = 0.070). Prenatal cat keeping was not associated with ADHD. In boys, but not girls, maternal prenatal dog keeping was positively associated with ADHD. Further study to confirm these findings and to identify potential mechanisms of this association (e.g., modification of the gut microbiome, exposure to environmental toxicants or pet-related medications) is needed.


Age of onset of schizophrenia in siblings: a test of the contagion hypothesis.
The possibility that schizophrenia is horizontally transmitted has been assessed in an analysis of age of onset in 264 recorded pairs of siblings with the disease. Age of onset was found to be correlated between siblings, and there was a tendency for the disease to occur at an earlier age in the younger sibling. Three explanations for this finding are considered: horizontal transmission, early detection, and ascertainment bias. An analysis by date of birth differences between siblings gives results consistent with horizontal transmission, but analysis by order of onset of illness (which shows that the age shift is not seen in elder-sibling-ill-first pairs) indicates that ascertainment bias (which arises from a tendency to include an excess of early onsets in younger siblings) is a more cogent explanation of the age shift. Although horizontal transmission is not altogether eliminated, the data suggest that age of onset is determined by genetic or prenatal factors rather than environmental precipitants in postnatal life. The retrovirus/transposon hypothesis (Crow, 1984) can accommodate the findings more readily than the gene-virus interaction hypothesis (Crow, 1983).


Left-handed Z-DNA in bands of acid-fixed polytene chromosomes.
Antibodies to DNA in the left-handed (Z) conformation bind to acid-fixed polytene chromosomes of both Chironomus thummi and Drosophila melanogaster, as shown by direct and indirect immunofluorescence. Comparison of the phase-contrast, immunofluorescence, and DNA staining patterns shows a predominant localization of the antibody to the regions of high contrast and DNA density, the bands. The immunofluorescence is completely abolished by competition with polynucleotides in the Z conformation but not by those in the B form. DNase but not RNase treatment eliminates the antibody staining. Actinomycin D inhibits binding, whereas mithramycin has no effect. The highly reproducible immunofluorescence patterns obtained with the anti-Z-DNA antibodies demonstrate variations in fluorescence intensity between particular bands, which can be quantitated by laser scanning and photon counting techniques. The telomeric regions and DNA strands associated with end-to-end chromosome linkage and ectopic pairing are exceptionally bright. At saturation, average values of 1 IgG molecule per 3,000 base pairs and 1 per 15,000 base pairs are found in the intensely and weakly staining regions, respectively. An alternative statement is that the left-handed Z-DNA conformation is present at a frequency of 0.02-0.1%. The measured differences reflect variations in the local density of Z-DNA sites and not in the affinity for the specific antibody, which appears to be relatively constant throughout the chromosomes (Kd approximately equal to 10 nM). These observations taken together with results of biophysical studies on the properties of Z-DNA in solution suggest that regions of DNA in the left-handed conformation could be involved in higher-order structural organization of chromosomes and possibly in modulation of their functional state.


The Escherichia coli PriA helicase-double-stranded DNA complex: location of the strong DNA-binding subsite on the helicase domain of the protein and the affinity control by the two nucleotide-binding sites of the enzyme.
The Escherichia coli PriA helicase complex with the double-stranded DNA (dsDNA), the location of the strong DNA-binding subsite, and the effect of the nucleotide cofactors, bound to the strong and weak nucleotide-binding site of the enzyme on the dsDNA affinity, have been analyzed using the fluorescence titration, analytical ultracentrifugation, and photo-cross-linking techniques. The total site size of the PriA-dsDNA complex is only 5±1 bp, that is, dramatically lower than 20±3 nucleotides occluded in the enzyme-single-stranded DNA (ssDNA) complex. The helicase associates with the dsDNA using its strong ssDNA-binding subsite in an orientation very different from the complex with the ssDNA. The strong DNA-binding subsite of the enzyme is located on the helicase domain of the PriA protein. The dsDNA intrinsic affinity is considerably higher than the ssDNA affinity and the binding process is accompanied by a significant positive cooperativity. Association of cofactors with strong and weak nucleotide-binding sites of the protein profoundly affects the intrinsic affinity and the cooperativity, without affecting the stoichiometry. ATP analog binding to either site diminishes the intrinsic affinity but preserves the cooperativity. ADP binding to the strong site leads to a dramatic increase of the cooperativity and only slightly affects the affinity, while saturation of both sites with ADP strongly increases the affinity and eliminates the cooperativity. Thus, the coordinated action of both nucleotide-binding sites on the PriA-dsDNA interactions depends on the structure of the phosphate group. The significance of these results for the enzyme activities in recognizing primosome assembly sites or the ssDNA gaps is discussed.


[Ankylosing spondylarthritis and partial cauda equina syndrome. Apropos of 4 cases and review of the literature].
Four new cases of ankylosing spondylitis complicated by a cauda equina syndrome are reported. Similarly to the previous descriptions, the patients present with long-standing and severe spondylitis at the time when neurological symptoms, mainly radicular pain, develop. Computed tomography of the lumbar spine demonstrates in all cases typical laminar erosions and posterior arachnoid diverticula. Up to now, magnetic resonance imaging has rarely been performed in this particular pathology, though it is helpful in determining the anatomical relations and the nature of the lesions. Based on the previous publications, our study aims at describing the clinical and pathogenic aspects of the disease and defining the most useful diagnostic investigations and treatment choices. Therapeutic possibilities are often limited because of a late diagnosis. Better knowledge of this rare complication could lead to earlier recognition and more efficient therapy.


Anti-inflammatory Effects of Extracts of Sweet Basil (Ocimum basilicum L.) on a Co-culture of 3T3-L1 Adipocytes and RAW264.7 Macrophages.
Obesity, a lifestyle disease resulting from excessive caloric intake and insufficient physical activity, results in a state of chronic inflammation. A food ingredient that suppresses chronic inflammation could help prevent associated diseases. Sweet basil (Ocimum basilicum L.) is a herb from the Lamiaceae family with some reported anti-inflammatory effects. Via this in vitro study, we aimed to investigate whether sweet basil exerts anti-inflammatory effects in obese patients. Fresh sweet basil leaves were freeze-dried and powered. After that, this was extracted with 80% methanol. After 3T3-L1 adipocytes were cultured with sweet basil extracts at final concentrations of either 5 or 25 μg/mL for 24h, RAW264.7 macrophages were seeded onto this adipocytes and co-cultured for 12h. We determined the effects of sweet basil extracts on inflammatory cytokine expression by real-time PCR or western blotting. Sweet basil extracts reduced the expression of inflammatory cytokine mRNA induced by co-culture, including that of IL-6 (Il6), IL-1β (Il1b), TNF-α (Tnf), and CCL2 (Ccl2). In addition, sweet basil extracts suppressed the mRNA expression of NF-κB (Nfκb1), a transcription factor of inflammatory cytokines. In an investigation of costimulatory CD137 (Tnfrsf9)/CD137L inflammatory signaling, a member of the TNF super-family, sweet basil extracts inhibited Tnfrsf9 expression induced by the co-culture. Therefore, the results of this study indicated that sweet basil extracts have an anti-inflammatory effect against adipocyte-induced inflammation, possibly through suppression of Tnfrsf9 expression.


Risk factors for in-hospital nonhemorrhagic stroke in patients with acute myocardial infarction treated with thrombolysis: results from GUSTO-I.
Nonhemorrhagic stroke occurs in 0.1% to 1.3% of patients with acute myocardial infarction who are treated with thrombolysis, with substantial associated mortality and morbidity. Little is known about the risk factors for its occurrence. We studied the 247 patients with nonhemorrhagic stroke who were randomly assigned to one of four thrombolytic regimens within 6 hours of symptom onset in the GUSTO-I trial. We assessed the univariable and multivariable baseline risk factors for nonhemorrhagic stroke and created a scoring nomogram from the baseline multivariable modeling. We used time-dependent Cox modeling to determine multivariable in-hospital predictors of nonhemorrhagic stroke. Baseline and in-hospital predictors were then combined to determine the overall predictors of nonhemorrhagic stroke. Of the 247 patients, 42 (17%) died and another 98 (40%) were disabled by 30-day follow-up. Older age was the most important baseline clinical predictor of nonhemorrhagic stroke, followed by higher heart rate, history of stroke or transient ischemic attack, diabetes, previous angina, and history of hypertension. These factors remained statistically significant predictors in the combined model, along with worse Killip class, coronary angiography, bypass surgery, and atrial fibrillation/flutter. Nonhemorrhagic stroke is a serious event in patients with acute myocardial infarction who are treated with thrombolytic, antithrombin, and antiplatelet therapy. We developed a simple nomogram that can predict the risk of nonhemorrhagic stroke on the basis of baseline clinical characteristics. Prophylactic anticoagulation may be an important treatment strategy for patients with high probability for nonhemorrhagic stroke, but further study is needed.


Postimplant biological aortic prosthesis degeneration: challenges in transcatheter valve implants.
Surgical aortic valve replacement (SAVR) is highly effective and can be achieved with relatively low risk in patients with severe aortic stenosis. Bioprostheses have been used most frequently during the past 60 years. However, the function of biological valves usually declines after 10-15 years from implant when structural valve degeneration occurs often mandating a reoperation once valve dysfunction becomes haemodynamically significant. Known for many years by surgeons and cardiologists taking care of patients with SAVR, the issue of postimplant structural valve degeneration has been recently highlighted also in patients with transcatheter aortic valve implant (TAVI). There is growing concern that TAVI valves exhibit structural valve degeneration due to inherent challenges of the deployment mode. The impact on postimplant degeneration of TAVI valves compared to SAVR has still to be understood and defined. Based on the ongoing process of expanding TAVI indications, several potential shortcomings and caveats, learned during the last 60 years of SAVR experience, should be taken into consideration to refine this technique.


Predictors of patient referrals by primary care residents to specialty care clinics.
Physician referral patterns significantly impact costs, quality of care, and access to the health system. This paper examines factors predictive of patient referrals to specialists by primary care residents. New adult patients (n=509) were randomly assigned to primary care residents at a university medical center. Patient referrals to specialists were monitored for 1 year of care. Self-reported patient health status, sociodemographic information, number of primary care visits, and physician practice style behaviors were incorporated into statistical analyses predicting specialty referrals. Patients who were referred to specialty care were significantly older, had poorer physical health, and saw their primary care physicians more often than patients who were not referred. Patients were most frequently referred to surgical specialty clinics. After controlling for physical health status, gender, and age, more frequent visits to a primary care resident physician who had a technically oriented style of care was associated with a greater total number of specialty clinic referrals. Patient variables, as well as physician practice style, have an important impact on the specialty referral process. Although the appropriateness of referrals was not evaluated, these findings have implications for health care delivery.


Evaluation of the potential antidepressant effects of soybean isoflavones.
The aim of the study was to determine whether isoflavones affect depressive symptoms in women. Literature searches were conducted to identify clinical and epidemiologic studies that evaluated the impact of soy intake and isoflavone exposure on depressive symptoms. References from identified studies were also evaluated to identify eligible studies. Only limited epidemiologic research has evaluated the impact of soy or isoflavone intake on depression although several studies from China and Japan did find soy product intake was inversely related to risk of depression. Often times, soy was, however, evaluated only as a component of a summative dietary pattern (eg, a "Japanese" or "Healthy" diet). Of the 20 intervention studies identified, roughly half found statistically significant reductions in depressive symptoms in response to isoflavones although several had design weakness. Of those studies reporting a lack of antidepressant effects of isoflavones, design limitations likely contributed to the lack of efficacy. In all but two trials, assessment of depression was, however, a secondary outcome. It is notable that both trials in which depression was a primary outcome found isoflavones significantly improved symptoms. Although the data are inconsistent and limited, the clinical and epidemiologic evidence suggests that isoflavones may offer a safe, well-tolerated option for management of depression. Furthermore, the intervention doses used in the clinical studies fall well within the dietary range. The extant literature reveals key design features for future studies, which based upon the results of this review, are clearly warranted.


Development and validation of a three-dimensional in vitro model for uterine leiomyoma and patient-matched myometrium.
To develop and validate a three-dimensional (3D) culture system of leiomyoma and myometrial cells. In vitro study of immortalized cultures of patient-matched leiomyoma and myometrium. University hospital. Women undergoing hysterectomy for symptomatic leiomyomas. Immortalized cell cultures, quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), cytoimmunofluorescence, and Western blot analysis. Morphologic features; expression of COL1A1, versican, fibronectin, dermatopontin, and transforming growth factor β3 (TGF-β3); and integrin-mediated 3D structural formation. Cells in 3D culture maintained spindle morphology. There was elevated expression of collagen 1A1 (6.66 ± 1.5), total versican (4.78 ± 0.5), fibronectin (3.94 ± 0.3), and TGF-β3 (2.21 ± 0.1) as was seen in progenitor tissue. Dermatopontin gene was down-regulated (0.29 ± 0.1), also similar to values in the surgical tissue sample. Myometrial cells in 3D culture responded to TGF-β3 with increased gene expression of collagen 1A1, fibronectin, and versican, and decreased expression of dermatopontin gene recapitulating the leiomyoma phenotype. Integrin-β1-inhibiting antibody disrupted the cell-extracellular matrix (ECM) communication and induced apoptosis. Three-dimensional 3D leiomyoma cell cultures maintain the molecular phenotype of progenitor tissue, produce ECM, and interact with the ECM directly. This model system allows for assessment of the mechanism of aberrant ECM formation as well as the effectiveness of various potential therapies.


Aerobic bacterial conjunctival flora in diabetic patients.
To study the aerobic conjunctival flora of diabetic patients and its relation to the presence and level of diabetic retinopathy and the duration of the disease. One hundred three patients from the diabetic retinopathy screening program of the Federal University of São Paulo with no evidence of ocular surface disease were included. The diabetic patient cohort was compared with 60 nondiabetic subjects. All patients underwent slit-lamp evaluation, conjunctival scrapings, and indirect ophthalmoscopy. The frequency of positive conjunctival cultures was significantly higher in the diabetic group (94.18%) than in the nondiabetic group (73.33%). Among diabetic patients, a significantly higher frequency of positive cultures was detected in those with diabetic retinopathy than in those without retinopathy. Neither the duration of the diabetes nor the hypoglycemic therapy correlated with the culture results. Coagulase-negative Staphylococcus was the most common microorganism isolated, and its identification was more frequent in patients with retinopathy than in those without diabetic retinopathy. Diabetic patients have a significantly higher number of positive conjunctival cultures. The presence of diabetic retinopathy was correlated with an increase in positive cultures and a higher proportion of coagulase-negative Staphylococcus.


Additive effect on hot carrier cooling in a hybrid perovskite.
Slowing hot carrier (HC) cooling in lead halide perovskites is important to further improve the efficiency of perovskite solar cells (PSCs). Herein, we found that HC cooling can be efficiently prolonged by incorporating an organic small molecule (TDGA) into the perovskite film as an additive through transient absorption spectroscopy measurements, which is conducive to the extraction of the HC energies by the carrier transport layers and reduces charge carrier recombination, consequently improving the efficiency of the TDGA-doped device.


A retrospective study of buprenorphine and norbuprenorphine in human hair after multiple doses.
The analysis of hair has been proposed as a tool for monitoring drug-treatment compliance. This study was performed to determine if buprenorphine (BPR) and norbuprenorphine (NBPR) could be detected in human hair after controlled administration of drug and to determine if segmental analysis of hair was an accurate record of the dosing history. Subjects with dark hair (six males, six females) received 8 mg sublingual BPR for a maximum of 180 days. Single hair collections were made once after BPR treatment and stored at -20 degrees C until analysis. Hair was aligned scalp-end to tip and then segmented in 3-cm sections. For this study, it was assumed that the mean hair growth rate was 1.0 cm/month. Deuterated internal standard was added to hair segments (2-20 mg of hair) and digested overnight at room temperature with 1 N NaOH. Specimens were extracted with a liquid-liquid procedure and analyzed by liquid chromatography-tandem mass spectrometry. The limits of quantitation for BPR and NBPR were 3 pg/mg and 5 pg/mg, respectively, for 20 mg of hair. BPR and NBPR concentrations were highest for all subjects in hair segments estimated to correspond to the subject's period of drug treatment. With one exception, NBPR was present in higher concentrations in hair than was the parent compound. BPR concentrations in hair segments ranged from 3.1 pg/mg to 123.8 pg/mg. NBPR concentrations ranged from 4.8 pg/mg to 1517.8 pg/mg. In one subject, BPR and NBPR were not detected in any hair segment. In some subjects, BPR and NBPR were detected in hair segments that did not correspond to the period of drug treatment, suggesting that drug movement may have occurred by diffusion in sweat and other mechanisms. The data from this study also indicate that there is a high degree of intersubject variability in measured concentration of BPR and NBPR in hair segments, even when subjects receive the same dose for an equivalent number of treatment days. Future prospective studies involving controlled drug administration will be necessary to evaluate whether hair can serve as an accurate historical record of variations in the pattern of drug use.


Conflicting perceptions on participation between citizens and members of local government.
There is a growing consensus among citizens and members of local government that citizen participation is desirable for local government. However in practice, there are differing perceptions between them regarding the level and extent of citizen participation. As citizen participation is a multi faceted concept, its meaning is construed differently by both the members of local government and the citizen groups. This paper attempts to describe the conflicts that arise from participation. The paper is based on the study of the process of citizen participation in local government carried out in Torbat-Heydarieh city, Iran. A qualitative research method is seen as the most suitable approach of collecting and analyzing the data. The method employed for data collection in this research is in-depth interviews. In-depth interviews were conducted to gauge the existence of conflicts regarding participation. The findings reveal four areas that give rise to conflicts. This study also attempts to highlight two different views regarding citizen participation; the people-centered view and authority-centered view.


Antimicrobial resistance surveillance of doripenem in China.
To investigate the antibacterial resistance to doripenem in China and to understand the distribution trends of resistant bacteria. All the clinical isolates were collected from hospitals and the susceptibility tests were performed using the agar dilution method recommended by the Clinical Laboratory Standards Institute (CLSI) central laboratory. The susceptibility of the isolates to antimicrobial agents was determined using the CLSI (2014) or European Committee on Antimicrobial Susceptibility Testing (EUCAST) (2013) guidelines. A total of 4047 pathogenic strains were isolated from 18 tertiary hospitals in 18 cities across China between July 2011 and June 2012. MIC results indicated that the vast majority of Enterobacteriaceae maintained high susceptibility to doripenem, with a lower resistance rate (1.9%) than that observed for other drugs tested. In the case of non-fermenting Gram-negative isolates, the resistance rate of Pseudomonas aeruginosa was 16.2%, which was less than that of imipenem and meropenem, and the Acinetobacter baumannii doripenem resistance rate was 67.4%. Doripenem also showed good in vitro activity against other the bacteria tested. This study suggests that the gradual increase in carbapenem nonsusceptible Enterobacteriaceae should be monitored carefully alongside the increasing multidrug-resistant and extensively drug-resistant A. baumannii.


Inflammation-induced GluA1 trafficking and membrane insertion of Ca2+ permeable AMPA receptors in dorsal horn neurons is dependent on spinal tumor necrosis factor, PI3 kinase and protein kinase A.
Peripheral inflammation induces sensitization of nociceptive spinal cord neurons. Both spinal tumor necrosis factor (TNF) and neuronal membrane insertion of Ca2+ permeable AMPA receptor (AMPAr) contribute to spinal sensitization and resultant pain behavior, molecular mechanisms connecting these two events have not been studied in detail. Intrathecal (i.t.) injection of TNF-blockers attenuated paw carrageenan-induced mechanical and thermal hypersensitivity. Levels of GluA1 and GluA4 from dorsal spinal membrane fractions increased in carrageenan-injected rats compared to controls. In the same tissue, GluA2 levels were not altered. Inflammation-induced increases in membrane GluA1 were prevented by i.t. pre-treatment with antagonists to TNF, PI3K, PKA and NMDA. Interestingly, administration of TNF or PI3K inhibitors followed by carrageenan caused a marked reduction in plasma membrane GluA2 levels, despite the fact that membrane GluA2 levels were stable following inhibitor administration in the absence of carrageenan. TNF pre-incubation induced increased numbers of Co2+ labeled dorsal horn neurons, indicating more neurons with Ca2+ permeable AMPAr. In parallel to Western blot results, this increase was blocked by antagonism of PI3K and PKA. In addition, spinal slices from GluA1 transgenic mice, which had a single alanine replacement at GluA1 ser 845 or ser 831 that prevented phosphorylation, were resistant to TNF-induced increases in Co2+ labeling. However, behavioral responses following intraplantar carrageenan and formalin in the mutant mice were no different from littermate controls, suggesting a more complex regulation of nociception. Co-localization of GluA1, GluA2 and GluA4 with synaptophysin on identified spinoparabrachial neurons and their relative ratios were used to assess inflammation-induced trafficking of AMPAr to synapses. Inflammation induced an increase in synaptic GluA1, but not GluA2. Although total GluA4 also increased with inflammation, co-localization of GluA4 with synaptophysin, fell short of significance. Taken together these data suggest that peripheral inflammation induces a PI3K and PKA dependent TNFR1 activated pathway that culminates with trafficking of calcium permeable AMPAr into synapses of nociceptive dorsal horn projection neurons.


Antiangiogenic photodynamic therapy (PDT) by using long-circulating liposomes modified with peptide specific to angiogenic vessels.
For the improvement of therapeutic efficacy in photodynamic therapy (PDT) by using a photosensitizer, benzoporphyrin derivative monoacid ring A (BPD-MA), we previously prepared polyethylene glycol (PEG)-modified liposomes encapsulating BPD-MA (PEG-Lip BPD-MA). PEGylation of liposomes enhanced the accumulation of BPD-MA in tumor tissue at 3 h after injection of it into Meth-A-sarcoma-bearing mice, but, unexpectedly, decreased the suitability of the drug for PDT when laser irradiation was performed at 3 h after the injection of the liposomal photosensitizer. To improve the bioavailability of PEG-Lip BPD-MA, we endowed the liposomes with active-targeting characteristics by using Ala-Pro-Arg-Pro-Gly (APRPG) pentapeptide, which had earlier been isolated as a peptide specific to angiogenic endothelial cells. APRPG-PEG-modified liposomal BPD-MA (APRPG-PEG-Lip BPD-MA) accumulated in tumor tissue similarly as PEG-Lip BPD-MA and to an approx. 4-fold higher degree than BPD-MA delivered with non-modified liposomes at 3 h after the injection of the drugs into tumor-bearing mice. On the contrary, unlike the treatment with PEG-Lip BPD-MA, APRPG-PEG-Lip BPD-MA treatment strongly suppressed tumor growth after laser irradiation at 3 h after injection. Finally, we observed vasculature damage in the dorsal air sac angiogenesis model by APRPG-PEG-Lip BPD-MA-mediated PDT. The present results suggest that antiangiogenic PDT is an efficient modality for tumor treatment and that tumor neovessel-targeted, long-circulating liposomes are a useful carrier for delivering photosensitizer to angiogenic endothelial cells.


Renomedullary Interstitial Cell Tumors: Pathologic Features and Clinical Correlations.
Renomedullary interstitial cell tumors are common incidental findings in kidney specimens. Despite their frequency, little is known about their morphology and pathogenesis. Kidneys from 402 unselected autopsies were sectioned at 1 to 2 mm intervals, and all lesions were examined histologically. A total of 421 renomedullary interstitial cell tumors were present in 150 patients (37%), ranging from 1 to 23 tumors per patient (mean=3). There was no statistically significant difference in age, sex, hypertension, heart weight, tobacco smoking, diabetes mellitus, and renal function between patients with renomedullary interstitial cell tumors and those without. Almost half the patients with renomedullary interstitial cell tumors (41%) had bilateral tumors, and they were older than patients with unilateral tumors (P=0.0007). The tumors ranged in size from 0.5 to 6 mm (mean 1.7 mm). The lesions varied in cellularity: fibrous stroma was found in older patients, whereas cellular and hypocellular stroma predominated in younger patients (P=0.001 and P<0.0001, respectively). Entrapped renal tubules were found throughout the tumor in younger patients and smaller tumors, whereas the absence of entrapped tubules or their location only at the periphery of the lesion were common in older patients and larger tumors (P=0.02 and P<0.0001, respectively). Ropey brightly eosinophilic material, found in 26% of tumors, was not amyloid but collagen type III. This material was observed in older patients (P<0.0001) with larger tumors (P<0.0001) and was also correlated to higher heart weight (P=0.003) but not to hypertension (P=0.11). On the basis of our findings, renomedullary interstitial cell tumors appear to originate as a proliferation of renomedullary interstitial cells between medullary tubules. As their size increases, cellularity decreases, ropey eosinophilic material is deposited, and tubules disappear.


Musicality - Tuned to the melody of vocal emotions.
Musicians outperform non-musicians in vocal emotion perception, likely because of increased sensitivity to acoustic cues, such as fundamental frequency (F0) and timbre. Yet, how musicians make use of these acoustic cues to perceive emotions, and how they might differ from non-musicians, is unclear. To address these points, we created vocal stimuli that conveyed happiness, fear, pleasure or sadness, either in all acoustic cues, or selectively in either F0 or timbre only. We then compared vocal emotion perception performance between professional/semi-professional musicians (N = 39) and non-musicians (N = 38), all socialized in Western music culture. Compared to non-musicians, musicians classified vocal emotions more accurately. This advantage was seen in the full and F0-modulated conditions, but was absent in the timbre-modulated condition indicating that musicians excel at perceiving the melody (F0), but not the timbre of vocal emotions. Further, F0 seemed more important than timbre for the recognition of all emotional categories. Additional exploratory analyses revealed a link between time-varying F0 perception in music and voices that was independent of musical training. Together, these findings suggest that musicians are particularly tuned to the melody of vocal emotions, presumably due to a natural predisposition to exploit melodic patterns.


Trans-dominant Tat mutants with alterations in the basic domain inhibit HIV-1 gene expression.
The Tat protein of the human immunodeficiency virus type 1 (HIV-1) is required for efficient viral gene expression. By means of mutational analyses, several domains of the Tat protein that are required for complete activation of HIV-1 gene expression have been defined. These include an amino-terminal activating domain, a cysteine-rich dimerization domain, and a basic domain important in the binding of Tat to the trans-activation response element (TAR) and in Tat nuclear localization. Recently, we described a mutation, known as delta tat, which resulted in a protein with a truncated basic domain. This protein had a "trans-dominant" phenotype in that it inhibited wild-type Tat activation of the HIV-1 LTR. To further characterize the requirements for generating a Tat trans-dominant phenotype, we constructed a variety of Tat proteins with truncations or substitutions in the basic domain. A number of these proteins showed a trans-dominant phenotype. These Tat mutants also inhibited activation of the HIV-1 LTR by a protein composed of Tat fused to the prokaryotic R17 (phage MS2) RNA-binding protein in which the R17 recognition element was inserted in the HIV-1 LTR in place of TAR. Thus, an intact TAR element was not required for this inhibition. We also studied the cellular localization of Tat and a trans-dominant Tat mutant by means of immunofluorescence staining with the use of antibodies reactive to different domains of the Tat protein. The results indicated that Tat becomes localized predominantly in the nucleus both in the presence and absence of the trans-dominant Tat construct, suggesting that the trans-dominant mutant does not inhibit Tat nuclear localization. These studies further define the requirements for the creation of trans-dominant Tat mutants, and suggest that the mechanism of trans-dominant Tat inhibition may be either the formation of an inactive complex between wild-type and mutant Tat or sequestration of cellular factors involved in regulating HIV-1 gene expression.


Staphylococcus lugdunensis in several niches of the normal skin flora.
Staphylococcus lugdunensis is a coagulase-negative staphylococcus (CNS). Its pathogenicity and virulence are more similar to Staphylococcus aureus than to a CNS. It causes severe infections with high mortality, such as endocarditis, but more often painful and prolonged skin- and soft-tissue infections. Little is known of its normal habitat. Whether it is an integral part of the normal skin flora like many other CNS has been questioned, since it is rarely seen in blood cultures. This study was designed to determine whether S. lugdunensis has a niche in the normal skin flora and to compare S. lugdunensis and S. aureus in these niches.From 75 healthy subjects in Kronoberg County, Sweden, 525 swabs were obtained from the nose, axilla, perineum, groin, breast, toe and nail bed of the first toe. Significantly more of the 525 skin samples as well as of the 75 healthy subjects yielded S. lugdunensis (50/75) as opposed to S. aureus.(16/75). Swabs from the nose frequently yielded S. aureus, but only rarely S. lugdunensis. Swabs from the groin and the lower extremities, especially the nail bed of the first toe, often yielded S. lugdunensis but rarely S. aureus. This study shows that S. lugdunensis is an integral part of the normal skin flora, primarily of the lower abdomen and extremities, and that the niches of this coagulase-negative staphylococcus are distinctly different from those of S. aureus. The predominant niches of S. lugdunensis explain why the bacterium is an uncommon contaminant of blood cultures.


A left bundle branch block activation sequence and ventricular pacing influence voltage amplitudes: an in vivo and in silico study.
The aim of this study was to investigate the influence of the activation sequence on voltage amplitudes by evaluating regional voltage differences during a left bundle branch block (LBBB) activation sequence vs. a normal synchronous activation sequence and by evaluating pacing-induced voltage differences. Twenty-one patients and three computer models without scar were studied. Regional voltage amplitudes were evaluated in nine LBBB patients who underwent endocardial electro-anatomic mapping (EAM). Pacing-induced voltage differences were evaluated in 12 patients who underwent epicardial EAM during intrinsic rhythm and right ventricular (RV) pacing. Three computer models customized for LBBB patients were created. Changes in voltage amplitudes after an LBBB (intrinsic), a normal synchronous, an RV pacing, and a left ventricular pacing activation sequence were assessed in the computer models. Unipolar voltage amplitudes in patients were approximately 4.5 mV (4.4-4.7 mV, ∼33%) lower in the septum when compared with other segments. A normal synchronous activation sequence in the computer models normalized voltage amplitudes in the septum. Pacing-induced differences were larger in electrograms with higher voltage amplitudes during intrinsic rhythm and furthermore larger and more variable at the epicardium [mean absolute difference: 3.6-6.2 mV, 40-53% of intrinsic value; interquartile range (IQR) differences: 53-63% of intrinsic value] compared to the endocardium (mean absolute difference: 3.3-3.8 mV, 28-30% of intrinsic value; IQR differences: 37-40% of intrinsic value). In patients and computer models without scar, lower septal unipolar voltage amplitudes are exclusively associated with an LBBB activation sequence. Pacing substantially affects voltage amplitudes, particularly at the epicardium.


25-hydroxycholecalciferol-enhanced bone maturation in the parathyroprivic state.
In vitro evidence presently favors a direct osteolytic effect of biologically active vitamin D metabolites. Studies were designed to evaluate the effect of 25-hydroxycholecalciferol (25OHD3) on bone collagen and mineral maturation in vivo and its dependence on parathyroid hormone (PTH). After treatment of sham-operated control and parathyroidectomized (PTX) mature rats with either 25OHD3 or an oil vehicle for 2 wk, tibial bone mineral-collagen maturation was quantitated by bromoform-toluene density gradient fractionation techniques. Intestinal calcium absorption was measured by in vivo 45Ca transport procedures. In contrast to the control group, the response to 25OHD3 of PTX rats was dramatic. Bone mineral and matrix maturation were both accelerated by 25OHD3 treatment without concomitant reduction in total bone mineral or collagen content or changes in the intestinal calcium absorption. These observations support the premise that biologically active vitamin D metabolites stimulate bone tissue maturation, and that PTH is not required in this regard.


SMS2D designs as starting points for lens optimization.
Traditional imaging design methods can often be ineffective when designing aspheric systems because of the large number of optimization parameters and lack of a good starting point. They are often trapped in a poor local minimum and it can be highly time-consuming to find a good solution in a bumpy design landscape. The simultaneous multiple surface (SMS) method can significantly shorten the time and effort needed to find a desired solution by providing a starting point to optimize close to a good local minimum. We investigate here two design examples and compare them with similar designs obtained via traditional design approaches, as well as global optimization. In the examples considered here, the SMS method combined with a shorter optimization leads to an optimal design.


Current therapeutic approaches for patients with myelodysplastic syndromes.
The myelodysplastic syndromes (MDS) are a heterogeneous spectrum of disorders requiring selective therapy based on patients' specific clinical features, predominantly their prognostic subgroups, age and performance status. Guidelines for management of patients with MDS have been generated by a number of national panels. This review focuses on evidence-based data supporting therapeutic approaches, which have also been recommended by the US National Comprehensive Cancer Network MDS Panel, with discussion of accessibility of recommended drugs in the US and in other countries. For lower risk disease (International Prognostic Scoring System Low and Intermediate-1) therapy is aimed at haematological improvement whereas for higher risk disease (Intermediate-2 and High) treatment focuses on altering disease natural history. Recent information regarding additional clinical and biological features has provided useful parameters for assessing disease prognosis that aid risk-based management decisions. The rationale for use of low versus high intensity therapies with these agents, including allogeneic haematopoietic stem cell transplantation, is discussed in detail.


Life-history constraints in grassland plant species: a growth-defence trade-off is the norm.
Plant growth can be limited by resource acquisition and defence against consumers, leading to contrasting trade-off possibilities. The competition-defence hypothesis posits a trade-off between competitive ability and defence against enemies (e.g. herbivores and pathogens). The growth-defence hypothesis suggests that strong competitors for nutrients are also defended against enemies, at a cost to growth rate. We tested these hypotheses using observations of 706 plant populations of over 500 species before and following identical fertilisation and fencing treatments at 39 grassland sites worldwide. Strong positive covariance in species responses to both treatments provided support for a growth-defence trade-off: populations that increased with the removal of nutrient limitation (poor competitors) also increased following removal of consumers. This result held globally across 4 years within plant life-history groups and within the majority of individual sites. Thus, a growth-defence trade-off appears to be the norm, and mechanisms maintaining grassland biodiversity may operate within this constraint.


Decision-making in low back surgery.
The author was the 1986 Sir Robert Jones Lecturer of the Hospital for Joint Diseases Orthopaedic Institute. This article is a slightly edited version of the speech he delivered in that capacity on October 24, 1986, at the Annual Scientific Program of the Alumni Association.


Axonal regeneration after spinal cord injury in zebrafish and mammals: differences, similarities, translation.
Spinal cord injury (SCI) in mammals results in functional deficits that are mostly permanent due in part to the inability of severed axons to regenerate. Several types of growth-inhibitory molecules expressed at the injury site contribute to this regeneration failure. The responses of axons to these inhibitors vary greatly within and between organisms, reflecting axons' characteristic intrinsic propensity for regeneration. In the zebrafish (Danio rerio) many but not all axons exhibit successful regeneration after SCI. This review presents and compares the intrinsic and extrinsic determinants of axonal regeneration in the injured spinal cord in mammals and zebrafish. A better understanding of the molecules and molecular pathways underlying the remarkable individualism among neurons in mature zebrafish may support the development of therapies for SCI and their translation to the clinic.


[Characteristics of quantitative variability of karyotype in cell line of fibroblasts from indian muntjac].
The numerical regularities of karyotypic variability in cell line of the Indian muntjac skin fibroblasts (Muntiacus muntjak) has been studied. It was found that the karyotypic structure of cell population is mainly determined by some number of specific variant deviations from the main structural variant of karyotype (MSVK) to be depended on internal connections between chromosomes. Specific regulations determining the karyotypic structure of cell population are: 1) nonrandom character of cell distribution according to the number of chromosomal deviations from MSVK; 2) specific character of deviations in each chromosome from MSVK; 3) presence of significant connections between individual chromosomes by simultaneous mainly single directed numeral deviations. Results presented in this investigation were thought owner by analysing the number of individual chromosomes. These results extend considerably the known ideas of regulations of karyotypic variability in cell populations in vitro.


Arc-fusion splicing of single-mode fibers. 1: Optimum splice conditions.
The optimum conditions for arc-fusion splicing of single-mode fibers with core eccentricity of a few microns are investigated in detail. A narrow, quick fusion method, where the fiber-fused region is restricted by the narrowing of the electrode gap and the arc-discharge time is short compared with the conventional multi-mode fiber splice, is presented that will reduce the surface tension effect. The optimum values of electrode gap, prefusion time, and discharge duration are found to be 0.7 mm, 0.2 sec, and 1 sec, respectively, when the discharge current is 18 mA. The optimum pressing stroke of a fiber after the fiber end faces contact each other is determined to be 20 microm. Splice loss <0.1 dB is achieved in the present conditions for fibers with 2-microm core eccentricity and +/-3-microm o.d. discrepancy.


First reported case of Campylobacter lanienae enteritis in a human.
Campylobacters are the most frequently identified bacteria causing diarrhoea in humans worldwide. Campylobacter lanienae was isolated for the first time in 2000 from faecal samples of two asymptomatic abattoir workers in Switzerland during a routine hygiene screen, but has never been associated with human disease. At hospital admission, the patient reported diarrhoea, lower abdominal cramps, nausea, one episode of bilious vomiting and low-grade fever of 38 °C. The patient was having 10 or more diarrheic stools per day as well as during the night, and had noticed blood mixed with the stools on several occasions. Stool cultures were negative for species of Salmonella and Shigella, Escherichia coli O157:H7 and Yersinia enterocolitica, but were positive for C. lanienae. Identification was made by classical biochemical testing, as well as 16S rRNA gene and cpn60 sequencing. The patient slowly improved without antibiotic treatment and was discharged nine days after admission with complete resolution of symptoms. On the whole it seems very likely that C. lanienae was the causative agent. Clinical microbiologists should be aware of this micro-organism which can be identified by phenotypic and molecular methods. The real burden of C. lanienae infection in humans might be underestimated and should be further investigated as a potential cause of human diarrhoea disease.


Coupling of a DNA piezoelectric biosensor and polymerase chain reaction to detect apolipoprotein E polymorphisms.
In this paper we report the coupling of the Polymerase Chain Reaction (PCR) with a piezoelectric biosensor to detect a point mutation in a human gene. Biotinylated 23-mer probes were immobilised on the streptavidin coated gold surface of a quartz crystal; streptavidin was covalently bound to the thiol/dextran modified gold surface. The hybridisation of the immobilised probes with a short sequence (23 mer) complementary, non-complementary and mismatched DNA was investigated: the device was able to distinguish the different synthetic oligonucleotides. Many cycles of measurements can be performed on the same crystal surface regenerating the single strand of DNA with 1 mM of HCl. The same hybridisation reaction was then performed using real samples of human DNA extracted from blood and amplified by PCR, following a standard procedure for genetic detection of the polymorphism of the apolipoprotein E (apoE) gene. The procedure was able to distinguish the sequences present in the different samples, which differ only in one base: in this way it was possible distinguish between different groups of genotypes with apoE typing. Experiments with 'blank' samples confirmed the absence of adsorption or non-specific effects on the quartz crystal treated with the reported procedure.


Methods for translating evidence-based behavioral interventions for health-disparity communities.
Populations composed of racial/ethnic minorities, disabled persons, and people with low socioeconomic status have worse health than their counterparts. Implementing evidence-based behavioral interventions (EBIs) to prevent and manage chronic disease and disability in community settings could help ameliorate disparities. Although numerous models of implementation processes are available, they are broad in scope, few offer specific methodological guidance, and few address the special issues in reaching vulnerable populations. Drawing from 2 existing models, we describe 7 methodological phases in the process of translating and implementing EBIs in communities to reach these vulnerable groups: establish infrastructure for translation partnership, identify multiple inputs (information gathering), review and distill information (synthesis), adapt and integrate program components (translation), build general and specific capacity (support system), implement intervention (delivery system), and develop appropriate designs and measures (evaluation). For each phase, we describe specific methodological steps and resources and provide examples from research on racial/ethnic minorities, disabled persons, and those with low socioeconomic status. Our methods focus on how to incorporate adaptations so that programs fit new community contexts, meet the needs of individuals in health-disparity populations, capitalize on scientific evidence, and use and build community assets and resources. A key tenet of our approach is to integrate EBIs with community best practices to the extent possible while building local capacity. We discuss tradeoffs between maintaining fidelity to the EBIs while maximizing fit to the new context. These methods could advance our ability to implement potentially effective interventions to reduce health disparities.


[The structure of the inbreeding coefficient in a rural Asian population].
The population-genetic study of an elementary rural population located in the Urgut district of Samarcand province was carried out. The pedigree for the whole population starting from the founders was evaluated. From 208 marriages presented in the population, 148 (71.2%) were consanguineous. The mean coefficient of inbreeding calculated from the pedigree was 0.028. A new approach to the evaluation of marital assortativity in a rural Uzbek population without tribial differentiation and inherited surnames was proposed. It consists in awarding artificial surnames to the founders of the population. Applying this approach to the population under study gives following values of F-statistics: FIT = 0.031, FIS = 0.01841, FST = 0.01282.


Preparation of ordered mesoporous Ag/WO3 and its highly efficient degradation of acetaldehyde under visible-light irradiation.
A highly active photocatalyst, silver loaded mesoporous WO(3), was successfully synthesized by an ultrasound assisted insertion method. The photodegradation of a common air pollutant acetaldehyde was adopted to evaluate the photocatalytic performance of the as-prepared sample under visible-light irradiation. The photocatalytic activity was about three and six times higher than that of pure mesoporous WO(3) and nitrogen-doped TiO(2), respectively. The photocatalytic mechanism was investigated to understand the much enhanced photocatalytic activity, which was mainly attributed to the largely improved electron-hole separation in the Ag-WO(3) heterojunction.


School-Located Influenza Vaccination: Do Vaccine Clinics at School Raise Vaccination Rates?
Only half of US schoolchildren receive influenza vaccine. School-located influenza vaccination (SLIV) might raise vaccination rates but conducting flu vaccine clinics at schools is challenging to implement. We compared 2 school-based programs designed to raise influenza vaccination rates: parent reminder/educational messages sent to parents from schools which is a low-intensity intervention vs the combination of reminder/educational messages plus SLIV clinics which is a high-intensity intervention. We assigned 36 schools (6 school districts, 2 per group) to 3 groups: (1) control, ie, no SLIV and no parent reminder/education, (2) parent reminder/education emailed by schools, and (3) parent reminder/education plus SLIV clinics. Some schools had SLIV clinics in prior years. Health department nurses conducted SLIV clinics. Among 24,832 children at 36 schools, vaccination rates were control (51.3%), parent reminder/education-only (41.2%), and reminder/education + SLIV (58.7%). On multivariate analyses which controlled for vaccination in prior seasons, children in reminder/education + SLIV schools had higher vaccination rates (OR 1.27, 95% CI 1.10-1.47), but children in reminder/education-only schools had lower rates (OR 0.87, 95% CI 0.75-1.00) than children in control schools. Parent reminder/education combined with SLIV clinics raise vaccination rates, but parent reminder/education alone does not.


[Our experience with the application of collagen-based preparations in reconstructive surgery of the middle ear].
This paper summarizes our experience with the application of collagen-based preparations for reconstructive surgery of the middle ear. The best morphological results (88.46%) were obtained by the closure of extensive defects with the Oblecolum membrane as a temporary supporting structure and the outer atraumatic dressing for the tympanic transplant (in 30 patients) or by the use of the compact-porous explants from the "Sanguicol" preparation as an overlay on the transplant (in 22 patients). Twenty seven patients presenting with the so-called "operated ear disease" underwent mastoidoplasty with the use of the compact-porous preparation "Stimul-oss" as a supporting structure to induce the ingrowth of the bone tissue and the subsequent substitution of the defect. This treatment ensured the reduction of the volume of the bony trepanation cavity. In addition, we have obtained preliminary encouraging results of the application of collagene preparations for the surgical intervention on the stirrup in the patients suffering otosclerosis.


Determinants of osmotic phenomena created by an isolated change in extracellular solute in anuria.
The magnitude of the osmotic fluid shifts between extracellular and intracellular compartments and the changes in solute concentration that follow a change in extracellular solute are determined by the following factors: (1) the rate constant of total body osmotic fluid transfer, (2) the change in the amount of solute per liter of initial extracellular volume, (3) the initial ratio of intracellular to extracellular volume, which is usually determined by the state of extracellular volume (for the same change in the amount of solute per liter of initial extracellular volume, the changes in both extracellular volume and osmolality are greater in edematous than nonedematous states) and (4) the initial osmolality of body fluids (comparatively, the lower the initial osmolality, the larger the osmotic fluid shifts will be). However, the magnitude of the change in osmolality will be the same regardless of initial osmolality, if the other determinants are the same. If the determining factors are known, formulae applied in clinical medicine to predict the changes in solute concentration are theoretically sound. The initial intracellular to extracellular volume ratio characterizes the state of body fluids and can be computed from the changes in solute concentration provided that osmotic equilibrium exists between intracellular and extracellular compartments before and after the osmotic disturbance.


A remote password authentication scheme for multiserver architecture using neural networks.
Conventional remote password authentication schemes allow a serviceable server to authenticate the legitimacy of a remote login user. However, these schemes are not used for multiserver architecture environments. We present a remote password authentication scheme for multiserver environments. The password authentication system is a pattern classification system based on an artificial neural network. In this scheme, the users only remember user identity and password numbers to log in to various servers. Users can freely choose their password. Furthermore, the system is not required to maintain a verification table and can withstand the replay attack.


[Functional characteristics of the endocrine glands in skin melanoma patients].
TI-2NOMO skin melanoma patients revealed pronounced functional disturbances of the pineal gland and pituitary-adrenal system. The decline in functional activity of the former was manifested by a decrease in urine excretion of melatonin. Enhanced levels of blood ACTH, alpha-MSH and cortisole pointed to the activation of pituitary-adrenal system which was particularly high in males. The degree of endocrine disorders was found to be in correlation with tumor stage. As far as pathogenesis of the lesion is concerned, preparations which bring function of endocrine glands to normal should be adjuvant to available treatment modalities for melanoma.


Purification of overexpressed hexahistidine-tagged BLM N431 as oligomeric complexes.
BLM is a DNA helicase encoded by a gene which is mutated in persons with Bloom's syndrome. The protein is a member of the RecQ subfamily of helicases and contains a central domain constituted by the seven motifs conserved in all helicases. In contrast, the N-terminal portion of BLM lacks similarity to any other known proteins or motifs. We have expressed the first 431 amino acids of this domain as a fusion to a hexahistidine tag (BLM N431) in Escherichia coli. A method of purification was developed which involves elution from Ni-NTA resin in imidazole and EDTA, followed by treatment with DTT and gel filtration on Sephacryl-300. The treatment with EDTA and DTT prevents and disrupts aggregation of BLM N431. The purified protein appears to form hexamers and dodecamers, suggesting that the N-terminal domain of BLM is involved in the organization of the quaternary structure of BLM.


Power and sample size estimation in microarray studies.
Before conducting a microarray experiment, one important issue that needs to be determined is the number of arrays required in order to have adequate power to identify differentially expressed genes. This paper discusses some crucial issues in the problem formulation, parameter specifications, and approaches that are commonly proposed for sample size estimation in microarray experiments. Common methods for sample size estimation are formulated as the minimum sample size necessary to achieve a specified sensitivity (proportion of detected truly differentially expressed genes) on average at a specified false discovery rate (FDR) level and specified expected proportion (pi1) of the true differentially expression genes in the array. Unfortunately, the probability of detecting the specified sensitivity in such a formulation can be low. We formulate the sample size problem as the number of arrays needed to achieve a specified sensitivity with 95% probability at the specified significance level. A permutation method using a small pilot dataset to estimate sample size is proposed. This method accounts for correlation and effect size heterogeneity among genes. A sample size estimate based on the common formulation, to achieve the desired sensitivity on average, can be calculated using a univariate method without taking the correlation among genes into consideration. This formulation of sample size problem is inadequate because the probability of detecting the specified sensitivity can be lower than 50%. On the other hand, the needed sample size calculated by the proposed permutation method will ensure detecting at least the desired sensitivity with 95% probability. The method is shown to perform well for a real example dataset using a small pilot dataset with 4-6 samples per group. We recommend that the sample size problem should be formulated to detect a specified proportion of differentially expressed genes with 95% probability. This formulation ensures finding the desired proportion of true positives with high probability. The proposed permutation method takes the correlation structure and effect size heterogeneity into consideration and works well using only a small pilot dataset.


PAHs increase the production of extracellular vesicles both in vitro in endothelial cells and in vivo in urines from rats.
Environmental contaminants, to which humans are widely exposed, cause or worsen several diseases, like cardiovascular diseases and cancers. Among these molecules, polycyclic aromatic hydrocarbons (PAHs) stand out since they are ubiquitous pollutants found in ambient air and diet. Because of their toxic effects, public Health agencies promote development of research studies aiming at increasing the knowledge about PAHs and the discovery of biomarkers of exposure and/or effects. Extracellular vesicles (EVs), including small extracellular vesicles (S-EVs or exosomes) and large extracellular vesicles (L-EVs or microvesicles), are delivery systems for multimolecular messages related to the nature and status of the originating cells. Because they are produced by all cells and detected within body fluids, EV releases could act as cell responses and thereby serve as biomarkers. To test whether EVs can serve as biomarkers of PAHs exposure, we evaluate the effects of these pollutants on EV production using an in vitro approach (human endothelial cell line, HMEC-1) and an in vivo approach (urine samples from PAHs-exposed rats). Our study indicates that, i) PAH exposure increases in vitro the EV production by endothelial cells and in vivo the release of EVs in urine, and that the stimulating effects of PAHs concern both S-EVs and L-EVs; ii) PAH exposure and more particularly exposure to B[a]P, can influence the composition of exosomes produced by endothelial cells; iii) the aryl hydrocarbon receptor, a cytosolic receptor associated to most deleterious effects of PAHs, would be involved in the PAH effects on the release of S-EVs, but not L-EVs. These results suggest that EVs may have utility for monitoring exposure to PAHs, and more particularly to B[a]P, considered as reference PAH, and to detect the related early cellular response prior to end-organ damages.


Clinical characteristics in obsessive-compulsive disorder with schizophrenia.
The objective of this study was to compare two groups of patients with obsessive-compulsive disorder (OCD) with and without comorbid schizophrenia in terms of demographic and clinical features. A total of 65 patients diagnosed with OCD were divided into two groups: one comprising 20 patients with schizophrenia and the other comprising 45 patients without schizophrenia. The groups were then compared with respect to demographic variables and scores obtained on various scales. The two groups were similar for the frequency and severity of obsessive-compulsive symptoms. Insight into obsessive-compulsive symptoms was significantly better in the group with schizophrenia. Our findings suggest that the characteristics of obsessive-compulsive symptoms in schizophrenic OCD patients are similar to those in nonschizophrenic OCD patients.


Attitudes and perceptions of next-of-kin/loved ones toward end-of-life HIV cure-related research: A qualitative focus group study in Southern California.
As end-of-life (EOL) HIV cure-related research expands, understanding perspectives of participants' next-of-kin (NOK) is critical to maintaining ethical study conduct. We conducted two small focus groups and two one-on-one interviews using focus group guides with the NOK of Last Gift study participants at the University of California, San Diego (UCSD). Participating NOK included six individuals (n = 5 male and n = 1 female), including a grandmother, grandfather, partner, spouse, and two close friends. Researchers double-coded the transcripts manually for overarching themes and sub-themes using an inductive approach. We identified six key themes: 1) NOK had an accurate, positive understanding of the Last Gift clinical study; 2) NOK felt the study was conducted ethically; 3) Perceived benefits for NOK included support navigating the dying/grieving process and personal growth; 4) Perceived drawbacks included increased sadness, emotional stress, conflicted wishes between NOK and study participants, and concerns around potential invasiveness of study procedures at the EOL; 5) NOK expressed pride in loved ones' altruism; and 6) NOK provided suggestions to improve the Last Gift study, including better communication between staff and themselves. These findings provide a framework for ethical implementation of future EOL HIV cure-related research involving NOK.


A novel biosurfactant produced by Aureobasidium pullulans L3-GPY from a tiger lily wild flower, Lilium lancifolium Thunb.
Yeast biosurfactants are important biotechnological products in the food industry, and they have medical and cosmeceutical applications owing to their specific modes of action, low toxicity, and applicability. Thus, we have isolated and examined biosurfactant-producing yeast for various industrial and medical applications. A rapid and simple method was developed to screen biosurfactant-producing yeasts for high production of eco-friendly biosurfactants. Using this method, several potential niches of biosurfactant-producing yeasts, such as wild flowers, were investigated. We successfully selected a yeast strain, L3-GPY, with potent surfactant activity from a tiger lily, Lilium lancifolium Thunb. Here, we report the first identification of strain L3-GPY as the black yeast Aureobasidium pullulans. In addition, we isolated a new low-surface-tension chemical, designated glycerol-liamocin, from the culture supernatant of strain L3-GPY through consecutive chromatography steps, involving an ODS column, solvent partition, silica gel, Sephadex LH-20, and an ODS Sep-Pak cartridge column. The chemical structure of glycerol-liamocin, determined by mass spectrometry and nuclear magnetic resonance spectroscopy, indicates that it is a novel compound with the molecular formula C33H62O12. Furthermore, glycerol-liamocin exhibited potent biosurfactant activity (31 mN/m). These results suggest that glycerol-liamocin is a potential novel biosurfactantfor use in various industrial applications.


Gender comparison in a murine model of allergen-driven airway inflammation and the response to budesonide treatment.
Evidence suggests that gender differences exist in the severity of many immunological diseases and their response to glucocorticosteroid treatment. In this report, we have used a murine model of ovalbumin-induced lung inflammation to address whether gender could affect the systemic response, airway inflammation and hyperreactivity and their responses to budesonide. Following an acute ovalbumin challenge, actively sensitised BALB/c mice developed a time-dependent increase in interleukin-4 and interleukin-5 production and inflammatory cell influx into bronchoalveolar lavage fluid. Apart from an increased number of lymphocytes in female mice at day 3 post-challenge, none of the above parameters were affected by gender. Blood leukocyte numbers were also unaffected, whereas a two-fold increase in total serum immunoglobulin E was observed in female mice. Budesonide, given intranasally, did not affect the blood parameters, but dose-dependently inhibited the pulmonary inflammation and airway hyperreactivity in both male and female mice. Female mice were slightly less sensitive to budesonide's inhibitory action on interleukin-5 production and the development of airway hyperreactivity. Our results suggest that, apart from a 2-fold increase in serum immunoglobulin E levels observed in female mice, gender is not a major factor in the present murine model of ovalbumin-induced lung inflammation. In contrast, gender might slightly influence the potency of test compounds such as steroids.


A causal role for right temporo-parietal junction in signaling moral conflict.
The right temporo-parietal junction (rTPJ) has been proposed to play a key role in guiding human altruistic behavior, but its precise functional contribution to altruism remains unclear. We aimed to disentangle three possible functions of the rTPJ for human altruism, namely: implementing the motivation to help, signaling conflicts between moral and material values, or representing social reputation concerns. Our novel donation-decision task consisted of decisions requiring trade-offs of either positive moral values and monetary cost when donating to a good cause, or negative moral values and monetary benefits when sending money to a bad cause. Disrupting the rTPJ using transcranial magnetic stimulation did not change the general motivation to give or to react to social reputation cues, but specifically reduced the behavioral impact of moral-material conflicts. These findings reveal that signaling moral-material conflict is a core rTPJ mechanism that may contribute to a variety of human moral behaviors.


Impact of combination HIV interventions on HIV incidence in hyperendemic fishing communities in Uganda: a prospective cohort study.
Targeting combination HIV interventions to locations and populations with high HIV burden is a global priority, but the impact of these strategies on HIV incidence is unclear. We assessed the impact of combination HIV interventions on HIV incidence in four HIV-hyperendemic communities in Uganda. We did an open population-based cohort study of people aged 15-49 years residing in four fishing communities on Lake Victoria. The communities were surveyed five times to collect self-reported demographic, behavioural, and service-uptake data. Free HIV testing was provided at each interview, with referral to combination HIV intervention services as appropriate. From November, 2011, combination HIV intervention services were rapidly expanded in these geographical areas. We evaluated trends in HIV testing coverage among all participants, circumcision coverage among male participants, antiretroviral therapy (ART) coverage and HIV viral load among HIV-positive participants, and sexual behaviours and HIV incidence among HIV-negative participants. From Nov 4, 2011, to Aug 16, 2017, data were collected from five surveys. Overall, 8942 participants contributed 20 721 person-visits; 4619 (52%) of 8942 participants were male. HIV prevalence was 41% (1598 of 3870) in the 2011-12 baseline survey and declined to 37% (1740 of 4738) at the final survey (p<0·0001). 3222 participants who were HIV-negative at baseline, and who had at least one repeat visit, contributed 9477 person-years of follow-up, and 230 incident HIV infections occurred. From the first survey in 2011-12 to the last survey in 2016-17, HIV testing coverage increased from 68% (2613 of 3870) to 96% (4526 of 4738; p<0·0001); male circumcision coverage increased from 35% (698 of 2011) to 65% (1630 of 2525; p<0·0001); ART coverage increased from 16% (254 of 1598) to 82% (1420 of 1740; p<0·0001); and population HIV viral load suppression in all HIV-positive participants increased from 34% (546 of 1596) to 80% (1383 of 1734; p<0·0001). Risky sexual behaviours did not decrease over this period. HIV incidence decreased from 3·43 per 100 person-years (95% CI 2·45-4·67) in 2011-12 to 1·59 per 100 person-years (95% CI 1·19-2·07) in 2016-17; adjusted incidence rate ratio (IRR) 0·52 (95% CI 0·34-0·79). Declines in HIV incidence were similar among men (adjusted IRR 0·53, 95% CI 0·30-0·93) and women (0·51, 0·27-0·96). The risk of incident HIV infection was lower in circumcised men than in uncircumcised men (0·46, 0·32-0·67). Rapid expansion of combination HIV interventions in HIV-hyperendemic fishing communities is feasible and could have a substantial impact on HIV incidence. However, incidence remains higher than HIV epidemic control targets, and additional efforts will be needed to achieve this global health priority. The National Institute of Mental Health, the National Institute of Allergy and Infectious Diseases, the National Institute of Child Health and Development, the National Cancer Institute, the National Institute for Allergy and Infectious Diseases Division of Intramural Research, Centers for Disease Control and Prevention Uganda, Karolinska Institutet, and the Johns Hopkins University Center for AIDS Research.


Identification of a therapeutic dose of continuously delivered erythropoietin in the eye using an inducible promoter system.
Erythropoietin (EPO) can protect the retina from acute damage, but long-term systemic treatment induces polycythemia. Intraocular gene delivery of EPO is not protective despite producing high levels of EPO likely due to its bellshaped dose curve. The goal of this study was to identify a therapeutic dose of continuously produced EPO in the eye. We packaged a mutated form of EPO (EPOR76E) that has equivalent neuroprotective activity as wild-type EPO and attenuated erythropoietic activity into a recombinant adeno-associated viral vector under the control of the tetracycline inducible promoter. This vector was injected into the subretinal space of homozygous postnatal 5-7 day retinal degeneration slow mice, that express the tetracycline transactivators from a retinal pigment epithelium specific promoter. At weaning, mice received a single intraperitoneal injection of doxycycline and were then maintained on water with or without doxycycline until postnatal day 60. Intraocular EPO levels and outer nuclear layer thickness were quantified and correlated. Control eyes contained 6.1 ± 0.1 (SEM) mU/ml EPO. The eyes of mice that received an intraperitoneal injection of doxycycline contained 11.8 ± 2.0 (SEM) mU/ml EPO-R76E. Treatment with doxycycline water induced production of 35.9 ± 2.4 (SEM) mU/ml EPO-R76E in the eye. The outer nuclear layer was approximately 8 μm thicker in eyes of mice that received doxycycline water as compared to the control groups. Our data indicates that drug delivery systems should be optimized to deliver at least 36 mU/ml EPO into the eye since this dose was effective for the treatment of a progressive retinal degeneration.


Causal Inference in the Age of Decision Medicine.
Causal analyses and causal inference is a growing area of biostatics. In parallel, there is increasing focus on using genomic information to guide medical practice, i.e. personalized medicine or decision medicine. This perspective discusses causal inference in the context of personalized or decision medicine, including the assumptions and the concept that the task is different depending on whether the primary goal is the average response of treatment in the population or the ability to characterize the response for an individual or a subgroup. This perspective provides a tutorial of modern causal inference and then provides suggestions how application of specific kinds of causal inference would promote advances in translational sciences. The concept of the subpopulation causal effect is one path toward improved decision medicine. A dataset containing cardiovascular disease risk factor levels and genomic information is analyzed and different causal effects are estimated.


Exposing the hidden curriculum influencing medical education on the health of Indigenous people in Australia and New Zealand: the role of the Critical Reflection Tool.
The disparity in health status between Indigenous and non-Indigenous people in Australia and New Zealand is widely known, and efforts to address this through medical education are evidenced by initiatives such as the Committee of Deans of Australian Medical Schools' Indigenous Health Curriculum Framework. These efforts have focused primarily on formal curriculum reform. In this article, the authors discuss the role of the hidden curriculum in influencing the teaching and learning of Indigenous health (i.e., the health of Indigenous people) during medical training and suggest that in order to achieve significant changes in learning outcomes, there needs to be better alignment of the formal and hidden curriculum. They describe the Critical Reflection Tool as a potential resource through which educators might begin to identify the dimensions of their institution's hidden curricula. If used effectively, the process may guide institutions to better equip medical school graduates with the training necessary to advance changes in Indigenous health.


Plate failure following plate osteosynthesis in periprosthetic femoral fractures.
Increasing numbers of total knee and hip arthroplasties result in a growing number of periprosthetic femoral fractures (PPFF). PPFF with a stable stem component are treated commonly with plate osteosynthesis. Therefore plate failure is seen as a major complication. The aim of this retrospective study was to investigate the patients' outcome after plate failure. The database of a Level 1 trauma center was searched for all patients treated for a PPFF with plate osteosynthesis. Patients with plate failure were investigated specifically. Standard demographic data, details on initial arthroplasty, trauma, and treatment were recorded for all patients. All fractures were classified and their outcome reviewed. Seven (8.8%) out of 80 patients treated with plate osteosynthesis following PPFF met our inclusion criterion being plate failure. All these patients were female, with an average age at primary surgery of 74 ± 13 years and a mean follow-up of 885 days (range, 264-2549). Four patients suffered a PPFF after total hip arthroplasty (THA) (2 Vancouver Type B1 and 2 Type C) and three after total knee arthroplasty (TKA) (Lewis-Rorabeck Type II). Following plate failure, four patients healed uneventfully and three patients experienced complications such as pseudarthrosis, screw loosening, and further plate failure. In patients with poor bone quality, bone graft, bone cement, and bone biologics have to be considered in revision surgery. Furthermore, long-stem revision and tumor prosthesis are an additional solution.


[The value of evoked acoustic oto-emissions in pediatric audiology].
The Evoked Otoacoustic Emissions (EOAE) technique seems to be an early detection method of deafness of particular interest for children. In order to verify the hypothesis, we have tested 157 children and compared the results of the EOAE with a complementary audiologic testing.


Tuberculosis patients submitted to supervised treatment. Ribeirão Preto-São Paulo-Brazil. 1998 and 1999.
This study presents a survey conducted among 132 Tuberculosis patients submitted to Supervised Treatment between 01/1998 and 12/1999, with a view to describing epidemiological aspects, according to the gender, (final) treatment result and HIV immunology result variables. The number of patients covered by Supervised Treatment rose from 19% to 30%. For each of these years, 64% and 71% of the patients were male, while 89% and 77% evolved towards cure. The rate of abandonment increased from 7% to 10%, while 4% and 10% of the patients died of Tuberculosis. The Tb/HIV co-infection represented 22% and 42% of the cases. The obtained results disclosed a tendency towards the gradual amplification of Supervised Treatment and its implementation implied.


Does country influence the health burden of informal care? An international comparison between Belgium and Great Britain.
The aim of this paper is to determine whether the association between the provision of informal care and the health status of caregivers is affected by the country of residence. We focus on two European countries, Belgium and Great Britain, and develop a methodology, which consists of matching a subset of areas from Britain with areas in Belgium that are demographically and socioeconomically similar. These pairs of areas are then used as fixed effects in logistic regressions of poor health. This allows us to take into account the influence of area type on health and to remove the influence of these local contextual characteristics from the estimated country effects. Results suggest that, although caregiving is more prevalent in Britain, the health burden associated with heavy caregiving activities is lower in Britain than in Belgium. This may be explained by the better targeting of long-term home care policies towards more severely dependent patients in Britain than in Belgium.


Pulmonary macrophage mobilization in cigarette smoke-exposed mice after halothane anesthesia.
The effects of halothane anesthesia on pulmonary tissue and lung macrophage population were evaluated in normal and in C57BL/6 mice exposed to cigarette smoke twice daily for one year. Morphologic assessment of pulmonary tissue revealed no lung abnormalities that could be attributed solely to halothane anesthesia. However, in animals that were exposed to smoke and subsequently halothane anesthesia, airways cilia were shorter in stature and fewer in number. Disorientation of ciliary basal bodies was also observed. Airway macrophages in smoke-exposed animals subjected to halothane anesthesia were, for the most part, larger in size and contained more lysosomes and inclusions than phagocytes in airways of all other animals. Smoke inhalation alone caused a significant increase in number of lung parenchymal macrophages when compared to the number of these cells in sham-treated and control animals. However, the total macrophage population was significantly greater in lungs of smoke-exposed mice 48 hr after anesthesia than in lungs of smoke-exposed mice not subjected to halothane anesthesia and to those of sham-treated and control animals that were or were not exposed to the anesthetic. Airway macrophage numbers were significantly elevated in smoke-exposed mice 48 hr after halothane when compared to those of all other groups. Conversely, the number of parenchymal macrophages decreased in lungs of these mice. It was proposed that in smoke-exposed mice subjected to halothane anesthesia, ciliary function is impaired and phagocytes are mobilized from alveoli into the airways.


Sarcopenia Is a Negative Prognostic Factor in Patients Undergoing Transarterial Chemoembolization (TACE) for Hepatic Malignancies.
: Background and Aims: While transarterial chemoembolization (TACE) represents a standard of therapy for intermediate-stage hepatocellular carcinoma (HCC) and is also routinely performed in patients with liver metastases, it is still debated which patients represent the ideal candidates for TACE therapy in terms of overall survival. Sarcopenia, the degenerative loss of skeletal muscle mass and strength, has been associated with an adverse outcome for various malignancies, but its role in the context of TACE has largely remained unknown. Here, we evaluated the role of sarcopenia on the outcome of patients undergoing TACE for primary and secondary liver cancer. The patients' psoas muscle size was measured on axial computed tomography (CT) scans and normalized for the patients' height squared. This value was referred to as the psoas muscle index (PMI). The PMI was correlated with clinical and laboratory markers. While pre-interventional sarcopenia had no impact on the direct tumor response to TACE, sarcopenic patients with a pre-interventional PMI below our ideal cut-off value of 13.39 mm/m2 had a significantly impaired long-term outcome with a median overall survival of 491 days compared to 1291 days for patients with a high PMI. This finding was confirmed by uni- and multivariate Cox-regression analyses. Moreover, a progressive rapid decline in muscle mass after TACE was a predictor for an unfavorable prognosis. Our data suggest that sarcopenia represents a previously unrecognized prognostic factor for patients undergoing TACE therapy which might yield important information on the patients' post-interventional outcome and should therefore be implemented into clinical stratification algorithms.


Adaptation to life on land at high O2 via transition from ferredoxin-to NADH-dependent redox balance.
Pyruvate : ferredoxin oxidoreductase (PFO) and iron only hydrogenase ([Fe]-HYD) are common enzymes among eukaryotic microbes that inhabit anaerobic niches. Their function is to maintain redox balance by donating electrons from food oxidation via ferredoxin (Fd) to protons, generating H2 as a waste product. Operating in series, they constitute a soluble electron transport chain of one-electron transfers between FeS clusters. They fulfil the same function-redox balance-served by two electron-transfers in the NADH- and O2-dependent respiratory chains of mitochondria. Although they possess O2-sensitive FeS clusters, PFO, Fd and [Fe]-HYD are also present among numerous algae that produce O2. The evolutionary persistence of these enzymes among eukaryotic aerobes is traditionally explained as adaptation to facultative anaerobic growth. Here, we show that algae express enzymes of anaerobic energy metabolism at ambient O2 levels (21% v/v), Chlamydomonas reinhardtii expresses them with diurnal regulation. High O2 environments arose on Earth only approximately 450 million years ago. Gene presence/absence and gene expression data indicate that during the transition to high O2 environments and terrestrialization, diverse algal lineages retained enzymes of Fd-dependent one-electron-based redox balance, while the land plant and land animal lineages underwent irreversible specialization to redox balance involving the O2-insensitive two-electron carrier NADH.


Discrimination between ricin and sulphur mustard toxicity in vitro using Raman spectroscopy.
A Raman spectroscopy cell-based biosensor has been proposed for rapid detection of toxic agents, identification of the type of toxin and prediction of the concentration used. This technology allows the monitoring of the biochemical properties of living cells over long periods of time by measuring the Raman spectra of the cells non-invasively, rapidly and without use of labels (Notingher et al. 2004 doi:10.1016/j.bios.2004.04.008). Here we show that this technology can be used to distinguish between changes induced in A549 lung cells by the toxin ricin and the chemical warfare agent sulphur mustard. A multivariate model based on principal component analysis (PCA) and linear discriminant analysis (LDA) was used for the analysis of the Raman spectra of the cells. The leave-one-out cross-validation of the PCA-LDA model showed that the damaged cells can be detected with high sensitivity (98.9%) and high specificity (87.7%). High accuracy in identifying the toxic agent was also found: 88.6% for sulphur mustard and 71.4% for ricin. The prediction errors were observed mostly for the ricin treated cells and the cells exposed to the lower concentration of sulphur mustard, as they induced similar biochemical changes, as indicated by cytotoxicity assays. The concentrations of sulphur mustard used were also identified with high accuracy: 93% for 200 microM and 500 microM, and 100% for 1,000 microM. Thus, biological Raman microspectroscopy and PCA-LDA analysis not only distinguishes between viable and damaged cells, but can also discriminate between toxic challenges based on the cellular biochemical and structural changes induced by these agents and the eventual mode of cell death.