Renal sodium transporters are increased in urinary exosomes of cyclosporine-treated kidney transplant patients.
Cyclosporine (CsA) is a calcineurin inhibitor widely used as an immunosuppressant in organ transplantation. Previous studies demonstrated the relationship between CsA and renal sodium transporters such as the Na-K-2Cl cotransporter in the loop of Henle (NKCC2). Experimental models of CsA-induced hypertension have shown an increase in renal NKCC2. Using immunoblotting of urinary exosomes, we investigated in CsA-treated kidney transplant patients (n = 39) the excretion of NKCC2 and Na-Cl cotransporter (NCC) and its association with blood pressure (BP) level. We included 8 non-CsA-treated kidney transplant patients as a control group. Clinical data, immunosuppression and hypertension treatments, blood and 24-hour urine tests, and 24-hour ambulatory BP monitoring were recorded. CsA-treated patients tended to excrete a higher amount of NKCC2 than non-CsA-treated patients (mean ± SD, 175 ± 98 DU and 90 ± 70.3 DU, respectively; p = 0.05) and showed higher BP values (24-hour systolic BP 138 ± 17 mm Hg and 112 ± 12 mm Hg, p = 0.003; 24-hour diastolic BP, 83.8 ± 9.8 mm Hg and 72.4 ± 5.2 mm Hg, p = 0.015, respectively). Within the CsA-treated group, there was no correlation between either NKCC2 or NCC excretion and BP levels. This was confirmed by a further analysis including potential confounding factors. On the other hand, a significant positive correlation was observed between CsA blood levels and the excretion of NKCC2 and NCC. Overall, these results support the hypothesis that CsA induces an increase in NKCC2 and NCC in urinary exosomes of renal transplant patients. The fact that the increase in sodium transporters in urine did not correlate with the BP level suggests that in kidney transplant patients, other mechanisms could be implicated in CsA-induced hypertension.


Effects on Decision Quality of Supporting Multi-attribute Evaluation in Groups
In this study the effectiveness of multi-attribute utility (MAU) decision support in groups is evaluated for personnel selection problems differing in complexity. Subjects were asked to make an initial individual decision with or without MAU decision support. Next individuals formed small groups and were asked to reach a decision about the same problem. Groups received either MAU support or no support. Results show that for relatively simple problems the most effective method is to provide subjects with both individual and group decision support. Here, decision support had a clear impact on subjects' preferences and the level of agreement between group members. In addition, satisfaction with the decision and the decision procedure was relatively high. Overall, decision support improved communication; subjects reported to find the problem easier, to have more influence on the group decision, and to find it easier to express their opinions. For more complex problems, however, decision making without group support (whether preceded by individual support or not) was evaluated most favorably. Individual decision support in this condition was sometimes better than no support; i.e., there was a lower reported problem difficulty, a higher satisfaction with the group decision, and a higher reported influence on the group decision. The effectiveness of group MAU decision support for complex problems was evaluated less favorably.


Isolation of Nocardia beijingensis from a pulmonary abscess reveals human immunodeficiency virus infection.
A strain of Nocardia was isolated from a pulmonary abscess of a human immunodeficiency virus-infected patient in France. Comparative 16S rRNA gene sequence analysis revealed that the isolate represented a strain of Nocardia beijingensis. Antimicrobial susceptibility testing was essential to guide the clinicians to successfully treat this infection.


Green emission fluorophores in eyes with atrophic age-related macular degeneration: a colour fundus autofluorescence pilot study.
To investigate the presence of short-wave fluorophores within regions of age-related macular degeneration (AMD)-associated macular atrophy (MA) area. This is a prospective, observational, cross-sectional case series. 25 eyes (18 patients) with late AMD and clinically identified MA were enrolled. Eyes were imaged using a confocal light-emitting diode blue-light fundus autofluorescence (FAF) device (EIDON, CenterVue, Padua, Italy) with 450 nm excitation wavelength and the capability for 'colour' FAF imaging, including both the individual red and green components of the emission spectrum. To produce images with a high contrast for isolating the green component, the red component was subtracted from the total FAF image. The main outcome measure was the presence of green emission fluorescence component (GEFC) within the MA area. Volume spectral domain optical coherence tomography (SD-OCT) scans were obtained through the macula and the OCT was correlated with the MA lesions identified on the FAF images, including regions of increased GEFC. Of the investigated eyes, 11 out of 25 (44.0 %) showed the absence of GEFC in the MA area, whereas 14 eyes (56.0%) were characterised by GEFC within the MA area. The presence and distribution of GEFC in the MA area correlated with the presence of hyper-reflective material over Bruch's membrane on the corresponding SD-OCT scans. Short-wave fluorophores, which contribute to the GEFC, are present in the MA area and appear to correspond to residual debris or drusenoid material. Short-wavelength fluorophores revealed by colour FAF imaging may warrant further study.


Skin necrosis complicating functional bracing.
We report a complication associated with functional bracing of a metacarpal shaft fracture that required operative intervention. A 30-year-old man with a closed, dorsally angulated, metacarpal shaft fracture of the right ring finger was treated with a functional brace. During brace immobilization, the patient developed full-thickness skin necrosis on the dorsum of the right hand. The patient underwent surgical debridement of the ulcerated area and fracture stabilization with an intramedullary Kirschner wire. Patients treated with a metacarpal brace should be instructed to release the strap every 5 to 6 hours for a short period to allow restoration of blood flow to the potentially ischemic skin.


Quantifying environmental DNA signals for aquatic invasive species across multiple detection platforms.
The use of molecular surveillance techniques has become popular among aquatic researchers and managers due to the improved sensitivity and efficiency compared to traditional sampling methods. Rapid expansion in the use of environmental DNA (eDNA), paired with the advancement of molecular technologies, has resulted in new detection platforms and techniques. In this study we present a comparison of three eDNA surveillance platforms: traditional polymerase chain reaction (PCR), quantitative PCR (qPCR), and digital droplet PCR (ddPCR) in which water samples were collected over a 24 h time period from mesocosm experiments containing a population gradient of invasive species densities. All platforms reliably detected the presence of DNA, even at low target organism densities within the first hour. The two quantitative platforms (qPCR and ddPCR) produced similar estimates of DNA concentrations. The analyses completed with ddPCR was faster from sample collection through analyses and cost approximately half the expenditure of qPCR. Although a new platform for eDNA surveillance of aquatic species, ddPCR was consistent with more commonly used qPCR and a cost-effective means of estimating DNA concentrations. Use of ddPCR by researchers and managers should be considered in future eDNA surveillance applications.


Effect of glyphosate on the microbial activity of two Romanian soils.
Glyphosate applied to soils potentially affect microbial activity. A series of field and laboratory experiments assessed the effect of this herbicide on soil microorganisms. The aim of experiments was to evaluate the effect of glyphosate application on the soil microbial community structure, function and their activity. We studied "in vitro", changes in the microbial activity of typical Chernozem and Gleysol soils, with and without applied glyphosate. The herbicide was applied at a rate of 2, respectively 4 mg kg(-1) of soil and microbial activity were measured by fluorescein diacetate (FDA) hydrolysis. We found an increase of 9 to 13% in FDA hydrolyses in the presence of glyphosate in rate of 2 mg kg (-1) compared with the same type of soil which had never received herbicide. The double quantity of glyphosate decrease soil microbial activity; the amount of hydrolyzed fluorescein is lower than the addition of 2 ppm. The greater decrease was observed in the Gleysol type where the fluorescein hydrolyzed is with 4, 85% lower than version control without glyphosate. Chemical characters of soil, influence soil biological activity when herbicide is added. In Chemozem case, rich in humus, whose predominant micro flora is represented by actinomycetes through glyphosate treatment these organisms growths of as major producers of antibiotics actinomycetes determine an inhibitory effect on eubacteria and micromycetes growth, which is highlighted by estimating a relatively small number of them. After 10 days, once with decreasing of glyphosate content in soil, decreases the number of active actinomycetes, therefore we are witnessing to a numerical growth of bacterial population. In Gleysol type the indigenous micro flora is represented by eubacteria, so when the glyphosate is added it was registered a high growth of these organisms fraction.


A longitudinal method of teaching pediatric palliative care to interns: preliminary findings regarding changes in interns' comfort level.
A longitudinal pediatric palliative care curriculum was introduced into the pediatric residency program at the University of California, Los Angeles. The present study explores the possible effects of this curriculum on the interns' self-assessed comfort levels regarding caring for children with life-threatening conditions. A newly created assessment tool was administered to interns in order to rate their comfort regarding pediatric palliative care at the beginning and conclusion of their intern year. Twenty-two of the 29 interns completed this survey. Baseline data indicated 55% of the interns had some experience with taking care of a dying pediatric patient during their medical school training, and 79% indicated that they had taken care of a dying adult. Only 7% of the interns felt adequately prepared to deal with death and dying, but all interns indicated interest in further learning about pediatric palliative care. Comparison of the overall comfort levels of the 22 responding residents before and after the first year of training in 20 different related tasks demonstrated a significant self-assessed improvement of comfort in seven areas. There was no increase in self-reported comfort in communication related to palliative care. Residents indicated increased comfort in some areas of pediatric palliative care after the first year of their training. The underlying cause of this increased comfort is unclear at this time. The overall effect of longitudinal palliative care curricula on residents' level of comfort in caring for this population deserves further assessment.


Performance and apparent total tract phosphorus and calcium digestibility in grower-finisher pigs fed diets with and without phytase.
The efficacy of a thermotolerant 6-phytase on performance and apparent total tract digestibility (ATTD) of P and Ca was evaluated in 96 crossbred barrows (8 replicates with 3 pigs each) fed 4 diets. Diets based on corn (Zea mays), a heat-treated grain mix, and soybean (Glycine max) meal with recommended [positive control (PC)] or reduced [negative control (NC)] P and Ca levels were fed from 25 to 115 kg BW. The PC diets contained 0.61% P and 0.72% Ca from 25 to 45 kg, 0.59% P and 0.66% Ca from 45 to 70 kg, and 0.48% P and 0.51% Ca from 70 kg to final BW. The NC diets were reduced in digestible P by 2.0, 2.0, and 1.1 g/kg and in Ca by 1.4, 1.0, and 0.8 g/kg, respectively, for the 3 phases. Phytase was added at 0, 250, and 500 phytase units (FTU)/kg to the NC diet. Performance was measured at the end of each feeding period and ATTD of P and Ca evaluated for a 3-d collection following a 7-d adaptation at an average BW of 45, 70, and 116 kg. Final BW of NC pigs (111.9 kg) was increased (P < 0.05) by P addition (120.3 kg; PC) and by phytase inclusion at both rates (116.5 and 117.6 kg, respectively). The ADG of NC pigs (781 g) was increased (P < 0.05) by both phytase levels (5.5 and 6.6%); pigs fed 500 FTU/kg achieved similar ADG as PC pigs (833 and 858 g, respectively). The G:F was reduced (P < 0.05) in NC pigs (0.308) compared to pigs fed the PC diet (0.328) or diets with 250 or 500 FTU phytase/kg (0.324 and 0.330, respectively). The ATTD of P was lowest in all periods for pigs fed NC diets (35.5% in starter, 32.2% in grower, and 32.1% in finisher period). Phytase increased (P < 0.05) ATTD of P in all periods at both application rates. Pigs fed 500 FTU/kg diet had a higher (P < 0.05) ATTD of P than pigs fed 250 FTU/kg and an ATTD of P at least similar to pigs fed PC. Similar but less pronounced effects were observed for ATTD of Ca. The phytase added to grower-finisher diets with reduced P and Ca nearly restored performance to the level of pigs fed diets with adequate P and Ca.


Geometrical optics and optimal transport.
The Fermat principle is generalized to a system of rays. It is shown that all the ray mappings that are compatible with two given intensities of a monochromatic wave, measured at two planes, are stationary points of a canonical functional, which is the weighted average of the actions of all the rays. It is further shown that there exist at least two stationary points for this functional, implying that in the geometrical optics regime the phase from intensity problem has inherently more than one solution. The caustic structures of all the possible ray mappings are analyzed. A number of simulations illustrate the theoretical considerations.


Carbon dynamics and energy recovery in a novel near-zero waste aquaponics system with onsite anaerobic treatment.
Aquaponics is gaining renewed interest to enhance food security. This study aimed to investigate the performance of a novel off-grid aquaponics system with near-zero water and waste discharge, focusing on the carbon cycle and energy recovery that was achieved by the addition of onsite anaerobic treatment of the solid waste streams. Following a stabilization stage, the system was closely monitored for four months. Fish tank water was recirculated via solid and nitrification reactors, from which 66% was recycled to the fish tank directly and 34% indirectly through the hydroponically grown plants. Fish solid waste was anaerobically treated, energy was recovered, and the nutrient-rich supernatant was recycled to the plants to enhance production. Plant waste was also digested anaerobically for further recovery of energy and nutrients. Fish stocking density was 15.3 and over time reached approximately 40 kg/m3 where it was maintained. Feed (45% protein content) was applied daily at 2% of body weight. Typical fish performance was observed with a survival rate >97% and feed conversion ratio of 1.33. Lettuce production was up to 5.65 kg/m2, significantly higher than previous reports, largely because of high nutrients reuse efficiency from the anaerobic supernatant that contained 130 and 34 mg/L N and P, respectively. Of the feed carbon, 24.5% was taken up by fish biomass. Fish solid wastes contained 38.2% carbon, of which 91.9% was recovered as biogas (74.5% CH4). Biogas production was 0.84 m3/kg for fish sludge and 0.67 m3/kg for dry plant material. CO2 sequestration was 1.4 higher than the feed carbon, which reduced the system's carbon footprint by 64%. This study is the first to demonstrate highly efficient fish and plant production with near-zero water and waste discharge and with energy recovery that can potentially supply the system's energy demand.


Frontal theta band oscillations predict error correction and posterror slowing in typing.
Performance errors are associated with robust behavioral and electroencephalography (EEG) effects. However, there is a debate about the nature of the relationship between these effects and implicit versus explicit error awareness. Our aim was to study the relationship between error related electrophysiological effects, such as spectral perturbations in fronto-medial theta band oscillations (FMT), and error awareness in typing. Typing has an advantage as an experimental paradigm in that detected errors are quickly and habitually signaled by the participant using backspace, allowing separation of detected from undetected errors without interruption in behavior. Typing is thought to be controlled hierarchically via inner and outer loops, which rely on different sources for error detection. Touch-typist participants were asked to copy-type 100 sentences as EEG was recorded in the absence of visual feedback. Continuous EEG data were analyzed using independent component analysis (ICA). Time-frequency and ERP analyses were applied to emergent independent components. The results show that single-trial FMT parameters and error related negativity (ERN) amplitude predict overt, adaptive posterror actions such as error correction via backspace; and, posterror slowing, reflecting implicit error awareness. In addition, we found that those uncorrected errors which were slowed down the most were also the ones associated with a high level of FMT activity. Our results as a whole show that FMT are related to neural mechanisms involved in explicit awareness of errors, and input from inner loop is sufficient for error correction in typing. (PsycINFO Database Record


Gram stain in the rapid determination of maternal colonization with group B beta-streptococcus.
To determine the usefulness of the Gram stain as a screening technique for maternal colonization with group B beta-streptococcus, we produced a Gram stain from a cervicovaginal swab taken at the time of sterile speculum examination in patients being evaluated for preterm rupture of membranes or preterm labor. The stain's interpretation was compared against the culture taken during the same examination. We found a sensitivity of 38% and a negative predictive power of 86%. Our findings differ from those of previous studies, and do not support the Gram stain as a useful screening approach for detection of colonization with this organism.


Suramin in combination with 5-fluorouracil (5-FU) and leucovorin (LV) in metastatic colorectal cancer patients resistant to 5-FU+LV-based chemotherapy.
Suramin has been shown to be of interest as a potential new anticancer agent because of its capacity to inhibit the binding of several growth factors to their receptors and to inhibit the growth of cancer cells in vitro. Since multi-autocrine loops involving growth factors which are antagonized by suramin have been demonstrated in colorectal cancer, we previously evaluated the activity of suramin in patients with advanced colorectal cancer. Interestingly, in this study three patients who had received 5-FU+LV after suramin, although heavily pretreated with fluoropyrimidines, obtained an objective response. This observation was intriguing as it might have been that suramin had changed the biology of the tumor, making it sensitive to 5-FU+LV. We therefore conducted the present study to investigate the possibility that suramin might overcome the resistance to 5-FU+LV. Only colorectal cancer patients with metastatic and progressive disease during 5-FU+LV-based chemotherapy were eligible for this study. Suramin was administered for eight weeks at doses determined by means of a computer-assisted dosing algorithm that used Bayesian pharmacokinetics to maintain suramin plasma concentrations of 200-250 microg/ml. 5-FU was administered weekly at a dosis of 450 mg/m2 halfway through a two-hour infusion of I-LV 250 mg/m2 starting one week after the initiation of suramin for a maximum of 26 weeks. Treatment was relatively well tolerated, but no objective responses were observed after the accrual of 13 patients in the first stage of the trial. Consequently, the trial was interrupted according to the initial two-stage sampling design. The present study does not support the hypothesis that suramin might overcome resistance to 5-FU+LV and its use in colorectal cancer is not recommended.


Individual differences in rat sensitivity to CO2.
Feelings of fear, anxiety, dyspnea and panic when inhaling carbon dioxide (CO2) are variable among humans, in part due to differences in CO2 sensitivity. Rat aversion to CO2 consistently varies between individuals; this variation in aversion may reflect CO2 sensitivity, but other personality traits could also account for individual differences in aversion. The aims of this study were to 1) assess the stability of individual differences in rat aversion to CO2, 2) determine if individual differences in sweet reward motivation are associated with variation in aversion to CO2, and 3) assess whether variation in aversion to CO2 is related to individual differences in motivation to approach gains (promotion focus) or maintain safety (prevention focus). Twelve female Sprague Dawley rats were exposed multiple times at three different ages (3, 9 and 16 months old) to CO2 in approach-avoidance testing to assess motivation to avoid CO2 against motivation to gain sweet rewards. Rats were also tested for motivation to find hidden sweet rewards, and for their motivation to approach rewards or darkness. Tolerance to CO2 increased with repeated exposures and was higher at older ages. Individual differences in aversion to CO2 were highly repeatable but unrelated to motivation for sweet rewards or the strength of promotion and prevention focus. These results indicate that individual differences in aversion to CO2 reflect variation in CO2 sensitivity.


Disparities in Telemedicine Use for Subspecialty Diabetes Care During COVID-19 Shelter-In-Place Orders.
During the COVID-19 pandemic, telemedicine use rapidly and dramatically increased for management of diabetes mellitus. It is unknown whether access to telemedicine care has been equitable during this time. This study aimed to identify patient-level factors associated with adoption of telemedicine for subspecialty diabetes care during the pandemic. We conducted an explanatory sequential mixed-methods study using data from a single academic medical center. We used multivariate logistic regression to explore associations between telemedicine use and demographic factors for patients receiving subspecialty diabetes care between March 19 and June 30, 2020. We then surveyed a sample of patients who received in-person care to understand why these patients did not use telemedicine. Among 1292 patients who received subspecialty diabetes care during the study period, those over age 65 were less likely to use telemedicine (OR: 0.34, 95% CI: 0.22-0.52, P < .001), as were patients with a primary language other than English (OR: 0.53, 95% CI: 0.31-0.91, P = .02), and patients with public insurance (OR: 0.64, 95% CI: 0.49-0.84, P = .001). Perceived quality of care and technological barriers were the most common reasons cited for choosing in-person care during the pandemic. Our findings suggest that, amidst the COVID-19 pandemic, there have been disparities in telemedicine use by age, language, and insurance for patients with diabetes mellitus. We anticipate telemedicine will continue to be an important care modality for chronic conditions in the years ahead. Significant work must therefore be done to ensure that telemedicine services do not introduce or widen population health disparities.


Is shorter always better? Relative importance of questionnaire length and cognitive ease on response rates and data quality for two dietary questionnaires.
In this study, the authors sought to determine the effects of length and clarity on response rates and data quality for two food frequency questionnaires (FFQs): the newly developed 36-page Diet History Questionnaire (DHQ), designed to be cognitively easier for respondents, and a 16-page FFQ developed earlier for the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The PLCO Trial is a 23-year randomized controlled clinical trial begun in 1992. The sample for this substudy, which was conducted from January to April of 1998, consisted of 900 control and 450 screened PLCO participants aged 55-74 years. Controls received either the DHQ or the PLCO FFQ by mail. Screenees, who had previously completed the PLCO FFQ at baseline, were administered the DHQ. Among controls, the response rate for both FFQs was 82%. Average amounts of time needed by controls to complete the DHQ and the PLCO FFQ were 68 minutes and 39 minutes, respectively. Percentages of missing or uninterpretable responses were similar between instruments for questions on frequency of intake but were approximately 3 and 9 percentage points lower (p < or = 0.001) in the DHQ for questions on portion size and use of vitamin/mineral supplements, respectively. Among screenees, response rates for the DHQ and the PLCO FFQ were 84% and 89%, respectively, and analyses of questions on portion size and supplement use showed few differences. These data indicated that the shorter FFQ was not better from the perspective of response rate and data quality, and that clarity and ease of administration may compensate for questionnaire length.


Leptospirosis in Ethiopia: a serological survey in domestic and wild animals.
Seven hundred and fifty-eight serum samples from domestic and wild animals in Ethiopia were tested for leptospiral antibodies by the microscopic agglutination test. The following percentages of seropositivity were obtained: horse (91.3 per cent), cow (70.7 per cent), pig (57.1 per cent), goat (47.3 per cent), sheep (43.4 per cent), camel (15.4 per cent), and dog (8.3 per cent). All 54 samples from birds and wild animals were seronegative. Most of the positive sera exhibited reaction to more than one serotype and antibodies to serotype butembo were predominant in sera of the majority of the examined species. However, grippotyphosa, rather than butembo was the predominant reacting serotype in camels and dogs. It is concluded that leptospirosis is of significant prevalence in domestic animals in Ethiopia and may constitute an occupational health hazard to man.


[Health education as a nursing intervention strategy for diabetes bearers].
A descriptive study with the objective of analyzing an educational process as a nursing intervention strategy for diabetic persons approaching the Problematization Methodology assumptions and Paulo Freire's theoretical references on freedom of education. Nineteen Diabetes bearers from the town of Nova Aurora, State of Goiás, Brazil, participated in the study over a 4-month period. The results evidenced that the dialogic educational activity was capable of contributing towards awakening the reflective, critical and creative potential of the group, presenting itself as an important intervention strategy for the nurse who works from the perspective of contributing for the patients' emancipation.


Development and Optimization of Mirabegron Solid Lipid Nanoparticles as an Oral Drug Delivery for Overactive Bladder.
Mirabegron (MBN), a β-3 adrenergic agent, is used in the treatment of overactive bladder. MBN has alow water solubility, high first-pass metabolism, and low bioavailability, consequently having poor absorption in the gastrointestinal tract. The present study is intended to formulate Mirabegron-loaded solid lipid nanoparticles (MBN-SLN) coated with PEG-400 to bypass hepatic first-pass metabolism and to improve its oral bioavailability. MBN-SLNs were developed using glyceryl monostearate by pre-emulsion-ultrasonication method, which was then optimized applying Box-Behnken Design. The optimized batch of MBN-SLN was selected for surface-modification with PEG-400 (MBN-PEG-SLN) and characterized by photon correlation spectroscopy, DSC, and XRD. Bioavailability studies were conducted in Wistar rats after oral administration of plain MBN dispersion, MBN-SLN, and MBN-PEG-SLN. Stable MBN-SLNs and MBN-PEG-SLN of the optimized batch having a mean particle size of 162.7 nm and 149.9 nm; zeta potential of -39.1 mV and -30.9 mV; % entrapment of 89.90% and 90.12%, respectively, were developed. The results of the in vitro drug release studies demonstrated a significant slow release of MBN from MBN-SLN (69.38%) and MBN-PEG-SLN (61.33%) as compared to the dispersion of pure drug (92.10%). The relative bioavailability, as a result of the in vivo studies, of MBN from MBN-PEG-SLN increased by 2-fold, based on the Cmax values, in comparison with the plain MBN dispersion. Thus, the study established that the oral bioavailability of MBN could be improved by the administration of MBN-PEG-SLN. The obtained results indicate SLNs as a potential drug delivery system for improving the bioavailability of poorly bioavailable drugs such as MBN by abating the first-pass metabolism.


Aging Systemic Milieu Impairs Outcome after Ischemic Stroke in Rats.
Compelling evidence indicates that factors in the blood can profoundly reverse aging-related impairments, as exposure of aged mice to young blood rejuvenates adult stem cell function, improves cognition, and ameliorates cardiac hypertrophy. Systemic factors from mice can also extend the life span of a partner exposed to a lethal treatment or disease. These findings suggest that the systemic milieu of a healthy young partner may be beneficial for an aged organism. However, it is unknown whether a healthy young systemic milieu can improve functional recovery after ischemic stroke. Intraperitoneal administration of young plasma into aged rats after ischemic stroke induced by distal middle cerebral artery occlusion (dMCAO) reduced infarct volume and motor impairment, compared with vehicle group. On the contrary, intraperitoneal administration of plasma from aged rats into young ischemic rats worsened brain injury and motor deficits. Using a proteomic approach, we found that haptoglobin levels were significantly increased in serum of aged rats and that intraperitoneal administration of haptoglobin impaired outcome after ischemic stroke in young rats. Our data suggest that the aging systemic milieu plays a critical role in functional outcome after ischemic stroke.


Arterial spin labeling and amide proton transfer imaging can differentiate glioblastoma from brain metastasis: a systematic review and meta-analysis.
Currently, arterial spin labeling (ASL) and amide proton transfer (APT) imaging have shown potential for distinguishing glioblastoma (GBM) from brain metastases. Thus, a meta-analysis was conducted to investigate this further. An extensive and comprehensive search was conducted in six English and Chinese databases according to predefined inclusion and exclusion criteria, encompassing data up to July 2023. Data from eligible literature were extracted, and bivariate models were employed to calculate pooled sensitivities, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) of the summary receiver operating characteristic curve. The meta-analysis included eleven articles. For ASL, the pooled sensitivity was 0.77 (95% CI 0.63-0.87), and the pooled specificity was 0.87 (95% CI 0.77-0.93). The pooled PLR was 5.89 (95% CI 2.97-11.69), the pooled NLR was 0.26 (95% CI 0.15-0.47), the pooled DOR was 22.33 (95% CI 6.89-72.34), and AUC was 0.90 (95% CI 0.87-0.92). For APT imaging, the pooled sensitivity was 0.78 (95% CI 0.70-0.85), and the pooled specificity was 0.86 (95% CI 0.77-0.92). The pooled PLR was 5.51 (95% CI 3.24-9.37), the pooled NLR was 0.25 (95% CI 0.17-0.37), the pooled DOR was 21.99 (95% CI 10.28-47.03), and the AUC was 0.90 (95% CI 0.87-0.92). This meta-analysis suggest that both ASL and APT imaging exhibit high accuracy in distinguishing between GBM and brain metastasis.


Paraffin treasures: do they last forever?
Formalin-fixed paraffin-embedded (FFPE) tissues stored in Departments of Pathology have become valuable sources of material for both diagnostic and research purposes. Obtaining nucleic acids from this material may be challenging, especially after storage for several years. The present study was aimed at evaluating DNA degradation over time by comparing the quality of DNA obtained in 2002 with the quality of DNA obtained in 2010 from the same paraffin blocks. The DNA obtained after several years from FFPE tissues was, in the majority of cases, of lower quality in terms of amplifiable length of nuclear DNA by PCR, and only a minority of them are still equally amplifiable. For this reason, if it is suspected that a molecular analysis may be necessary in the future, it would be important to obtain nucleic acids shortly after the diagnostic process is over or, when possible, to keep frozen samples at the institutional biorepository.


The human gut resistome.
In recent decades, the emergence and spread of antibiotic resistance among bacterial pathogens has become a major threat to public health. Bacteria can acquire antibiotic resistance genes by the mobilization and transfer of resistance genes from a donor strain. The human gut contains a densely populated microbial ecosystem, termed the gut microbiota, which offers ample opportunities for the horizontal transfer of genetic material, including antibiotic resistance genes. Recent technological advances allow microbiota-wide studies into the diversity and dynamics of the antibiotic resistance genes that are harboured by the gut microbiota ('the gut resistome'). Genes conferring resistance to antibiotics are ubiquitously present among the gut microbiota of humans and most resistance genes are harboured by strictly anaerobic gut commensals. The horizontal transfer of genetic material, including antibiotic resistance genes, through conjugation and transduction is a frequent event in the gut microbiota, but mostly involves non-pathogenic gut commensals as these dominate the microbiota of healthy individuals. Resistance gene transfer from commensals to gut-dwelling opportunistic pathogens appears to be a relatively rare event but may contribute to the emergence of multi-drug resistant strains, as is illustrated by the vancomycin resistance determinants that are shared by anaerobic gut commensals and the nosocomial pathogen Enterococcus faecium.


Brain Structure and Function of Chronic Low Back Pain Patients on Long-Term Opioid Analgesic Treatment: A Preliminary Study.
Chronic low back pain (CLBP) is often treated with opioid analgesics (OA), a class of medications associated with a significant risk of misuse. However, little is known about how treatment with OA affect the brain in chronic pain patients. Gaining this knowledge is a necessary first step towards understanding OA associated analgesia and elucidating long-term risk of OA misuse. Here we study CLBP patients chronically medicated with opioids without any evidence of misuse and compare them to CLBP patients not on opioids and to healthy controls using structural and functional brain imaging. CLBP patients medicated with OA showed loss of volume in the nucleus accumbens and thalamus, and an overall significant decrease in signal to noise ratio in their sub-cortical areas. Power spectral density analysis (PSD) of frequency content in the accumbens' resting state activity revealed that both medicated and unmedicated patients showed loss of PSD within the slow-5 frequency band (0.01-0.027 Hz) while only CLBP patients on OA showed additional density loss within the slow-4 frequency band (0.027-0.073 Hz). We conclude that chronic treatment with OA is associated with altered brain structure and function within sensory limbic areas.


Effectiveness of an intervention to increase the knowledge, attitude, and practice regarding the return and disposal of unused medications.
This study aimed to evaluate the effectiveness of an educational intervention (Safe D.U.M.P) to improve the knowledge, attitude, and practice regarding the return and disposal of unused medications. Community-dwelling adults in Malaysia who could understand English were recruited from two healthcare events. Participants were asked to fill out the validated Return and Disposal of Unused Medications (ReDiUM) questionnaire (pre-intervention), view six educational intervention posters on how to dispose of unused medications (Safe D.U.M.P), then answer the ReDiUM questionnaire immediately after viewing the posters (post-intervention). A total of 390 out of 456 participants participated (response rate=85.5%). Most were female (71%) with a median age of 42 years. The overall knowledge of participants significantly increased from 60% to 80% (p<0.001). However, no improvement was seen regarding their overall attitude and practice. This outcome was as expected as it may be more difficult to improve attitude and practice (when compared to knowledge) with a single educational session.


Carbon dioxide fixation by mouse embryos prior to implantation.
Mouse embryos in the stage of development prior to implantation were cultured in vitro in a medium that contained radioactive bicarbonate. The radioactivity was incorporated into the proteins and nucleic acids that were acid soluble. Uptake of radioactivity occurred into protein in the unfertilized ovum and was highest in all fractions in the early blastocyst stage. No incorporation was detected in the lipid fraction.


[Continuous arteriovenous hemofiltration in acute renal failure. Value of regulating the rate of ultrafiltration].
Continuous arteriovenous hemofiltration (CAVH) requires constant supervision and frequent readjustment of the rate of infusion of the substitution fluid because of variable filtration rate. In order to lighten the management of patients treated with CAVH, an ultrafiltration-pump assisted CAVH was used in 16 patients with oliguric renal failure and cardiovascular instability treated in the intensive care unit. A plate hemofilter (Biospal) was used which is equipped with the high hydraulic permeability AN 69 S membrane. The driving pump was set in order to modulate the ultrafiltration rate from 400 to 1000 ml/h. Ultrafiltration-pump assisted CAVH was given for 8.1 +/- 5.3 days and the filtration volume was 16.3 +/- 3.1 l/day. The mean life span of the hemofilter was 36.4 +/- 27.3 hours. No adverse reaction toward the artificial membrane was detected. Adequate control of fluid balance and electrolyte and acid-base homeostasis were obtained allowing parenteral nutrition. However, in two instances additional hemodialysis was required to adequately control urea generation. Ultrafiltration-pump assisted CAVH proved to be a simple and effective method of fluid removal and urea subtraction by convective transport. Maintenance of stable fluid balance and parenteral nutrition without osmotic disequilibrium was allowed. The pump driven hemofiltration allows optimal use of the filter.


Cutaneous myiasis from Dermatobia hominis.
We present a case report of cutaneous myiasis in a foreign traveler who was infected by Dermatobia hominis while visiting South America. This patient developed a painful furuncular lesion on the anterior scalp and noted that the lesion drained a serosanguinous fluid for more than a month before definitive treatment. Invasion of mammalian tissue by the larval forms of D. hominis typically results in the formation of a classic furuncular lesion. For persons who present with a lesion that contains a central draining stoma located on an exposed body surface, the diagnosis of myiasis should always be considered. In addition to the case report, we present a discussion of furuncular myiasis and describe the peculiar life cycle of the human botfly. We also describe the various therapies that may be employed for treating cutaneous myiasis, including surgical extraction of the larva and asphyxiation of the larva by application of petroleum jelly or other fat derivatives to the central stoma or breathing aperture.


Effectiveness and safety of intracardiac electrocardiogram guidance for epicutaneo-cava catheters via the lower extremity in preterm infants: a retrospective study.
In recent years, intracardiac electrocardiogram (IC-ECG) technology has been widely used for epicutaneo-cava catheter (ECC) placement and has shown many potential advantages. However, evidence about the quantitative changes, effectiveness, and safety of IC-ECG for lower extremity ECC is sparse. This study aimed to explore the quantitative changes in IC-ECG for lower extremity ECC and determine its effectiveness and safety. A retrospective study was conducted on 303 premature infants who underwent successful IC-ECG-guided lower extremity ECC placement between January 2019 and December 2021. All patients underwent chest X-ray postoperatively to verify the position of the catheter tip. The amplitudes of the surface electrocardiogram and IC-ECG QRS waves and the difference between the two amplitudes were measured. The effectiveness (matching rate between IC-ECG and chest X-ray) and safety (incidence of catheter-related complications) of IC-ECG for lower extremity ECC were evaluated. The matching rate between IC-ECG and chest X-ray was 95.0%. When the catheter tip was optimally positioned, the QRS amplitude of the IC-ECG was 0.85 ± 0.56 mv higher than that of the surface electrocardiogram. The overall incidence of catheter-related complications was 10.6%. The actual ECC insertion length was associated with a noticeably increased risk of catheter-related complications. This study suggests that IC-ECG is an effective and safe method by observing the dynamic changes in both QRS complexes and P wave to locate the tip of lower extremity ECC in preterm infants. Our findings would facilitate the application of IC-ECG for ECC localization.


Variations in the Detection of Anorectal Anomalies at Birth among European Cities.
The diagnosis of anorectal malformations (ARMs) is made at birth by perineal examination of the newborn, yet small series reported late diagnosis in almost 13%. No large series to date have looked into the magnitude of missed ARM cases in the neonatal period across Europe. This study aimed to define the rate of missed ARM at birth across four United Kingdom and European Union centers. All ARM cases treated at two United Kingdom tertiary centers in the past 15 years were compared with two tertiary European centers. Demographic and relevant clinical data were collected. Late diagnosis was defined as any diagnosis made after discharge from the birth unit. Factors associated with late diagnosis were explored with descriptive statistics. Across the four centers, 117/1,350, 8.7% were sent home from the birth unit without recognizing the anorectal anomaly. Missed cases showed a slight female predominance (1.3:1), and the majority (113/117, 96.5%) were of the low anomaly with a fistula to the perineum. The rate of missed ARM cases was significantly higher in the United Kingdom centers combined (74/415, 17.8%) compared with those in the European Union (43/935, 4.6%) (p < 0.00001), and this was independent of individual center and year of birth. Significant variation exists between the United Kingdom and other European countries in the detection of ARM at birth. We recommend raising the awareness of accurate perineal examination at the time of newborn physical examination. We feel this highlights an urgent need for a national initiative to assess and address the timely diagnosis of ARM in the United Kingdom.


ABO blood group and incidence of skin cancer.
Previous studies have examined the association between ABO blood group and the risk of some malignancies. However, no prospective cohort study to date has examined the association between ABO blood group and the risk of skin cancer. Using two large cohorts in the US, we examined ABO blood type and incidence of skin cancer, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). We followed up study participants (70,650 female nurses and 24,820 male health professionals) on their diagnosis of incident skin cancer from cohort baseline (1976 in women and 1986 in men) until 2006. Study participants reported their blood type in 1996 in both cohorts. During the follow-up, 685 participants developed melanoma, 1,533 developed SCC and 19,860 developed BCC. We used Cox proportional hazards models to calculate the hazard ratios (HR) and 95% confidence intervals (CI) of each type of skin cancer. We observed that non-O blood group (A, AB, and B combined) was significantly associated with a decreased risk of non-melanoma skin cancer overall. Compared to participants with blood group O, participants with non-O blood group had a 14% decreased risk of developing SCC (multivariable HR: 0.86; 95% CI: 0.78, 0.95) and a 4% decreased risk of developing BCC (multivariable HR: 0.96; 95% CI: 0.93, 0.99). The decreased risk of melanoma for non-O blood group was not statistically significant (multivariable HR: 0.91; 95% CI: 0.78, 1.05). In two large independent populations, non-O blood group was associated with a decreased risk of skin cancer. The association was statistically significant for non-melanoma skin cancer. Additional studies are needed to confirm these associations and to define the mechanisms by which ABO blood type or closely linked genetic variants may influence skin cancer risk.


Quantification of Training Load During Return to Play After Upper- and Lower-Body Injury in Australian Rules Football.
Training volume, intensity, and distribution are important factors during periods of return to play. To quantify the effect of injury on training load (TL) before and after return to play (RTP) in professional Australian Rules football. Perceived training load (RPE-TL) for 44 players was obtained for all indoor and outdoor training sessions, while field-based training was monitored via GPS (total distance, high-speed running, mean speed). When a player sustained a competition time-loss injury, weekly TL was quantified for 3 wk before and after RTP. General linear mixed models, with inference about magnitudes standardized by between-players SDs, were used to quantify effects of lower- and upper-body injury on TL compared with the team. While total RPE-TL was similar to the team 2 wk before RTP, training distribution was different, whereby skills RPE-TL was likely and most likely lower for upper- and lower-body injury, respectively, and most likely replaced with small to very large increases in running and other conditioning load. Weekly total distance and high-speed running were most likely moderately to largely reduced for lower- and upper-body injury until after RTP, at which point total RPE-TL, training distribution, total distance, and high-speed running were similar to the team. Mean speed of field-based training was similar before and after RTP compared with the team. Despite injured athletes' obtaining comparable TLs to uninjured players, training distribution is different until after RTP, indicating the importance of monitoring all types of training that athletes complete.


Handgrip strength, but not other nutrition parameters, predicts circulatory congestion in peritoneal dialysis patients.
Handgrip strength (HGS) is a marker of lean muscle mass. This study aims to test the hypothesis that a low HGS reflects a diseased cardiac status and predicts future risk of circulatory congestion in chronic peritoneal dialysis (PD) patients. Two hundred and eighteen chronic PD patients were prospectively recruited from a single regional dialysis unit in Hong Kong. HGS, serum albumin, lean body mass (LBM) by creatinine kinetics (CK) and subjective global assessment (SGA) were assessed at study entry and examined in relation to the risk of developing circulatory congestion over a 4-year follow-up. Adjusting for age, gender and height, HGS showed significant correlations with LBM by CK, SGA, serum albumin, atherosclerotic vascular disease, left ventricular (LV) mass index and early mitral inflow velocity to peak mitral annulus velocity (E/Em ratio). In the multivariable Cox regression analysis, HGS (P = 0.004) and ejection fraction (P = 0.004) were both second to LV mass index (P < 0.001) as the most significant factors in predicting circulatory congestion at 4 years. Serum albumin, LBM by CK and SGA were not independently predictive of circulatory congestion. Patients with systolic dysfunction and HGS < gender-specific median had an adjusted hazard ratio of 2.77 [95% confidence interval (CI), 1.46-5.28; P = 0.002] in developing circulatory congestion than those with normal systolic function and HGS ≥ gender-specific median. A low HGS reflects a diseased cardiac status and predicts future risk of circulatory congestion independent of other nutritional, echocardiographic and clinical parameters in PD patients. The important link between skeletal myopathy and myocardial disease in uraemic patients warrants further investigation.


Computational and artificial intelligence-based approaches for drug metabolism and transport prediction.
Drug metabolism and transport, orchestrated by drug-metabolizing enzymes (DMEs) and drug transporters (DTs), are implicated in drug-drug interactions (DDIs) and adverse drug reactions (ADRs). Reliable and precise predictions of DDIs and ADRs are critical in the early stages of drug development to reduce the rate of drug candidate failure. A variety of experimental and computational technologies have been developed to predict DDIs and ADRs. Recent artificial intelligence (AI) approaches offer new opportunities for better predicting and understanding the complex processes related to drug metabolism and transport. We summarize the role of major DMEs and DTs, and provide an overview of current progress in computational approaches for the prediction of drug metabolism, transport, and DDIs, with an emphasis on AI including machine learning (ML) and deep learning (DL) modeling.


Time to antivenom administration is not associated with total antivenom dose administered in a copperhead-predominant snakebite population.
To prevent unnecessary antivenom administration in crotaline snakebite, observation for progression is recommended for the patient with minor envenomation whose condition is stable and not progressing. The objective of this study was to determine the association between the time from bite to initial antivenom administration (Time(AV)) and the total amount of antivenom administered (Total(AV)) and to determine what proportion of patients did not have progression of the envenomation syndrome and did not receive antivenom. This was a retrospective chart review of patients presenting with crotaline snakebite within 24 hours from 2009 through 2012. Blinded dual-chart abstraction and strict data point definitions were used. Spearman correlation was used to determine the association between Time(AV) and Total(AV). A general linear model was used to examine this association using Time(AV) categorized to early and late administration, adjusted for likely confounders. Confounders included age, extremity involved, initial severity, and year of envenomation. Ninety-five eligible patients were analyzed with 45 (47%) males and a mean (±SD) age of 36.5 (±21.1) years. Eighty-five (89%) received antivenom, with a median Time(AV) of 3.3 hours (interquartile range [IQR] = 2.5 to 5.2 hours). The median Total(AV) was 10 vials (IQR = 6 to 14 vials). The univariate analysis showed a small but statistically significant decrease in Total(AV) given to patients treated greater than 6 hours from bite (r = -0.26, p = 0.015). The multivariate analysis resulted in no significant relation between early or late Time(AV) and Total(AV) (p = 0.10) after adjustment for confounders. Most minimal envenomation syndromes (80%, or 41 of 51) progressed to moderate grade envenomations. Time(AV) was not associated with Total(AV) when adjusted for likely confounders and supports current recommendations to observe for progression in minor envenomation. The majority of envenomations progressed, resulting in only a small proportion of patients not eventually receiving antivenom. The authors recommend observation in an environment where the patient can be adequately reassessed for progression of the envenomation.


In HIV-Infected Immunological Non-Responders, Hepatitis C Virus Eradication Contributes to Incomplete Normalization of Systemic Inflammation Indexes, but Does Not Lead to Rapid CD4+ T-Cell Count Recovery.
In HIV-positive individuals taking antiretroviral therapy, coinfection with hepatitis C virus (HCV) increases systemic inflammation, which interferes with the CD4+ T-cells regeneration. This study evaluated the effect of HCV eradication on systemic inflammation and CD4+ T-cell regeneration in patients who gave poor response to antiretroviral therapy, the so-called "immunological non-responders" (INRs). HIV-infected patients who received a course of direct-acting antivirals for treating hepatitis C were examined. The control groups included HIV/HCV-coinfected INRs and relatively healthy volunteers. It was established for the first time that HCV eradication is not accompanied by a complete suppression of systemic inflammation, but improves the T-cell pool composition: in INRs, the blood CD4+/CD8+ T-lymphocyte ratio increases and approaches those of healthy individuals. Apparently, in INRs treated for hepatitis C, the immune system recovery takes time and may be incomplete.


esATAC: an easy-to-use systematic pipeline for ATAC-seq data analysis.
ATAC-seq is rapidly emerging as one of the major experimental approaches to probe chromatin accessibility genome-wide. Here, we present 'esATAC', a highly integrated easy-to-use R/Bioconductor package, for systematic ATAC-seq data analysis. It covers essential steps for full analyzing procedure, including raw data processing, quality control and downstream statistical analysis such as peak calling, enrichment analysis and transcription factor footprinting. esATAC supports one command line execution for preset pipelines and provides flexible interfaces for building customized pipelines. esATAC package is open source under the GPL-3.0 license. It is implemented in R and C++. Source code and binaries for Linux, MAC OS X and Windows are available through Bioconductor (https://www.bioconductor.org/packages/release/bioc/html/esATAC.html). Supplementary data are available at Bioinformatics online.


Rhabdomyolysis from an intramuscular injection of glyphosate-surfactant herbicide.
Glyphosate-surfactant herbicide (GlySH) is widely used as a non-selective herbicide. Most intoxicated cases are from ingestion, inhalation, and skin exposure. Intramuscular injection of GlySH has never been reported. We present a case of GlySH intoxication via intramuscular injection. A 42-year-old woman came to the emergency department complaining of painful swelling of left upper limb for 12 h. She had performed an intramuscular injection of 6 mL of GlySH over the lateral aspect of the left elbow 15 h previously. Physical examination disclosed painful swelling over left distal arm, elbow, and forearm with three needle punctures. CT scan revealed ill-defined areas of heterogeneous high density with marked swelling at subcutaneous tissue over posterior aspect of the elbow. The mechanism of toxicity of GlySH is complicated and surfactant was thought to play an important role in GlySH intoxication. Intramuscular GlySH poisoning is different from oral GlySH intoxication. Care should be taken when monitoring acute rhabdomyolysis and compartment syndrome, which may develop rapidly and contribute to the surfactant component of glyphosate formulation.


Oculodermal melanocytosis--Nevus of Ota (with palatal pigmentation).
Nevus of Ota is a benign dermal melanocytosis, that involves facial skin as a macular discoloration, appearing as blotchy blue to blue gray. It involves the upper portion of the face, especially over the periorbital area. It also involves ocular structures such as episclera, sclera, conjunctiva, cornea, retina, uveal tract and also nasopharynx, auricular mucosa, tymphanic membrane and dura. Glaucoma and malignant melanoma are the two known ocular complications in patients with Nevus of Ota. 12-18% of these patients exhibits palatal pigmentation. Here we are reporting two cases of Oculodermal melanocytosis, one of which exhibited palatal pigmentation.


Coumarins give misleading absorbance with Ellman's reagent suggestive of thiol conjugates.
In the course of a screening for phytochelatins in cadmium-exposed bryophytes in the terrestrial mosses Polytrichum formosum and Atrichum undulatum we detected compounds with absorption properties and retention times similar to phytochelatins when applying the commonly used standard method RP-HPLC and post-column derivatization with thiol-specific DTNB (Ellman) reagent. Moreover, as with phytochelatins known in other plants, the concentrations of these compounds increased slightly after Cd stress. The concentration of the precursor glutathione (gamma-ECG), however, increased in the presence of Cd. In order to verify the identity of these putative phytochelatins we performed LC-ESI-MS analyses as well as 1H NMR on extracts from P. formosum and A. undulatum. Spectroscopic investigations indicated that the detected compounds were neither phytochelatins nor other thiol compounds. From the results of HPLC-1H NMR and mass spectrometry we concluded that at least one of these substances was a coumarin, probably a 5,8-dihydroxy-7-methoxycoumarin-5-beta-glucopyranoside, which has already been described for A. undulatum and P. formosum. The results of our investigations prove that under the basic pH conditions essential for the Ellman test for thiol compounds, coumarins show comparable UV/VIS absorption properties. Therefore, a positive post-column Ellman reaction cannot unambiguously prove the presence of thiol-containing compounds in plants.


Structural and Functional Insights into the Biomineralized Zeolite Imidazole Frameworks.
Biomineralization is a natural process of mineral formation mediated by biomacromolecules, allowing access to hierarchical structures integrating biological, chemical, and material properties. In this contribution, we comprehensively investigate the biomineralization of zeolite imidazole frameworks (ZIFs) for one-step synthesis of an enzyme-MOF biocomposite, in terms of differential crystallization behaviors, fine microstructure of resultant ZIF biominerals, the enzyme's conformation evolution, and protective effect of ZIF mineral. We discover that the biomineralization ability is ZIF organic linker dependent and the biocatalytic function is highly related to the ZIF mineral species and their distinguishable topologies and defect structures. Importantly, a side-by-side analysis suggests that the protective effect of ZIF mineral toward the hosted enzyme is highly associated with the synergistic effect of size dimension and chemical microenvironment of the ZIF pores. This work provides important insight into the ZIF-dependent biomineralization behaviors and highlights the important role of the ZIF microstructure in its biocatalytic activity and durability, which has been underestimated previously.


The Hyperactivity-Impulsivity-Irritiability-Disinhibition-Aggression-Agitation Domain in Alzheimer's Disease: Current Management and Future Directions.
Behavioral and psychological symptoms of dementia (BPSD) afflict the vast majority of patients with dementia, especially those with Alzheimer's disease (AD). In clinical settings, patients with BPSD most often do not present with just one symptom. Rather, clusters of symptoms commonly co-occur and can, thus, be grouped into behavioral domains that may ultimately be the result of disruptions in overarching neural circuits. One major BPSD domain routinely identified across patients with AD is the hyperactivity-impulsivity-irritiability-disinhibition-aggression-agitation (HIDA) domain. The HIDA domain represents one of the most difficult sets of symptoms to manage in AD and accounts for much of the burden for caregivers and hospital staff. Although many studies recommend non-pharmacological treatments for HIDA domain symptoms as first-line, they demonstrate little consensus as to what these treatments should be and are often difficult to implement clinically. Certain symptoms within the HIDA domain also do not respond adequately to these treatments, putting patients at risk and necessitating adjunct pharmacological intervention. In this review, we summarize the current literature regarding non-pharmacological and pharmacological interventions for the HIDA domain and provide suggestions for improving treatment. As epigenetic changes due to both aging and AD cause dysfunction in drug-targeted receptors, we propose that HIDA domain treatments could be enhanced by adjunct strategies that modify these epigenetic alterations and, thus, increase efficacy and reduce side effects. To improve the implementation of non-pharmacological approaches in clinical settings, we suggest that issues regarding inadequate resources and guidance for implementation should be addressed. Finally, we propose that increased monitoring of symptom and treatment progression via novel sensor technology and the "DICE" (describe, investigate, create, and evaluate) approach may enhance both pharmacological and non-pharmacological interventions for the HIDA domain.


Fluconazole and propolis co-encapsulated in chitosan nanoparticles for the treatment of vulvovaginal candidiasis in a murine model.
Vulvovaginal candidiasis (VVC) is a fungal infection caused mainly by Candida albicans. The treatment of VVC with azoles has been impaired due to the increased cases of resistance presented by this pathogen. The aim of the present study was to investigate the antifungal activity of mucoadhesive chitosan nanoparticles encapsulating both green propolis and fluconazole for topical use in the treatment of VVC. The nanoparticles were prepared by the ionic gelation method, resulting in a size of 316.5 nm containing 22 mg/kg of green propolis and 2.4 mg/kg of fluconazole. The nanoparticles were non-toxic in vitro using red blood cells or in vivo in a Galleria mellonella toxicity model. The treatment of female BALB/c mice infected by C. albicans ATCC 10231 with topical nanoparticles co-encapsulating fluconazole and green propolis was effective even using a fluconazole amount 20 times lower than the amount of miconazole nitrate 2% cream. Considering that the mucoadhesive property of chitosan, which is known to allow a prolonged retention time of the compounds at the mucous epithelia, the antifungal potential of the phenols and flavonoids present in green propolis may have favored the effectiveness of this treatment. These results indicate that this formulation of topical use for fluconazole associated with green propolis can be used as a promising approach to therapy for the treatment of VVC, thus contributing to reducing the development of resistance to azoles.


Optical Writing of Magnetic Properties by Remanent Photostriction.
We present an optically induced remanent photostriction in BiFeO_{3}, resulting from the photovoltaic effect, which is used to modify the ferromagnetism of Ni film in a hybrid BiFeO_{3}/Ni structure. The 75% change in coercivity in the Ni film is achieved via optical and nonvolatile control. This photoferromagnetic effect can be reversed by static or ac electric depolarization of BiFeO_{3}. Hence, the strain dependent changes in magnetic properties are written optically, and erased electrically. Light-mediated straintronics is therefore a possible approach for low-power multistate control of magnetic elements relevant for memory and spintronic applications.


Headlines win elections: Mere exposure to fictitious news media alters voting behavior.
Repeatedly encountering a stimulus biases the observer's affective response and evaluation of the stimuli. Here we provide evidence for a causal link between mere exposure to fictitious news reports and subsequent voting behavior. In four pre-registered online experiments, participants browsed through newspaper webpages and were tacitly exposed to names of fictitious politicians. Exposure predicted voting behavior in a subsequent mock election, with a consistent preference for frequent over infrequent names, except when news items were decidedly negative. Follow-up analyses indicated that mere media presence fuels implicit personality theories regarding a candidate's vigor in political contexts. News outlets should therefore be mindful to cover political candidates as evenly as possible.


A microbial muramidase improves growth performance and reduces inflammatory cell infiltration in the intestine of broilers chickens under Eimeria and Clostridium perfringens challenge.
The objective of the present studies was to evaluate muramidase (MUR) supplementation in broilers under Eimeria and/or Clostridium perfringens challenge. For this, 2 experiments were conducted. Experiment 1. A total of 256 one-day old male Cobb 500 chicks were placed in battery cages in a completely randomized design, with 5 treatment groups, 7 replicate cages per treatment and 8 birds per cage. The treatments were: nonchallenged control (NC), challenged control (CC), CC + MUR at 25,000 or 35,000 LSU(F)/kg, and CC + Enramycin at 10 ppm (positive control-PC). Challenge consisted of 15× the recommended dose of coccidiosis vaccine at placement, and Clostridium perfringens (108 CFU/bird) inoculation at 10, 11, and 12 d. Macro and microscopic evaluation, immunohistochemistry, and gene expression were evaluated at 7, 14, 21, and 28 d of age. Experiment 2. A total of 1,120 one-day old male Cobb 500 chicks were placed in floor pens with fresh litter in a completely randomized design, with 4 treatment groups, 8 replicate pens per treatment, and 35 birds per pen. The treatments were: Control, supplementation of MUR at 25,000 or 45,000 LSU(F)/kg, and a positive control (basal diet plus Enramycin). At 10, 11, and 12 d of the experiment all the birds were inoculated by oral gavage with a fresh broth culture of a field isolate Clostridium perfringens (0.5 mL containing 106 CFU/bird). It was observed that in Experiment 1 MUR supplementation reduced the infiltration of macrophages and CD8+ lymphocytes in the liver and ileum of infected birds, downregulated IL-8 and upregulated IL-10 expression. In Experiment 2, MUR linearly improved the growth performance of the birds, increased breast meat yield, and improved absorption capacity. MUR supplementation elicited an anti-inflammatory response in birds undergoing a NE challenge model that may explain the improved growth performance of supplemented birds.


Does it make clinical sense to equate terminally ill patients who require life-sustaining interventions with those who do not?
Two US courts of appeals have ruled that competent, terminally ill patients have a constitutional right to physician-assisted suicide. The cases are now before the US Supreme Court, which is expected to issue a ruling later this year. This article analyzes the keystone of the courts' ruling: their assertion that competent, terminally ill patients who are being kept alive on life support are equivalent to competent, terminally ill patients who do not require such support. Because the former are permitted to end their lives by refusing treatment, the courts found that the latter also have a right to determine the time and manner of their death, through prescriptions for lethal doses of medication. This article analyzes whether the courts' thinking is premised on a clinically plausible view of the care of terminally ill patients. Based on a discussion of common situations involving terminal illness, we argue that the courts' reasoning is deeply flawed. The article also analyzes how the implications of the courts' reasoning might undermine the care of terminally ill patients.


Isolated infection of a decommissioned penile prosthesis reservoir with Actinomyces neuii.
Inflatable penile prostheses (IPPs) are a well-established and reliable treatment for medication refractory erectile dysfunction. The most serious complication with IPPs is infection, with the reported incidence after primary placement 1% to 3% and after revision surgery 8% to 18%. The aim of this report is to describe an infected decommissioned IPP reservoir with Actinomyces neuii with successful preservation of a functioning implant. After 9 years of successful use with an IPP (AMS 700 CX) for Peyronie's disease and organic erectile dysfunction, a 79-year-old man underwent replacement with an AMS 700 LGX. The decommissioned reservoir was kept in the right prevesical space, and the new reservoir was placed in the left prevesical space. Three months later, he presented with right inguinal pain and swelling. He was found to have an infected right reservoir with A. neuii, sparing his new IPP. After removal of the right reservoir, he had an uneventful recovery and has shown no evidence of infection in the new device. Revision surgery for IPPs carries a higher risk for implant infection. This is the first report of a genitourinary implant infection with A. neuii. Aggressive surgical and medical treatment may allow preservation of the functioning implant, despite gross infection of the decommissioned reservoir.


[Study of various factors affecting the colonization of the digestive tract in white mice by Candida albicans].
This paper deals with the quantitative localization of Candida albicans in different parts of white micr gastrointestinal tract after oral inoculation of the yeast. Animals are previously treated with ampicillin, cortisone, or estradiol. Female pregnant and normal adult mice are also used. Our results show that the number of yeasts increases respectively in small intestine, stomach, caecum, and sigmoid. As compared with normal adult mice, C. albicans is more abundant in mice treated wtih ampicillin or cortisone whereas the yeast growth is lower in pregnant animals or in mice receiving estradiol. Moreover, male animals ordinarily show higher values than those found in female mice.


The aetiology of pharyngotonsillitis in adolescents and adults - Fusobacterium necrophorum is commonly found.
Sore throat is common in primary healthcare. Aetiological studies have focused on the presence of a limited number of pathogens. The aim of the present study was to investigate the presence of a wide range of bacteria and viruses, including Fusobacterium necrophorum, in patients with pharyngotonsillitis and in asymptomatic controls. A prospective case control study was performed in primary healthcare in Kronoberg County, Sweden. Patients (n=220) aged 15 to 45 years with a suspected acute pharyngotonsillitis, and controls (n=128), were included. Nasopharyngeal and throat swabs were analysed for β-hemolytic streptococci, F. necrophorum, Mycoplasma pneumoniae, and Chlamydophila pneumoniae, and 13 respiratory viruses. Serum samples were analysed for antibodies to Epstein-Barr virus. The patient history and symptoms, including Centor score, were analysed in relation to pathogens. In 155/220 (70.5%) of the patients, as compared to 26/128 (20.3%) of the controls (p <0.001), at least one microorganism was found. Group A streptococci, F. necrophorum, and influenza B virus were the three most common findings, and all significantly more common in patients than in controls (p <0.001, p 0.001, and p 0.002, respectively). Patients with F. necrophorum only (n=14) displayed a lower Centor score than patients with Group A streptococcus only (n=46), but a higher score than patients with influenza B, other viruses, or no potential pathogen (Kruskal-Wallis p <0.001). A pathogen was detected in 70% of the patients, displaying a wide range of pathogens contributing to the aetiology of pharyngotonsillitis. This study supports F. necrophorum as one of the pathogens to be considered in the aetiology of pharyngotonsillitis.


Placing constraints on the use of the ACGME milestones: a commentary on the limitations of global performance ratings.
As part of the outcomes-based accreditation process, the Accreditation Council for Graduate Medical Education (ACGME) now requires that medical specialties formulate and use educational milestones to assess residents' performance. These milestones are specialty-specific achievements that residents are expected to demonstrate at established intervals in their training. In this Commentary, the authors argue that the pressure to efficiently use program directors' and faculty members' time, particularly in the increasingly clinical-revenue-dependent model of the academic medical center, will lead program directors to meet these new accreditation expectations solely by adding items that assess these competencies to global end-of-rotation rating forms. This approach will increase the workload of faculty but will not provide new and useful information about residents' competence. These same concerns could apply if assessment committees attempt to measure these new performance dimensions without using direct observation to evaluate residents' performance. In these circumstances, the milestones movement will fall short of its intention and potential. In this Commentary, the authors outline and provide evidence from the literature for their concerns. They discuss the role that human judges play in measuring performance, the measurement characteristics of global performance ratings, and the problems associated with simply adding items to existing global rating forms.


Professional Mental Health Help-Seeking Amongst Afghan and Iraqi Refugees in Australia: Understanding Predictors Five Years Post Resettlement.
The current longitudinal study sought to identify predictors of professional help seeking for mental health problems amongst Afghan and Iraqi refugees five years post-settlement utilising the Building a New Life in Australia dataset (BNLA). Data were collected via face-to-face or phone interviews across five waves from October 2013 to March 2018. Afghan and Iraqi born refugees numbering 1180 and over 18 years of age with a permanent humanitarian visa were included in this study. The results suggest differences in help-seeking behaviors amongst the two ethnic groups. Amongst the Afghan sample, older adults with high psychological distress were more likely to seek help, while living in regional Australia, not requiring interpreters, and knowing how to find out information about government services were related to lower likelihood of help-seeking. Within the Iraqi sample, poor overall health and knowing how to find out about services were related to a greater likelihood of help-seeking, while fewer financial hardships decreased the likelihood of help-seeking. Amongst those with probable PTSD, disability was associated with an increased likelihood of help-seeking while experiencing fewer financial hardships and living in regional Australia resulted in a lower likelihood of help-seeking in this group. These results have implications for promotional material and mental health interventions, suggesting that more integrated services tailored to specific characteristics of ethnic groups are needed.


Macular Edema of Choroidal Origin.
Macular edema is most often clinically defined as an accumulation of serous fluid within the neurosensory retina with increased thickness of the central retina. In exudative age-related macular degeneration the leakage of fluid from the choroidal new vessels may be the origin of macular edema. Their abnormal permeability and the inflammatory reaction are mechanisms involved in this accumulation of fluid, which occurs in all layers. Cystoid macular edema is more often associated with subepithelial occult choroidal neovascularization (CNV) than it is with pre-epithelial classic CNV. The simultaneous presence of choroidal new vessels and ME implies a number of cellular dysfunctions especially of Müller cells and subsequently metabolic alterations. The leakage from the choroidal new vessels, predominantly vascular endothelial growth factor (VEGF)-induced, may produce a large accumulation of fluid under the neurosensory retina. It is also likely that the key signaling steps occur prior to the upregulation of VEGF either initiated by, or facilitated by, cytokines, which act under normal basic conditions to counterbalance the integral VEGF effects and, in pathologic circumstances, may either counteract or serve to amplify the process.


Systemic and regional hemodynamic effects of leukotrienes D4 and E4 in the conscious rat.
The effect of leukotrienes (LTs) D4 and E4 on systemic and regional hemodynamic variables were studied in the conscious rat (n = 5-9). Renal (R), mesenteric (M), and hindquarter (HQ) blood flow (BF) were monitored by directional pulsed Doppler velocimetry, and mean arterial blood pressure (MAP) and heart rate were recorded through a catheter in the femoral artery. In a separate series of experiments, cardiac index (CI) was measured by the thermodilution method. Systemic injection of LTD4 or LTE4 (0.1-10 micrograms/kg) produced dose-dependent pressor responses; BF in the M, HQ, and R vessels declined, due to increased vascular resistance (VR) at the following order: M much greater than HQ greater than R. Low doses of LTD4 or LTE4 produced vasodilation in the HQ area. Infusion of LTD4 (3 micrograms X kg-1 X min-1) for 10 min produced progressive and pronounced vascular constriction in the M and HQ regions along with reduction in BF. The LTD4 infusion also markedly decreased CI with a concomitant rise in total peripheral resistance index (TPRI). Indomethacin (5 mg/kg iv) pretreatment did not modify any of the hemodynamic effects of LTD4 or LTE4. FPL 55712 (10 mg/kg iv) and LY 171883 (30 mg/kg iv), two different LT-receptor antagonists, partially blocked the constriction effects of these LTs. LY 171883, but not FPL 55172, blocked the HQ vasodilation produced by LTE4. LY 171883 alone increased HQ-BF and reduced HQ-VR. These data indicate that LTD4 and LTE4 are potent constrictors of the M vascular bed, but at low doses they also produce dilation of the HQ blood vessels. Furthermore, no escape from the effects of prolonged infusion of the LTs was demonstrated in this species. Finally, the hemodynamic responses to LTD4 and LTE4 in the conscious rat are independent of cyclooxygenase products of LTs and are only partially blocked by FPL 55712 or LY 171883. These studies taken together suggest a differential distribution of multiple LT receptors in the rat vasculature.


AACN's healthy work environment standards and an empowering nurse advancement system.
An empowering clinical nurse advancement system can facilitate institutional behaviors that embrace all of AACN's healthy work environment standards and thus serve as a building block for developing a flourishing health care environment. The results generate positive outcomes that are evident to health care professionals, patients, patients' families, and health care organizations. Patients benefit from highly satisfied employees who work in a culture of caring and excellence.


Impedance cardiography for cardiac output measurement: an evaluation of accuracy and limitations.
The Kubicek thoracic cylinder model of impedance cardiography (IC) for measuring beat-by-beat stroke volume (SV) was evaluated in controlled studies using the electromagnetic flowmeter (FM) as the reference technique. Assuming the validity of the Kubicek equation for stroke volume calculation, IC stroke volume was found to be a linear function of EM values at any one haematocrit over a wide range of SV, but the slope of the relationship fell as haematocrit fell. Experiments using the same equation in dogs, in which blood resistivity in vivo (rho tau) was made the dependent variable, and the EM-derived value was used for stroke volume, showed that rho tau was almost constant over a wide range of haematocrits. These findings were supported by studies in man and rabbit where Fick and thermodilution-derived values were used for stroke volume. When these data were applied to normotensive and hypertensive human subjects with normal hearts and lungs in controlled studies at rest, during tilting, with drug therapy and on exercise, IC measured stroke volume and cardiac output with a variability at least as good as the 9-11% acceptable for clinical use. This conclusion applied to thoracic configurations of different sizes and shapes from adult man to the neonate. In chronic disease states, while assessments of relative changes are valuable, absolute data are questionable. Further research is required under these conditions, as it is also for other models of IC, which are based on different assumptions.


Immunoproteasome subunit ß5i/LMP7-deficiency in atherosclerosis.
Management of protein homeostasis by the ubiquitin-proteasome system is critical for atherosclerosis development. Recent studies showed controversial results on the role of immunoproteasome (IP) subunit β5i/LMP7 in maintenance of protein homeostasis under cytokine induced oxidative stress. The present study aimed to investigate the effect of β5i/LMP7-deficiency on the initiation and progression of atherosclerosis as a chronic inflammatory, immune cell driven disease. LDLR-/-LMP7-/- and LDLR-/- mice were fed a Western-type diet for either 6 or 24 weeks to induce early and advanced stage atherosclerosis, respectively. Lesion burden was similar between genotypes in both stages. Macrophage content and abundance of polyubiquitin conjugates in aortic root plaques were unaltered by β5i/LMP7-deficiency. In vitro experiments using bone marrow-derived macrophages (BMDM) showed that β5i/LMP7-deficiency did not influence macrophage polarization or accumulation of polyubiquitinated proteins and cell survival upon hydrogen peroxide and interferon-γ treatment. Analyses of proteasome core particle composition by Western blot revealed incorporation of standard proteasome subunits in β5i/LMP7-deficient BMDM and spleen. Chymotrypsin-, trypsin- and caspase-like activities assessed by using short fluorogenic peptides in BMDM whole cell lysates were similar in both genotypes. Taken together, deficiency of IP subunit β5i/LMP7 does not disturb protein homeostasis and does not aggravate atherogenesis in LDLR-/- mice.


Incidence, risk factors and clinical outcomes of peripherally inserted central catheter spontaneous dislodgment in oncology patients: a prospective cohort study.
Peripherally inserted central catheter (PICC) spontaneous dislodgment is insidious in onset and prone to cause complications. We performed a prospective cohort study to examine the incidence, risk factors and clinical results of PICC spontaneous dislodgment in oncology patients to facilitate successful early diagnosis, prophylaxis and management. Consecutive oncology patients, undergoing placement of PICCs, were enrolled and prospectively followed up until their catheters were removed or PICC spontaneous dislodgment presented. The patients with PICC spontaneous dislodgment or catheter-associated thrombosis (CRT) were followed up for an extra three months from the date of diagnosis. The main endpoint was PICC spontaneous dislodgment, and the sub-endpoints were CRT and catheter in-place time. The PICC insertion team, nurses, interventional radiologists and oncology doctors collected longitudinal data. Over a total of 60,894 days of cumulative follow-up, 21 out of 510 PICCs presented spontaneous dislodgment, leading to an incidence rate of 4.12%. The CRT rate of the group with PICC spontaneous dislodgment was much higher than that of the group without PICC spontaneous dislodgment (RR=17.46, 95% CI: 8.29-36.82, p=1.09×10(-17)). Five baseline exposure factors, including primary lung cancer, metastatic lung cancer, chest radiotherapy, vigorous coughing and severe vomiting, were significant risk factors of PICC spontaneous dislodgment. Basilic vein access (odds ratio [OR]=0.39, 95% CI: 0.16-0.95, P=0.04) was a protective factor against PICCSD in univariate analysis. Among these factors, the independent significant risk factors were vigorous coughing (OR=6.14, 95% CI: 1.70-22.16, P=0.01) and severe vomiting (OR=3.70, 95% CI: 1.28-10.68, P=0.02). The incidence rate of PICC spontaneous dislodgment is 4.12% (0.34 per 1000 catheter-days); PICC spontaneous dislodgment significantly increases the risk of CRT and shortens catheter in-place time. Vigorous coughing and severe vomiting were independent risk factors of PICC spontaneous dislodgment among oncology patients.


Lignin biosynthesis genes play critical roles in the adaptation of Arabidopsis plants to high-salt stress.
Salinity is a major abiotic stressor that limits the growth, development, and reproduction of plants. Our previous metabolic analysis of high salt-adapted callus suspension cell cultures from Arabidopsis roots indicated that physical reinforcement of the cell wall is an important step in adaptation to saline conditions. Compared to normal cells, salt-adapted cells exhibit an increased lignin content and thickened cell wall. In this study, we investigated not only the lignin biosynthesis gene expression patterns in salt-adapted cells, but also the effects of a loss-of-function of CCoAOMT1, which plays a critical role in the lignin biosynthesis pathway, on plant responses to high-salt stress. Quantitative real-time PCR analysis revealed higher mRNA levels of genes involved in lignin biosynthesis, including CCoAOMT1, 4CL1, 4CL2, COMT, PAL1, PAL2, and AtPrx52, in salt-adapted cells relative to normal cells, which suggests activation of the lignin biosynthesis pathway in salt-adapted cells. Moreover, plants harboring the CCoAOMT1 mutants, ccoaomt1-1 and ccoaomt1-2, were phenotypically hypersensitive to salt stress. Our study has provided molecular and genetic evidence indicating the importance of enhanced lignin accumulation in the plant cell wall during the responses to salt stress.


Obesity and exercise-induced ectopic ventricular arrhythmias in apparently healthy middle aged adults.
Obesity and overweight are strongly associated with cardiovascular morbidity and mortality. However, there are limited data on the association between excess weight and the risk of ectopic ventricular activity. We investigated the association between body mass index (BMI) and the risk for ectopic ventricular activity (defined as multiple ventricular premature beats (≥3), ventricular bigeminy, nonsustained ventricular tachycardia or sustained ventricular tachycardia) during exercise stress testing among 22,516 apparently healthy men and women who attended periodic health screening examinations between the years 2000 and 2014. All subjects had completed maximal exercise stress testing annually according to the Bruce protocol. Subjects were divided at baseline into three groups: normal weight (BMI ≥ 18.5 kg/m(2) and<25; N = 9,994), overweight (BMI ≥ 25 and < 30; N = 9,613) and obese (BMI ≥ 30; N = 2,906). The mean age of study subjects was 47 ± 10 years and 72% were men. Kaplan-Meier survival analysis showed that the cumulative probability for the development of exercise-induced ectopic ventricular activity arrhythmias was highest among obese subjects, intermediate among overweight subjects and lowest among subjects with normal weight (3.4%, 2.7% and 2.2% respectively; p < 0.001). Multivariate binary logistic regression with repeated measures of 92,619 ESTs, showed that obese subjects were 33% more likely to have ectopic ventricular arrhythmias during exercise compared with subjects with normal weight (p = 0.005), and that each 1 kg/m(2) increase in BMI was associated with a significant 4% (p = 0.002) increased adjusted risk for exercise-induced ventricular arrhythmias. Obesity is independently associated with increased likelihood of ectopic ventricular arrhythmia during exercise.


Topography of Protein Kinase C βII in Benign and Malignant Melanocytic Lesions.
Protein kinase C βII promotes melanogenesis and affects proliferation of melanocytic cells but is frequently absent or decreased in melanoma cells in vitro. To investigate PKC-βII expression and spatial distribution within a lesion in various benign and malignant melanocytic proliferations. Expression of PKC-βII was semiquantitatively assessed in the various existing compartments (intraepidermal [not nested], junctional [nested], and dermal) of benign (n = 43) and malignant (n = 28) melanocytic lesions by immunohistochemistry. Melanocytes in the basal layer of normal skin or in lentigo simplex stained strongly for PKC-βII. Common nevi lacked completely PKC-βII. All other lesions expressed variably PKC-βII, with cutaneous melanoma metastases displaying the lowest rate of positivity (14%). In the topographical analysis within a lesion, PKC-βII expression was largely retained in the intraepidermal and junctional part of all other lesions (dysplastic nevus, lentigo maligna, and melanoma). Reduced expression of PKC-βII was found in the dermal component of benign and malignant lesions ( P = .041 vs intraepidermal). PKC-βII expression in the various compartments did not differ significantly between benign and malignant lesions. The current study revealed a significant correlation between PKC-βII expression and spatial localization of melanocytes, with the lowest expression found in the dermal compartment and the highest in the epidermal compartment.


Diagnosis of pulmonary mucormycosis aiding the diagnosis of small cell lung cancer.
Mucormycosis is a rare complication in immunocompromised patients. Antemortem diagnosis of mucormycosis is difficult and often incorrect. We report a case of pulmonary mucormycosis caused by Cunninghamella bertholletiae in an elderly man with interstitial pneumonia. The diagnosis of mucormycosis was established by bronchoalveolar lavage. A coexisting immune deficiency condition was considered. Lung cancer was suspected because of an elevated progastrin-releasing peptide level and bilateral hilar and mediastinal lymphadenopathy; it was diagnosed after performing endoscopic ultrasound-guided fine-needle aspiration. Treatment by intravenous liposomal amphotericin B was effective, but relapse occurred because of bone marrow suppression caused by chemotherapy for lung cancer. Treatment for mucormycosis was resumed, but the patient died of carcinomatous lymphangiosis. Autopsy confirmed the diagnosis of pulmonary mucormycosis and revealed refractory anaemia with small cell lung cancer. Mucormycosis often occurs in immunocompromised patients, but this case is rare because the mucormycosis was diagnosed before the diagnosis of malignancy. Because prognosis is often poor, the possibility of coexisting malignancies should always be investigated in patients with mucormycosis infections.


Buthionine sulfoximine enhances glutathione-but attenuates glutamate-stimulated cell proliferation.
Buthionine sulfoximine (BSO) inhibits proliferation of human lung carcinoma A549 cells, and exogenous glutathione (GSH) overcomes the antiproliferative effect. The BSO antiproliferation may result from inhibition of cellular uptake of amino acids, and the antagonistic effect of GSH would result from supplementation of amino acids via the gamma-glutamyl cycle. To explore these possibilities, the present study was undertaken to determine effects of BSO on glutamate- and GSH-stimulated cell proliferation. A549 cells were cultured in a glutamine-deficient Dulbecco's modified Eagle's medium (Gln-(-)DMEM), in which they did not proliferate. Addition of glutamate or GSH in the medium to a concentration of 4 mM stimulated cell proliferation. BSO of 0.1 mM enhanced the GSH-stimulated cell proliferation and attenuated the glutamate-stimulated cell proliferation. This BSO effect correlated with changes in cellular glutamate levels; that is, BSO increased and decreased glutamate concentrations, respectively, in GSH- and glutamate-stimulated cells. GSH or glutamate alone significantly increased cellular GSH levels. BSO depleted cellular GSH in both GSH- and glutamate-stimulated cells to the same level. These changes in GSH levels did not correlate with the respective growth modulatory effect. Because BSO inhibits cellular uptake of some amino acids and the A549 cells contain high levels of gamma-glutamyl transpeptidase activity, the results suggest that the BSO inhibition of glutamate-stimulated cell proliferation may result from decreased glutamate uptake. GSH would supplement the cells with glutamate via the gamma-glutamyl pathway to bypass the inhibition of amino acid uptake and overcome the BSO-antiproliferative effect.


The effect of cigarette smoke extract exposure on the size and sexual behaviour of Drosophila melanogaster.
Drosophila melanogaster is a widely used animal model in human diseases and to date it has not been applied to the study of the impact of tobacco use on human sexual function. Hence, this report examines the effects of different concentrations of cigarette smoke extract (CSE) exposure on the size and sexual behavior of D. melanogaster. Wild-type flies were held in vials containing CSE-infused culture media at concentrations of 10%, 25%, and 50% for three days, and their offspring were reared under the same conditions before measuring their body size and mating behavior. CSE exposure during development reduced the tibia length and body mass of emerging adult flies and prolonged the time required for successful courtship copulation success, while courtship behaviors (wing extension, tapping, abdomen bending, attempted copulation) remained largely unchanged. Our findings indicate that CSE exposure negatively affects the development of flies and their subsequent reproductive success. Future experiments should investigate the CSE effect on male female fertility.


Elevated Serum Liver-Type Fatty Acid Binding Protein Levels in Non-acetaminophen Acute Liver Failure Patients with Organ Dysfunction.
Liver-type fatty acid binding protein (FABP1) has previously been demonstrated to improve prognostic discrimination in acetaminophen (APAP)-induced ALF but has not been investigated in other etiologies of ALF. To determine whether FABP1 levels (early: admission or late: days 3-5) are associated with 21-day transplant-free survival in non-APAP ALF. FABP1 was measured in serum samples from 384 ALF patients (n = 88 transplant-free survivors (TFS), n = 296 died/LT-NTFS) using solid-phase enzyme-linked immunosorbent assay and analyzed with US ALFSG registry data. Of 384 ALF patients (autoimmune hepatitis n = 125, drug-induced liver injury n = 141, Hepatitis B n = 118), 177 (46%) patients received LT. Early FABP1 levels were significantly higher in ALF patients requiring vasopressor support (203.4 vs. 76.3 ng/mL) and renal replacement therapy (203.4 vs. 78.8 ng/mL; p < 0.001 for both). Late FABP1 levels were significantly higher in patients requiring mechanical ventilation (77.5 vs. 53.3 ng/mL), vasopressor support (116.4 vs. 53.3 ng/mL) and in patients with grade 3/4 hepatic encephalopathy (71.4 vs. 51.4 ng/mL; p = 0.03 for all). Late FABP1 levels were significantly lower in TFS patients (TFS 54 vs. NTFS 66 ng/mL; p = 0.049) but not admission (TFS 96 vs. NTFS 87 ng/mL; p = 0.67). After adjusting for significant covariates, serum FABP1 did not discriminate significantly between TFS and patients who died/received LT at day 21 either on admission (p = 0.29) or late (days 3-5, p = 0.087) time points. In this first report of FABP1 in non-APAP ALF, FABP1 levels at late time points (days 3-5) were significantly lower in ALF patients who were alive without transplant at day 21 but not after adjusting for covariates reflecting severity of illness. Higher FABP1 levels were associated with the presence of increased organ failure.


Characterization and In Vitro Skin Permeation of Meloxicam-Loaded Liposomes versus Transfersomes.
The goal of this study was to develop and evaluate the potential use of liposome and transfersome vesicles in the transdermal drug delivery of meloxicam (MX). MX-loaded vesicles were prepared and evaluated for particle size, zeta potential, entrapment efficiency (%EE), loading efficiency, stability, and in vitro skin permeation. The vesicles were spherical in structure, 90 to 140 nm in size, and negatively charged (-23 to -43 mV). The %EE of MX in the vesicles ranged from 40 to 70%. Transfersomes provided a significantly higher skin permeation of MX compared to liposomes. Fourier Transform Infrared Spectroscopy (FT-IR) and Differential Scanning Calorimetry (DSC) analysis indicated that the application of transfersomes significantly disrupted the stratum corneum lipid. Our research suggests that MX-loaded transfersomes can be potentially used as a transdermal drug delivery system.


Covalently crosslinked complexes of bovine adrenodoxin with adrenodoxin reductase and cytochrome P450scc. Mass spectrometry and Edman degradation of complexes of the steroidogenic hydroxylase system.
NADPH-dependent adrenodoxin reductase, adrenodoxin and several diverse cytochromes P450 constitute the mitochondrial steroid hydroxylase system of vertebrates. During the reaction cycle, adrenodoxin transfers electrons from the FAD of adrenodoxin reductase to the heme iron of the catalytically active cytochrome P450 (P450scc). A shuttle model for adrenodoxin or an organized cluster model of all three components has been discussed to explain electron transfer from adrenodoxin reductase to P450. Here, we characterize new covalent, zero-length crosslinks mediated by 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide between bovine adrenodoxin and adrenodoxin reductase, and between adrenodoxin and P450scc, respectively, which allow to discriminate between the electron transfer models. Using Edman degradation, mass spectrometry and X-ray crystallography a crosslink between adrenodoxin reductase Lys27 and adrenodoxin Asp39 was detected, establishing a secondary polar interaction site between both molecules. No crosslink exists in the primary polar interaction site around the acidic residues Asp76 to Asp79 of adrenodoxin. However, in a covalent complex of adrenodoxin and P450scc, adrenodoxin Asp79 is involved in a crosslink to Lys403 of P450scc. No steroidogenic hydroxylase activity could be detected in an adrenodoxin -P450scc complex/adrenodoxin reductase test system. Because the acidic residues Asp76 and Asp79 belong to the binding site of adrenodoxin to adrenodoxin reductase, as well as to the P450scc, the covalent bond within the adrenodoxin-P450scc complex prevents electron transfer by a putative shuttle mechanism. Thus, chemical crosslinking provides evidence favoring the shuttle model over the cluster model for the steroid hydroxylase system.