Localization of five annexins in J774 macrophages and on isolated phagosomes.
Annexins are a family of structurally related proteins which bind phospholipids in a calcium-dependent manner. Although the precise functions of annexins are unknown, there is an accumulating set of data arguing for a role for some of them in vesicular transport and, specifically, in membrane-membrane or membrane-cytoskeletal interactions during these processes. Here we describe our qualitative and quantitative analysis of the localization of annexins I-V in J774 macrophages that had internalized latex beads, both with and without IgG opsonization. Our results show that whereas all these annexins are present on both the plasma membrane and on phagosomes, the localization on other organelles differs. Annexins I, II, III and V were detected on early endosomes, while only annexin V was seen on late endocytic organelles and mitochondria. Annexins I and II distributed along the plasma membrane non-uniformly and co-localized with F-actin at the sites of membrane protrusions. We also investigated by western blot analysis the association of annexins with purified phagosomes isolated at different time-points after latex bead internalization. While the amounts of annexins I, II, III and V associated with phagosomes were similar at all times after their formation, the level of annexin IV was significantly higher on older phagosomes. Whereas annexins I, II, IV and V could be removed from phagosome membranes with a Ca2+ chelator they remained membrane bound under low calcium conditions. In contrast, annexin III was removed under these conditions and needed a relatively high Ca2+ concentration to remain phagosome bound. Because of their purity and ease of preparation we suggest that phagosomes are a powerful system to study the potential role of annexins in membrane traffic.


Expiratory and expiratory plus inspiratory muscle training improves respiratory muscle strength in subjects with COPD: systematic review.
Inspiratory muscle training (IMT) produces beneficial effects in COPD subjects, but the effects of expiratory muscle training (EMT) and EMT plus IMT in ventilatory training are still unclear. The aim of this study was to systematically review the effects of EMT and EMT plus IMT compared to control groups of COPD subjects. This study is a systematic review and meta-analysis. The search strategy included MEDLINE, Embase, LILACS, PEDro, and Cochrane CENTRAL and also manual search of references in published studies on the subject. Randomized trials comparing EMT and EMT plus IMT versus control groups of subjects with COPD were included. The outcomes analyzed were respiratory muscle strength and functional capacity. Two reviewers independently extracted the data. The search retrieved 609 articles. Five studies were included. We observed that EMT provided higher gain in maximum expiratory pressure (P(E(max)) 21.49 cm H2O, 95% CI 13.39-29.59) and maximum inspiratory pressure (P(I(max)) 7.68 cm H2O, 95% CI 0.90-14.45) compared to control groups. There was no significant difference in the 6-min walk test distance (29.01 m, 95% CI -39.62 to 97.65) and dyspnea (0.15, 95% CI -0.77 to 1.08). In relation to EMT plus IMT, we observed that P(E(max)) (31.98 cm H2O, 95% CI 26.93-37.03) and P(I(max)) (27.98 cm H2O, 95% CI 20.10-35.85) presented higher values compared to control groups. EMT and EMT plus IMT improve respiratory muscle strength and can be used as part of the treatment during pulmonary rehabilitation of subjects with severe to very severe COPD.


Effects of Listeria monocytogenes and its components on adenosine triphosphate concentrations in mice.
The effects of Listeria monocytogenes and its components on adenosine triphosphate (ATP) concentrations in mice were examined by in vitro and in vivo techniques. White female mice were intraperitoneally injected with L monocytogenes strain 9-125 and its components, and certain tissues of mice were exposed to the various listerial components in vitro, and the ATP concentrations in these tissues were measured. Results of in vivo experiments indicated that live listerial cells and certain components (hemolysin, cell wall, and cytoplasm) decreased the ATP concentrations in some tissues of the mice, whereas other components (peptidoglycan and endotoxin-like material) did not have any effects on ATP concentrations. Although hemolysin from L monocytogenes decreased the tissue ATP concentrations in vitro, other listerial components did not effect any of the exposed tissues. The data indicated some impairment of host energy metabolism occurred in mice exposed to L monocytogenes or to its components or to both.


Array comparative genomic hybridization analysis discloses chromosome copy number alterations as indicators of patient outcome in lymph node-negative breast cancer.
Patients with lymph node metastasis-negative (pN0) invasive breast cancer have favorable outcomes following initial treatment. However, false negatives which occur during routine histologic examination of lymph nodes are reported to underestimate the clinical stage of disease. To identify a high-risk group in pN0 invasive breast cancer, we examined copy number alterations (CNAs) of 800 cancer-related genes. Using array-based comparative genomic hybridization (CGH) in 51 pN0 cases (19 relapsed and 32 non-relapsed cases), the positivities of specific gene CNAs in the relapsed and non-relapsed groups were compared. An unsupervised hierarchical cluster analysis was then performed to identify case groups that were correlated with patient outcomes. The cluster analysis identified three distinct clusters of cases: groups 1, 2, and 3. The major component was triple-negative cases (69%, 9 of 13) in group 1, luminal B-like (57%, 13 of 23) and HER2-overexpressing (26%, 6 of 23) subtypes in group 2, and luminal A-like subtype (60%, 9 of 15) in group 3. Among all 51 cases, those in group 1 showed significantly worse overall survival (OS) than group 2 (p = 0.014), and 5q15 loss was correlated with worse OS (p = 0.017). Among 19 relapsed cases, both OS and relapse-free survival (RFS) rates were significantly lower in group 1 than in group 2 (p = 0.0083 and 0.0018, respectively), and 5q15 loss, 12p13.31 gain, and absence of 16p13.3 gain were significantly correlated with worse OS and RFS (p = 0.019 and 0.0027, respectively). As the target genes in these loci, NR2F1 (5q15), TNFRSF1A (12p13.31), and ABCA3 (16p13.3) were examined. 5q15 loss, 12p13.31 gain, and absence of 16q13.3 gain were potential indicators of high-risk recurrence and aggressive clinical behavior of pN0 invasive breast cancers.


Sensitive molecular diagnostics using volume-amplified magnetic nanobeads.
In this letter, we demonstrate a new principle for diagnostics based on DNA sequence detection using single-stranded oligonucleotide tagged magnetic nanobeads. The target DNA is recognized and volume-amplified to large coils by circularization of linear padlock probes through probe hybridization and ligation, followed by rolling circle amplification (RCA). Upon hybridization of the nanobeads in the RCA coils, the complex magnetization spectrum of the beads changes dramatically, induced by the attached volume-amplified target molecules. We show that the magnetization spectrum of the nanobeads can be used for concentration determination of RCA coils down to the pM range, thus creating the opportunity for nonfluorescence-based cost-efficient high-sensitivity diagnostics tool. We also show that the bead incorporation in the coils is diffusion-controlled and consequently may be accelerated by incubating the sample at higher temperatures.


Ion mobility mass spectrometry of peptide ions: effects of drift gas and calibration strategies.
One difficulty in using ion mobility (IM) mass spectrometry (MS) to improve the specificity of peptide ion assignments is that IM separations are performed using a range of pressures, gas compositions, temperatures, and modes of separation, which makes it challenging to rapidly extract accurate shape parameters. We report collision cross section values (Ω) in both He and N(2) gases for 113 peptide ions determined directly from drift times measured in a low-pressure, ambient temperature drift cell with radio-frequency (rf) ion confinement. These peptide ions have masses ranging from 231 to 2969 Da, Ω(He) of 89-616 Å(2), and Ω(N(2)) of 151-801 Å(2); thus, they are ideal for calibrating results from proteomics experiments. These results were used to quantify the errors associated with traveling-wave Ω measurements of peptide ions and the errors concomitant with using drift times measured in N(2) gas to estimate Ω(He). More broadly, these results enable the rapid and accurate determination of calibrated Ω for peptide ions, which could be used as an additional parameter to increase the specificity of assignments in proteomics experiments.


[External morphology of Triatoma rickmani Zeledón & Ponce, 1972 seen under scanning electron microscopy].
A male of Triatoma ryckmani Zeledón & Ponce, 1972, was studied by scanning electron microscopy. Only few specimens of this species are known. In this paper, some structures from the head, thorax, abdomen and distal region of the second leg are shown. Some of them could have taxonomic importance, as the oculo-ocellar region, the buccula, the anterolateral angle of the collar, the scutellum with the process longer than the main body, the stridulatory sulcus with an unusual backward vermiform area, and the tibia-tarsal articulation, with a spongy fossula. The last structure was absent in specimens previously studied (Lent & Wygodzinsky 1979). Differences between this specimen and others previously described by several authors are discussed.


About 3D Printability of Thermoplastic Collagen for Biomedical Applications.
With more than 1.5 million total knee and hip implants placed each year, there is an urgent need for a drug delivery system that can effectively support the repair of bone infections. Scaffolds made of natural biopolymers are widely used for this purpose due to their biocompatibility, biodegradability, and suitable mechanical properties. However, the poor processability is a bottleneck, as highly customizable scaffolds are desired. The aim of the present research is to develop a scaffold made of thermoplastic collagen (TC) using 3D printing technology. The viscosity of the material was measured using a rheometer. A 3D bioplotter was used to fabricate the scaffolds out of TC. The mechanical properties of the TC scaffolds were performed using tension/compression testing on a Zwick/Roell universal testing machine. TC shows better compressibility with increasing temperature and a decrease in dynamic viscosity (η), storage modulus (G'), and loss modulus (G″). The compressive strength of the TC scaffolds was between 3-10 MPa, depending on the geometry (cylinder or cuboid, with different infills). We have demonstrated for the first time that TC can be used to fabricate porous scaffolds by 3D printing in various geometries.


Affective State Level Recognition in Naturalistic Facial and Vocal Expressions.
Naturalistic affective expressions change at a rate much slower than the typical rate at which video or audio is recorded. This increases the probability that consecutive recorded instants of expressions represent the same affective content. In this paper, we exploit such a relationship to improve the recognition performance of continuous naturalistic affective expressions. Using datasets of naturalistic affective expressions (AVEC 2011 audio and video dataset, PAINFUL video dataset) continuously labeled over time and over different dimensions, we analyze the transitions between levels of those dimensions (e.g., transitions in pain intensity level). We use an information theory approach to show that the transitions occur very slowly and hence suggest modeling them as first-order Markov models. The dimension levels are considered to be the hidden states in the Hidden Markov Model (HMM) framework. Their discrete transition and emission matrices are trained by using the labels provided with the training set. The recognition problem is converted into a best path-finding problem to obtain the best hidden states sequence in HMMs. This is a key difference from previous use of HMMs as classifiers. Modeling of the transitions between dimension levels is integrated in a multistage approach, where the first level performs a mapping between the affective expression features and a soft decision value (e.g., an affective dimension level), and further classification stages are modeled as HMMs that refine that mapping by taking into account the temporal relationships between the output decision labels. The experimental results for each of the unimodal datasets show overall performance to be significantly above that of a standard classification system that does not take into account temporal relationships. In particular, the results on the AVEC 2011 audio dataset outperform all other systems presented at the international competition.


Injuries of the clavicle and its articulations.
Injuries to the clavicle and articulations have been reviewed. Attention has been drawn to the more common symptoms, signs, and treatment associated with these injuries.


[Appropriateness of referral to the emergency department through a telecardiology service. "Boario Home-Care" researchers].
The use of telemedicine appears particularly promising in cardiovascular diseases; it may reduce the decisional time during an acute myocardial infarction, which is the greater part of the so-called "avoidable delay" and the inappropriate admission to the Emergency Department with the possibility of ruling out an acute pathology. The aim of our study was to show the diagnostic accuracy of a telecardiology service in the daily activity of general practitioners. From February 1998 to February 1999, 150 general practitioners received a portable electrocardiographer (Card-Guard 7100) transferring, by a mobile or fixed telephone, a 12-lead ECG to a receiving station, where a cardiologist was available for the reporting and interactive teleconsultation. During 1 year 3456 calls took place. At the time of the ECG recording 44% of patients were symptomatic. Chest pain was present in 669 patients (44%), dyspnea in 21%, palpitation in 18%, dizziness in 7%, and asthenia in 13%. ECG and teleconsultation solved all the problems for 2452 patients (71%) and further diagnostic tests were requested in 862 patients (25%); 142 patients (4%) were sent to the Emergency Department. Cardiological diagnosis was confirmed in 95 patients (73%), while anxiety or gastritis were presumed in 35 patients (27%). In the group of patients (n = 3314) for whom the cardiologist solved the problem without admission to the Emergency Department, there were 5 patients who were admitted to the Emergency Department for myocardial ischemia in the following 48 hours after the teleconsultation. Telecardiology service showed versus Emergency Department admission a sensitivity of 95%, a specificity of 97.5%, and a diagnostic accuracy of 92.5%. These data confirm a good diagnostic value to the service and a useful support to the general practitioners' activity.


Outcomes of Trauma "Walk-Ins" in the American College of Surgeons Trauma Quality Program Database.
Outcomes of trauma "walk-in" patients (using private vehicles or on foot) are understudied. We compared outcomes of ground ambulance vs walk-ins, hypothesizing that delayed resuscitation and uncoordinated care may worsen walk-in outcomes. A retrospective analysis 2020 American College of Surgeons Trauma Quality Programs (ACS-TQP) databases compared outcomes between ambulance vs "walk-ins." The primary outcome was in-hospital mortality, excluding external facility transfers and air transports. Data was analyzed with descriptive statistics, bivariate, multivariable logistic regression, including an Inverse Probability Weighted Regression Adjustment with adjustments for injury severity and vital signs. The primary outcome for the 2019 (pre-COVID-19 pandemic) data was similarly analyzed. In 2020, 707,899 patients were analyzed, 556,361 (78.59%) used ambulance, and 151,538 (21.41%) were walk-ins. We observed differences in demographics, hospital attributes, medical comorbidities, and injury mechanism. Ambulance patients had more chronic conditions and severe injuries. Walk-ins had lower in-hospital mortality (850 (.56%) vs 23,131 (4.16%)) and arrived with better vital signs. Multivariable logistic regression models (inverse probability weighting for regression adjustment), adjusting for injury severity, demographics, injury mechanism, and vital signs, confirmed that walk-in status had lower odds of mortality. For the 2019 (pre-COVID-19 pandemic) database, walk-ins also had lower in-hospital mortality. Our results demonstrate better survival rates for walk-ins before and during COVID-19 pandemic. Despite limitations of patient selection bias, this study highlights the need for further research into transportation modes, geographic and socioeconomic factors affecting patient transport, and tailoring management strategies based on their mode of arrival.


Age-specific cost of first reproduction in female southern elephant seals.
When to commence breeding is a crucial life-history decision that may be the most important determinant of an individual's lifetime reproductive output and can have major consequences on population dynamics. The age at which individuals first reproduce is an important factor influencing the intensity of potential costs (e.g. reduced survival) involved in the first breeding event. However, quantifying age-related variation in the cost of first reproduction in wild animals remains challenging because of the difficulty in reliably recording the first breeding event. Here, using a multi-event capture-recapture model that accounts for both imperfect detection and uncertainty in the breeding status on an 18-year dataset involving 6637 individuals, we estimated age and state-specific survival of female elephant seals (Mirounga leonina) in the declining Macquarie Island population. We detected a clear cost of first reproduction on survival. This cost was higher for both younger first-time breeders and older first-time breeders compared with females recruiting at age four, the overall mean age at first reproduction. Neither earlier primiparity nor delaying primiparity appear to confer any evolutionary advantage, rather the optimal strategy seems to be to start breeding at a single age, 4 years.


Inhibition of mutation and combating the evolution of antibiotic resistance.
The emergence of drug-resistant bacteria poses a serious threat to human health. In the case of several antibiotics, including those of the quinolone and rifamycin classes, bacteria rapidly acquire resistance through mutation of chromosomal genes during therapy. In this work, we show that preventing induction of the SOS response by interfering with the activity of the protease LexA renders pathogenic Escherichia coli unable to evolve resistance in vivo to ciprofloxacin or rifampicin, important quinolone and rifamycin antibiotics. We show in vitro that LexA cleavage is induced during RecBC-mediated repair of ciprofloxacin-mediated DNA damage and that this results in the derepression of the SOS-regulated polymerases Pol II, Pol IV and Pol V, which collaborate to induce resistance-conferring mutations. Our findings indicate that the inhibition of mutation could serve as a novel therapeutic strategy to combat the evolution of antibiotic resistance.


Pre-clinical evaluation of the mechanical properties of a low-stiffness cement-injectable hip stem.
In total hip arthroplasty (THA), the femoral stem can be fixed with or without bone cement. Cementless stem fixation is recommended for young and active patients as it eliminates the risk of loss of fixation at the bone-cement and cement-implant interfaces. Cementless fixation, however, suffers from a relatively high early revision rate. In the current research, a novel low-stiffness hip stem was designed, fabricated and tested. The stem design provided the option to inject biodegradable bone cement that could enhance initial stem stability. The stem was made of Ti6Al4V alloy. The proximal portion of the stem was porous, with cubic cells. The stem was fabricated using electron beam melting (EBM) technology and tested in compression and bending. Finite-element analysis was used to evaluate stem performance under a dynamic load representing a stair descending cycle and compare it to the performance of a solid stem with similar geometry. The von Mises stresses and maximum principal strains generated within the bone increased after porous stem insertion compared to solid stem insertion. The low-modulus stem tested in this study has acceptable mechanical properties and generates strain patterns in bone that appear compatible with clinical use.


Midwives' views on appropriate antenatal counselling for congenital anomaly tests: do they match clients' preferences?
this study aims to provide insight into: (a) midwives' views on appropriate antenatal counselling for congenital anomaly tests, and (b) whether these views match clients' preferences regarding antenatal counselling. a comparative (midwives versus clients) questionnaire survey. Cognitive interviews (n=8) were used to validate the internal validity of the midwifery questionnaire results. 1416 Dutch midwives (response 62%) completed a questionnaire measuring their views on appropriate antenatal counselling for congenital anomaly tests. we used the 58-item midwives' version of the QUOTE (prenatal), an instrument to assess clients' counselling preferences. Descriptive statistics were used to explore midwives' views on appropriate counselling and how these relate to client preferences as measured previously with the clients' version of the QUOTE (prenatal). almost all midwives consider the client-midwife relation (100%) and health education (95%) to be (very) important for appropriate antenatal counselling for congenital anomaly tests. Almost half of the midwives consider decision-making support (47%) to be (very) important. These findings are practically congruent with client preferences. Still, clinically relevant differences were found regarding 13 individual items, e.g. more clients than midwives value 'medical information about congenital anomalies' and 'getting advice whether to take prenatal tests or not'. like clients, most midwives value a good client-midwife relation and health education as (very) important for antenatal counselling for congenital anomaly tests. Less than half of them value decision-making support. These findings are in contrast with the literature in which decision-making support is seen as the most important part of antenatal counselling for congenital anomaly tests. preferably, antenatal counselling for congenital anomaly tests should be consistent with the three-function model of antenatal counselling i.e. maintaining a client-midwife relation, providing health education as well as decision-making support, and tailored to clients' individual preferences. As not all midwives subscribe to these functions, reflection on their views is important. Furthermore, midwives need to bridge their views on appropriate antenatal counselling and client preferences. To do so, midwives may benefit from the Shared Decision Making approach.


Fast Adaptive Bilateral Filtering.
In the classical bilateral filter, a fixed Gaussian range kernel is used along with a spatial kernel for edge-preserving smoothing. We consider a generalization of this filter, the so-called adaptive bilateral filter, where the center and width of the Gaussian range kernel are allowed to change from pixel to pixel. Though this variant was originally proposed for sharpening and noise removal, it can also be used for other applications, such as artifact removal and texture filtering. Similar to the bilateral filter, the brute-force implementation of its adaptive counterpart requires intense computations. While several fast algorithms have been proposed in the literature for bilateral filtering, most of them work only with a fixed range kernel. In this paper, we propose a fast algorithm for adaptive bilateral filtering, whose complexity does not scale with the spatial filter width. This is based on the observation that the concerned filtering can be performed purely in range space using an appropriately defined local histogram. We show that by replacing the histogram with a polynomial and the finite range-space sum with an integral, we can approximate the filter using analytic functions. In particular, an efficient algorithm is derived using the following innovations: the polynomial is fitted by matching its moments to those of the target histogram (this is done using fast convolutions), and the analytic functions are recursively computed using integration-by-parts. Our algorithm can accelerate the brute-force implementation by at least , without perceptible distortions in the visual quality. We demonstrate the effectiveness of our algorithm for sharpening, JPEG deblocking, and texture filtering.


Transcriptional regulation of the human cytomegalovirus major immediate-early gene is associated with induction of DNase I-hypersensitive sites.
Human teratocarcinoma cells were used to examine structural features associated with expression of the major immediate-early (IE) gene of human cytomegalovirus. By immunofluorescence, comparison of RNA levels, and in vitro transcription of nuclei, we showed that the major IE gene is inactive in undifferentiated but active in differentiated cells. Therefore, the block in human cytomegalovirus replication in teratocarcinoma cells appears to be at the transcriptional level, in one of the initial genes transcribed. In addition, the in vitro transcription experiments demonstrated that in permissive infections the gene was transcriptionally inactive late in infection. A comparison of the structural features of the promoter region with the active and inactive IE genes showed the presence of constitutive and inducible DNase I-hypersensitive sites. The majority of the constitutive sites existed at -175, -275, -375, -425, and -525 relative to the cap site in an area which has been shown to be capable of simian virus 40 enhancer function. In contrast, the inducible DNase I sites were located outside this region at -650, -775, -875, and -975.


The use of anticholinergic drugs in nocturnal asthma.
Nocturnal asthma is a common and potentially dangerous condition. The mechanisms in its production are multifactorial. One factor appears to be increased vagal tone at night so that an anticholinergic drug might prove effective. The evidence for a bronchodilator action of anticholinergic drugs is reviewed. A clinical trial of one such anticholinergic in nocturnal asthma is described. In 12 patients with morning dipping a dose of 160 micrograms of ipratropium bromide inhaled at night significantly reduced the extent of morning dipping. The implications are discussed.


Comparison of 3% sorbitol vs psyllium fibre as oral contrast agents in MR enterography.
To compare the degree of small bowel distension achieved by 3% sorbitol, a high osmolarity solution, and a psyllium-based bulk fibre as oral contrast agents (OCAs) in MR enterography (MRE). This retrospective study was approved by our institutional review board. A total of 45 consecutive normal MRE examinations (sorbitol, n = 20; psyllium, n = 25) were reviewed. The patients received either 1.5 l of 3% sorbitol or 2 l of 1.6 g kg(-1) psyllium prior to imaging. Quantitative small bowel distension measurements were taken in five segments: proximal jejunum, distal jejunum, proximal ileum, distal ileum and terminal ileum by two independent radiologists. Distension in these five segments was also qualitatively graded from 0 (very poor) to 4 (excellent) by two additional independent radiologists. Statistical analysis comparing the groups and assessing agreement included intraclass coefficients, Student's t-test and Mann-Whitney U-test. Small bowel distension was not significantly different in any of the five small bowel segments between the use of sorbitol and psyllium as OCAs in both the qualitative (p = 0.338-0.908) and quantitative assessments (p = 0.083-0.856). The mean bowel distension achieved was 20.1 ± 2.2 mm for sorbitol and 19.8 ± 2.5 mm for psyllium (p = 0.722). Visualization of the ileum was good or excellent in 65% of the examinations in both groups. Sorbitol and psyllium are not significantly different at distending the small bowel and both may be used as OCAs for MRE studies. This is the first study to directly compare the degree of distension in MRE between these two common, readily available and inexpensive OCAs.


Effects of Acute 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure on the Circulating and Cecal Metabolome Profile.
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a polyhalogenated planar hydrocarbon belonging to a group of highly toxic and persistent environmental contaminants known as "dioxins". TCDD is an animal teratogen and carcinogen that is well characterized for causing immunosuppression through activation of aryl hydrocarbon receptor (AHR). In this study, we investigated the effect of exposure of mice to an acute dose of TCDD on the metabolic profile within the serum and cecal contents to better define the effects of TCDD on host physiology. Our findings demonstrated that within the circulating metabolome following acute TCDD exposure, there was significant dysregulation in the metabolism of bioactive lipids, amino acids, and carbohydrates when compared with the vehicle (VEH)-treated mice. These widespread changes in metabolite abundance were identified to regulate host immunity via modulating nuclear factor-kappa B (NF-κB) and extracellular signal-regulated protein kinase (ERK1/2) activity and work as biomarkers for a variety of organ injuries and dysfunctions that follow TCDD exposure. Within the cecal content of mice exposed to TCDD, we were able to detect changes in inflammatory markers that regulate NF-κB, markers of injury-related inflammation, and changes in lysine degradation, nicotinamide metabolism, and butanoate metabolism, which collectively suggested an immediate suppression of broad-scale metabolic processes in the gastrointestinal tract. Collectively, these results demonstrate that acute TCDD exposure results in immediate irregularities in the circulating and intestinal metabolome, which likely contribute to TCDD toxicity and can be used as biomarkers for the early detection of individual exposure.


Kinetic modeling of the X-ray-induced damage to a metalloprotein.
It is well-known that biological samples undergo X-ray-induced degradation. One of the fastest occurring X-ray-induced processes involves redox modifications (reduction or oxidation) of redox-active cofactors in proteins. Here we analyze room-temperature data on the photoreduction of Mn ions in the oxygen-evolving complex (OEC) of photosystem II, one of the most radiation damage-sensitive proteins and a key constituent of natural photosynthesis in plants, green algae, and cyanobacteria. Time-resolved X-ray emission spectroscopy with wavelength-dispersive detection was used to collect data on the progression of X-ray-induced damage. A kinetic model was developed to fit experimental results, and the rate constant for the reduction of OEC Mn(III) and Mn(IV) ions by solvated electrons was determined. From this model, the possible kinetics of X-ray-induced damage at a variety of experimental conditions, such as different rates of dose deposition as well as different excitation wavelengths, can be inferred. We observed a trend of increasing dosage threshold prior to the onset of X-ray-induced damage with increasing rates of dose deposition. This trend suggests that experimentation with higher rates of dose deposition is beneficial for measurements of biological samples sensitive to radiation damage, particularly at pink beam and X-ray free electron laser sources.


Maintaining clinical tissue archives and supporting human research: challenges and solutions.
The increasing number of requests for use of clinically archived tissue in translational research poses unique challenges. Conflicts may arise between pathologists who are responsible for overseeing and preserving the tissues and investigators who need these materials for research purposes. To evaluate the status of our institution's Tissue Registry Archive and to develop updated written policies and procedures to support a new modern and robust tracking system with features of a library loan system. An observational study was performed. We found the existing process for managing loans of tissue (slides and paraffin blocks) to be insufficient for the complexity and volume of this task. After extensive customization, a new tracking system was implemented in January 2008. Analysis of the first year of the system's use (2008) showed that of the 206,330 slides and 51,416 blocks loaned out in 2008, 92% and 94%, respectively, were returned by the due date. These rates were markedly improved from those before the new system: 61% and 47%, respectively, in 2005. Material permanently "lost" in 2008 represented only 0.02% of slides and 0.05% of blocks, none of which was the only diagnostic material for the case. With expanding needs for archived tissues for clinical care and growing demands for translational research, it is essential that pathology departments at institutions with large tissue-based research endeavors have a tracking and management system in place to meet clinical, educational, and research needs, as well as legal requirements.


Seasonal variations of bromophenols in brown algae (Padina arborescens, Sargassum siliquastrum, and Lobophora variegata) collected in Hong Kong.
Distributions and seasonal variations of the key seafood flavor compounds including 2-bromophenol, 4-bromophenol, 2,4-dibromophenol, 2,6-dibromophenol, and 2,4,6-tribromophenol in three species of brown algae (Padina arborescens, Sargassum siliquastrum, and Lobophora variegata) found in Hong Kong waters were investigated. Bromophenols were extracted by simultaneous steam distillation and solvent extraction apparatus and analyzed by gas chromatography-mass spectrometry. On a dried weight basis, the total bromophenol content (TBC) determined varied widely with seasons (from 40.9 to 7030 ng/g). The TBCs detected were higher in winter and lower in summer. Except for 2-bromophenol, the rest of the bromophenols were detected in all of the algal samples. The TBC of L. variegata was generally the highest among all of the algae collected. Relatively high concentrations of bromophenols in algae supported the fact that marine algae were major producers of bromophenols in the marine environment.


[The age-related characteristics of changes in osmotic and ionic homeostasis in spontaneously hypertensive rats].
The 3-month old SHR differ from the WKY rats in that the former have an increased osmolality, concentration of albumins, activity (but not the concentration) of sodium and a reduced activity of potassium. The shifts in the albumins concentration occur, mainly, on account of the amino acid phenylalanine. The gradient increase of the sodium and potassium concentration between the plasma and muscular tissue in followed by a slight hyperpolarisation of the muscle fibers, a drop in the lability and a increase in pO2. The above shifts of homeostatic parameters were not revealed in the SHR and WKY rats of 1.5 and 6.0 months of age.


Unbiased Label-Free Quantitative Proteomics of Cells Expressing Amyotrophic Lateral Sclerosis (ALS) Mutations in CCNF Reveals Activation of the Apoptosis Pathway: A Workflow to Screen Pathogenic Gene Mutations.
The past decade has seen a rapid acceleration in the discovery of new genetic causes of ALS, with more than 20 putative ALS-causing genes now cited. These genes encode proteins that cover a diverse range of molecular functions, including free radical scavenging (e.g., SOD1), regulation of RNA homeostasis (e.g., TDP-43 and FUS), and protein degradation through the ubiquitin-proteasome system (e.g., ubiquilin-2 and cyclin F) and autophagy (TBK1 and sequestosome-1/p62). It is likely that the various initial triggers of disease (either genetic, environmental and/or gene-environment interaction) must converge upon a common set of molecular pathways that underlie ALS pathogenesis. Given the complexity, it is not surprising that a catalog of molecular pathways and proteostasis dysfunctions have been linked to ALS. One of the challenges in ALS research is determining, at the early stage of discovery, whether a new gene mutation is indeed disease-specific, and if it is linked to signaling pathways that trigger neuronal cell death. We have established a proof-of-concept proteogenomic workflow to assess new gene mutations, using CCNF (cyclin F) as an example, in cell culture models to screen whether potential gene candidates fit the criteria of activating apoptosis. This can provide an informative and time-efficient output that can be extended further for validation in a variety of in vitro and in vivo models and/or for mechanistic studies. As a proof-of-concept, we expressed cyclin F mutations (K97R, S195R, S509P, R574Q, S621G) in HEK293 cells for label-free quantitative proteomics that bioinformatically predicted activation of the neuronal cell death pathways, which was validated by immunoblot analysis. Proteomic analysis of induced pluripotent stem cells (iPSCs) derived from patient fibroblasts bearing the S621G mutation showed the same activation of these pathways providing compelling evidence for these candidate gene mutations to be strong candidates for further validation and mechanistic studies (such as E3 enzymatic activity assays, protein-protein and protein-substrate studies, and neuronal apoptosis and aberrant branching measurements in zebrafish). Our proteogenomics approach has great utility and provides a relatively high-throughput screening platform to explore candidate gene mutations for their propensity to cause neuronal cell death, which will guide a researcher for further experimental studies.


Conserved changes in the dynamics of metabolic processes during fruit development and ripening across species.
Computational analyses of molecular phenotypes traditionally aim at identifying biochemical components that exhibit differential expression under various scenarios (e.g. environmental and internal perturbations) in a single species. High-throughput metabolomics technologies allow the quantification of (relative) metabolite levels across developmental stages in different tissues, organs, and species. Novel methods for analyzing the resulting multiple data tables could reveal preserved dynamics of metabolic processes across species. The problem we address in this study is 2-fold. (1) We derive a single data table, referred to as a compromise, which captures information common to the investigated set of multiple tables containing data on different fruit development and ripening stages in three climacteric (i.e. peach [Prunus persica] and two tomato [Solanum lycopersicum] cultivars, Ailsa Craig and M82) and two nonclimacteric (i.e. strawberry [Fragaria × ananassa] and pepper [Capsicum chilense]) fruits; in addition, we demonstrate the power of the method to discern similarities and differences between multiple tables by analyzing publicly available metabolomics data from three tomato ripening mutants together with two tomato cultivars. (2) We identify the conserved dynamics of metabolic processes, reflected in the data profiles of the corresponding metabolites that contribute most to the determined compromise. Our analysis is based on an extension to principal component analysis, called STATIS, in combination with pathway overenrichment analysis. Based on publicly available metabolic profiles for the investigated species, we demonstrate that STATIS can be used to identify the metabolic processes whose behavior is similarly affected during fruit development and ripening. These findings ultimately provide insights into the pathways that are essential during fruit development and ripening across species.


The comparative effects of esmolol and amiodarone on isolated coronary artery bypass grafts
Background/aim: Esmolol and amiodarone are two most commonly used antiarrhythmic drugs in coronary artery bypass grafting (CABG) surgery. Nevertheless, blockade of beta-2 receptors by increasing doses raise concerns about possible vasospasms. We studied the vasoactive effects of amiodarone and esmolol on left internal mammary artery (LIMA), radial artery (RA), and saphenous vein (SV) grafts. Materials and methods: After determining the presence of functional smooth muscle and endothelial layers, the responses of submaximally preconstricted graft samples were recorded in a tissue bath system. A total of 96 graft samples from 40 patients were used: 16 LIMA, 16 RA, and 16 SV grafts for each drug. Esmolol and amiodarone were added to reservoirs separately, starting from a concentration of 10-8 M until a concentration of 10-4 M. Results: Although both drugs caused vasodilatation, amiodarone exhibited a more potent vasodilatory effect than esmolol (P < 0.0001 for LIMA, P = 0.0128 for RA, and P < 0.0001 for SV). The vasodilatation rates with esmolol were 48.99 ± 2.28% in LIMA, 49.77 ± 3.03% in RA, and 41.90 ± 4.05% in SV grafts and with amiodarone they were 71.65 ± 5.18% in LIMA, 58.61 ± 5.87% in RA, and 65.07 ± 4.09% in SV grafts. Conclusion: This in vitro study revealed that even increasing doses of both drugs induce vasodilatation of CABG grafts, with amiodarone having a more potent vasodilatory effect than esmolol.


Mercury levels and relationships in water, sediment, and fish tissue in the Willamette Basin, Oregon.
In Oregon's Willamette River Basin (the Basin), health advisories currently limit consumption of fish that have accumulated methylmercury (MeHg) to levels posing a significant human health risk. These advisories created the requirement for a mercury total maximum daily load for the Basin, which required a greater understanding of the behavior, distribution, and levels of mercury and MeHg in the Basin. In 2002, the Oregon Department of Environmental Quality initiated a study to measure (using ultraclean techniques) mercury and MeHg levels in water, sediment, and fish samples collected throughout the Basin. Results from the Middle Fork (nominal background) suggested that naturally occurring surface-water concentrations of mercury and MeHg would on an annual average basis be expected in the range of 0.5 to 1.0 and 0.04 to 0.06 ng L(-1), respectively. Concentrations in the Coast Fork (Cottage Grove), which were markedly higher, are likely the result of historical mining discharges. The possibility exists that wetlands alone could contribute the dissolved MeHg levels (approximately 0.04 ng L(-1)) observed in the Main Stem. Mercury levels in sediment were similar, and near background, in the Main Stem, Coast Fork (Row River), and Middle Fork but significantly increased in the Coast Fork (Cottage Grove). Fish tissue mercury levels were typically highest in piscivorous and lowest in invertivorous species but highest in the Coast Fork (Cottage Grove). In the Coast Fork and Cottage Grove Reservoir, discharges from historical mercury mining activities appear to have significantly impacted water, sediment, and fish tissue levels; however these impacts do not appear to extend into the Main Stem. Basinwide mercury data are at present too spottily distributed to determine whether significant mercury point sources exist along the Main Stem.


The HLF/IL-6/STAT3 feedforward circuit drives hepatic stellate cell activation to promote liver fibrosis.
Liver fibrosis is a wound-healing response that disrupts the liver architecture and function by replacing functional parenchyma with scar tissue. Recent progress has advanced our knowledge of this scarring process, but the detailed mechanism of liver fibrosis is far from clear. The fibrotic specimens of patients and HLF (hepatic leukemia factor)PB/PB mice were used to assess the expression and role of HLF in liver fibrosis. Primary murine hepatic stellate cells (HSCs) and human HSC line Lx2 were used to investigate the impact of HLF on HSC activation and the underlying mechanism. Expression of HLF was detected in fibrotic livers of patients, but it was absent in the livers of healthy individuals. Intriguingly, HLF expression was confined to activated HSCs rather than other cell types in the liver. The loss of HLF impaired primary HSC activation and attenuated liver fibrosis in HLFPB/PB mice. Consistently, ectopic HLF expression significantly facilitated the activation of human HSCs. Mechanistic studies revealed that upregulated HLF transcriptionally enhanced interleukin 6 (IL-6) expression and intensified signal transducer and activator of transcription 3 (STAT3) phosphorylation, thus promoting HSC activation. Coincidentally, IL-6/STAT3 signalling in turn activated HLF expression in HSCs, thus completing a feedforward regulatory circuit in HSC activation. Moreover, correlation between HLF expression and alpha-smooth muscle actin, IL-6 and p-STAT3 levels was observed in patient fibrotic livers, supporting the role of HLF/IL-6/STAT3 cascade in liver fibrosis. In aggregate, we delineate a paradigm of HLF/IL-6/STAT3 regulatory circuit in liver fibrosis and propose that HLF is a novel biomarker for activated HSCs and a potential target for antifibrotic therapy.


DNA histogram of parathyroid tissue in determining extent of parathyroidectomy.
In an attempt to better define hyperplasia from adenoma and for more accurate discernment of grossly normal but histologically abnormal presumed hyperfunctioning gland, parathyroid tissue obtained at operation was subjected to flow cytometric analysis producing DNA histogram. Seventeen abnormal specimens and seven normal specimens obtained from parathyroidectomy cases were placed in RPMI 1640 culture medium, treated to produce a monodispersed cell suspension, and stained with propidium iodide fluorescent dye to provide a measure of DNA content that could be graphically demonstrated. All cell cycles for affected cell populations could be demonstrated on DNA histogram in the G0G1, S, and G2M phases. Proliferative index was arbitrarily derived by combining percentages of G2M plus S phases. It was apparent that the value so derived showed a tendency for higher value for the abnormal parathyroid tissue but the overlap was sufficient so that no specific discriminating value could be placed on DNA histogram. While flow cytometry may not be of significant use in intraoperative identification of abnormal parathyroid tissue, the values obtained may indicate that a spectrum of activity occurs in hyperparathyroidism that cannot be fully appreciated at the present time and that may in the light of incomplete knowledge manifest itself in the clinical state of hyperparathyroidism and hypercalcemia. The findings of our flow cytometry study may indeed lend credence to the view that all hyperparathyroidism represents a four-gland hyperfunction although this does not support as a consequence routine subtotal parathyroidectomy but should stimulate further inquiry into the pathogenesis of primary hyperparathyroidism.


Out of the burrow and into the nest: Functional anatomy of three life history stages of Ozaena lemoulti (Coleoptera: Carabidae) reveals an obligate life with ants.
The carabid subfamily Paussinae contains many species known to be obligately associated with ants during at least one stage of their life history. Myrmecophilous larvae have been documented for members of the tribe Paussini as well as several genera in the tribes Ozaenini, including Physea and Eustra. Here we describe the first instar larva of Ozaena lemoulti, and find it to be the most highly modified ozaenine larva that we have examined to date. Many structures of the larva suggest that it is a myrmecophile. Unlike all other described ozaenine larvae, which live in burrows that they construct and seal with their terminal disk, the completely unique larval morphology suggests Ozaena has adapted to living without the protection of a burrow and therefore must have a completely different feeding strategy than the typical ambush strategy of burrow dwelling larvae. We hypothesize that Ozaena larvae live in association with ants and use their long legs for running within the nest, and modifications of the mouthparts suggest the larva feeds on soft lightly sclerotized prey, such as ant brood. Our findings support an earlier hypothesis that Ozaena is mymecophilous during the adult stage. Comparisons of the functional anatomy of the eggs, larvae and adult between Ozaena lemoulti and the closely related, non-myrmecophilous general arthropod predator, Goniotropis kuntzeni, provide complementary, yet independent, evidence suggestive of this shift in lifestyle. We also examine and molecularly identify gut contents, providing direct evidence that adult Ozaena exclusively eat Camponotus ants. We conclude that Ozaena represents an independent shift to adopting a life of myrmecophily among beetles classified within the carabid subfamily Paussinae and document the morphological changes at each life history stage associated with the shift to a nest parasite lifestyle.


Hypertension and microvascular remodelling.
In the present review, microvascular remodelling refers to alterations in the structure of resistance vessels contributing to elevated systemic vascular resistance in hypertension. We start with some historical aspects, underscoring the importance of Folkow's contribution made half a century ago. We then move to some basic concepts on the biomechanics of blood vessels, and explicit the definitions proposed by Mulvany for specific forms of remodelling, especially inward eutrophic and inward hypertrophic. The available evidence for the existence of remodelled resistance vessels in hypertension comes next, with relatively more weight given to human, in comparison with animal data. Mechanisms are discussed. The impact of antihypertensive drug treatment on remodelling is described, again with emphasis on human data. Some details are given on the three studies to date which point to remodelling of subcutaneous resistance arteries as an independent predictor of cardiovascular risk in hypertensive patients. We terminate by considering the potential role of remodelling in the pathogenesis of end-organ damage and in the perpetuation of hypertension.


Familial STAG2 germline mutation defines a new human cohesinopathy.
We characterize a novel human cohesinopathy originated from a familial germline mutation of the gene encoding the cohesin subunit STAG2, which we propose to call STAG2-related X-linked Intellectual Deficiency. Five individuals carry a STAG2 p.Ser327Asn (c.980 G > A) variant that perfectly cosegregates with a phenotype of syndromic mental retardation in a characteristic X-linked recessive pattern. Although patient-derived cells did not show overt sister-chromatid cohesion defects, they exhibited altered cell cycle profiles and gene expression patterns that were consistent with cohesin deficiency. The protein level of STAG2 in patient cells was normal. Interestingly, STAG2 S327 is located at a conserved site crucial for binding to SCC1 and cohesin regulators. When expressed in human cells, the STAG2 p.Ser327Asn mutant is defective in binding to SCC1 and other cohesin subunits and regulators. Thus, decreased amount of intact cohesin likely underlies the phenotypes of STAG2-SXLID. Intriguingly, recombinant STAG2 p.Ser327Asn binds normally to SCC1, WAPL, and SGO1 in vitro, suggesting the existence of unknown in vivo mechanisms that regulate the interaction between STAG2 and SCC1.


Regulation of the Rana sylvatica brevinin-1SY antimicrobial peptide during development and in dorsal and ventral skin in response to freezing, anoxia and dehydration.
Brevinin-1SY is the only described antimicrobial peptide (AMP) of Rana sylvatica. As AMPs are important innate immune molecules that inhibit microbes, this study examined brevinin-1SY regulation during development and in adult frogs in response to environmental stress. The brevinin-1SY nucleotide sequence was identified and used for protein modeling. Brevinin-1SY was predicted to be an amphipathic, hydrophobic, alpha helical peptide that inserts into a lipid bilayer. Brevinin-1SY transcripts were detected in tadpoles and were significantly increased during the later stages of development. Effects of environmental stress (24 h anoxia, 40% dehydration or 24 h frozen) on the mRNA levels of brevinin-1SY in the dorsal and ventral skin were examined. The brevinin-1SY mRNA levels were increased in dorsal and ventral skin of dehydrated frogs, and in ventral skin of anoxic frogs, compared with controls (non-stressed). Brevinin-1SY protein levels in peptide extracts of dorsal skin showed a similar, but not significant, trend to that of brevinin-1SY mRNA levels. Antimicrobial activity of skin extracts from control and stressed animals were assessed for Escherichia coli, Bacillus subtilis, Saccharomyces cerevisiae, Botrytis cinerea, Rhizopus stolonifer and Pythium sulcatum using disk diffusion assays. Peptide extracts of dorsal skin from anoxic, frozen and dehydrated animals showed significantly higher inhibition of E. coli and P. sulcatum than from control animals. In ventral skin peptide extracts, significant growth inhibition was observed in frozen animals for E. coli and P. sulcatum, and in anoxic animals for B. cinerea, compared with controls. Environmental regulation of brevinin-1SY may have important implications for defense against pathogens.


The Dynamic Process and Its Dual Effects on Tumors of Therapy-Induced Senescence.
Cellular senescence is traditionally considered as stable cell cycle arrest state with other phenotypic alterations including the production of an array of cytokines and growth factors. Cancer cells undergo senescence in response to chemotherapeutic agents, radiotherapy and molecular targeted therapy. This form of senescence is termed therapy-induced senescence (TIS) and represents a desirable target in cancer therapy. Recent studies have shown that cellular senescence is a highly heterogeneous and dynamic process. Apart from being cleared by the immune system, the senescent cancer cells may survive for a long time and escape from senescence state. Notably, these cells even have the potential to regain stem-like state with high aggressiveness that eventually facilitates cancer recurrence. Furthermore, the senescence-associated secretory phenotype (SASP) of senescent cells is not always the same, and could establish immunosuppression and a protumor microenvironment. Given these detrimental effects, senescence-inducing chemotherapy followed by senotherapy (the "one-two punch" approach), has emerged. This combined therapy could mitigate unnecessary side effects of the persistent senescent cells, reduce the toxicity of pro-senescence therapy and prolong the survival of cancer patients, and it has a potential future in the precise treatment of cancer. Herein, we review the complex effects of therapy-induced senescence in cancer and highlight the great promise of two-step strategies in anticancer therapies.


Lack of proconvulsant action of GABA depletion in substantia nigra in several seizure models.
The effect of intranigral application of a gamma-aminobutyric acid (GABA) synthesis inhibitor, was examined in 3 different rat seizure models. Bilateral intranigral infusion of isoniazid (150 micrograms) did not potentiate the effect of subcutaneous administration of a threshold dose (1.5 mg/kg) of the GABA antagonist bicuculline. Similarly, following pretreatment with intranigral isoniazid, neither severity nor latency to onset of seizures elicited by systemic injection of kainic acid (9 mg/kg) were modified. In addition, convulsive seizures evoked by the focal injection of bicuculline methiodide (40 ng) in an epileptogenic site within the deep prepiriform cortex (area tempestas) were not potentiated by intranigral isoniazid. These results were in sharp contrast to the marked potentiating effect of intranigral isoniazid (150 or 85 micrograms) on seizures induced by systemic administration of a subconvulsant dose of pilocarpine (150 mg/kg). In addition, we attempted to evoke a proconvulsant action from striatum. The striatum, origin of GABAergic projections to substantia nigra, is a region in which application of GABA antagonists have been found to be anticonvulsant in several seizure models. We therefore examined the effect of bilateral intrastriatal infusion of the GABA agonist, muscimol (5 ng) on the convulsant effect of threshold doses of systemically administered bicuculline (1.5 mg/kg). As was true with intranigral isoniazid, no proconvulsant effect was found using intrastriatal muscimol. Our data demonstrate that whereas striatonigral GABA circuitry can be activated by exogenous treatments so as to produce anticonvulsant actions in most seizure models, suppression of this circuitry does not potentiate convulsant activity in many of the same models.


Comparing primary care Interprofessional and non-interprofessional teams on access to care and health services utilization in Ontario, Canada: a retrospective cohort study.
Many countries, including Canada, have introduced primary care reforms to improve health system functioning and value. The purpose of this study was to examine the association between receiving care from interprofessional primary care teams and after-hours access to care, patient-reported walk-in clinic visits and emergency department use. We conducted a retrospective cohort study linking population-based administrative databases to Ontario's Health Care Experience Survey (HCES) between 2012 and 2018. We adjusted for physician group characteristics as well as individual physician and patient characteristics while assessing the relationship between receiving care from interprofessional teams and the outcomes of interest. As of March 31st, 2015, there were 465 physician groups with HCES respondents of which 177 (38.0%) were interprofessional teams and 288 (62.0%) were non-interprofessional teams in the same blended capitation reimbursement model. In this period, there were 4518 physicians with HCES respondents, of whom 2131 (47.2%) were in interprofessional teams and 2387 (52.8%) were in non-interprofessional teams. There were 10,102 HCES respondents included in this study, of whom 42.4% were in interprofessional teams and 42.3% were in non-interprofessional teams. After adjustment, we found that being in an interprofessional team was associated with an increase in the odds of patients reporting same/next day access to care by 12.0% (OR = 1.12 CI = 1.00 to 1.24 p-value 0.0436) and a decrease in the odds of patients reporting walk-in clinic use by 16% (OR = 0.84 CI = 0.75 to 0.94 p-value 0.0019). After adjustment, there were no significant differences in patient-reported after-hours access to care and emergency department use. Ontario has invested heavily in interprofessional primary care teams. As compared to patients in non-interprofessional teams, patients in interprofessional teams self-reported more timely access to care and less walk-in clinic use but no significant difference in self-reported access to after-hours care or in emergency department use. For jurisdictions aiming to expand physician voluntary participation in interprofessional teams, our study results inform expectations around access to care and health services utilization.


[Clinical analysis of severe burn patients with sepsis during shock stage].
To investigate the pathogenesis, management and prognosis of severe burn patients with sepsis during shock stage. Fourty-four patients inflicted with over 60% TBSA burn injury and admitted to our hospital within 48 hours after injury during the past 8 years were enrolled in the study. The application of antibiotics in this group of patients was analyzed. The incidence of burn sepsis during shock stage in this group was calculated according to the results of the bacterial culture of the blood samples and burn wound samples,as well as the diagnostic criteria of sepsis. The relationship between sepsis during shock stage and the possibility of enteral bacterial translocation was discussed. Other postburn complications in patients with burn sepsis during shock stage were also observed and their prognosis was explored. This group of patients were all treated with 3rd and 4th generation of Cephalosporins and Imipenem/Cilastatin sodium after hospitalization. Burn sepsis during shock stage occurred in 4 cases (9.09%), in which one was caused by Pseudomonas aeruginosa and other three possibly by Escherichia coli, Streptococcus faecalis and Bacillus gasoformans. Among the 4 cases, severe disorder in water and electrolytes happened in 1 case, stress ulcer in 2 and acute renal failure in 2. As a result, only one out of the 4 patients survived. Bacterial translocation was probable cause of sepsis during shock stage. Shock might predispose sepsis. Early postburn applications of antibiotics sensitive to enteric bacteria could be beneficial to the management of burn sepsis during shock stage.


Steroids and nonsteroidal anti-inflammatory drugs in the postoperative regime after trabeculectomy - which provides the better outcome? A systematic review and meta-analysis.
Surgical outcome after trabeculectomy depends on maintaining a functional bleb which requires a delicate balance between incomplete wound healing to prevent fibrosis and enough wound healing to prevent hyperfiltration. Thus, controlling the inflammatory response is essential. We conducted a systematic review and meta-analysis to compare the effectiveness of different formulations of steroids (topical, systemic and depot) and nonsteroidal anti-inflammatory drugs (NSAIDs) in achieving long-term pressure control with fewer antiglaucomatous medications, preserving visual acuity and visual fields while considering surgical and postoperative complications. We used the PubMed, EMBASE and Cochrane Libraries to identify randomized controlled trials (RCTs) comparing the effect of different formulations of steroids (topical, systemic or depot) to NSAIDs. Data on prespecified outcomes from eligible references were entered into a meta-analysis using the Review Manager 5.3 program. We identified seven RCTs with a total of 342 included patients. Topical steroids were superior to placebo in controlling intraocular pressure (IOP) and reducing the risk of complications. Supplementing topical steroids with a perioperative steroid depot (subtenon or intracamerally) or systemic steroids in the early postoperative period did not provide better outcome or a change in the risk of complications. Addition of topical NSAIDs to topical steroids in patients undergoing trabeculectomy did not change the outcome or risk profile. For patients undergoing phacotrabeculectomy and topical NSAID, there was a nonsignificant trend towards better intermediate IOP control and a reduced need for antiglaucomatous medications compared to topical steroids but there was no difference in effect for patients undergoing trabeculectomy. In conclusion, there is a low level of evidence to support the clinician in deciding which postoperative regime provides a more favourable outcome because of inconsistency in the reported outcomes between studies and a low number of patients for each comparable intervention and outcome. It does seem that topical steroids are better than no anti-inflammatory treatment after glaucoma surgery, but further research is recommended.


Mammospheres from murine mammary stem cell-enriched basal cells: clonal characteristics and repopulating potential.
Identification of murine mammary stem cells (MaSCs) has been attempted with various in vitro and in vivo assays. While, the in vivo repopulation assay remains as the most definitive assay for MaSC detection, it is expensive, time-consuming, and technically challenging. The in vitro mammosphere assay was considered unreliable because of major concerns about its clonal origin. In the current study, co-culture experiments with mammary cells from fluorescent protein transgenic mice and time-lapse video microscopy revealed that >90% mammospheres formed from sorted basal epithelial-enriched cells were of clonal origin in terms of stem cell. These basal-cell derived mammospheres were further distinguished morphologically in a 3-dimensional extracellular matrix culture and functionally in the in vivo repopulation assay. Transplant of single mammospheres or the resultant 3-dimensional solid structures into gland-free mammary fat pads yielded a 70% success rate of multilineage mammary gland reconstitution. Thus, this in vitro sphere formation and differentiation assay is a reliable alternative to the in vivo repopulation assay for the study of MaSCs.


[The characteristics of the work activities, their autonomic support and the work capacity of coal mine workers ill with chronic bronchitis].
In miners with chronic bronchitis, diminution of bodily energy reserves does not permit optimizing their functional state in full measure. Patients are provided with ample opportunity to realize various forms of behaviour in order that they might continue their labour activities under usual conditions they are accustomed to. Exclusion from the activity those labour operations of high energy content, lowering of density of work, and increase in duration/number of breaks for rest--all such measures serve to secure professional activity. From the standpoint of self-preservation of the organism the above-named changes can be regarded as quite expedient since they minimize the action of adverse factors of the labour process. Nevertheless, this does not save the miners weakened by their illnesses from development of unfavourable states of overstrain during the process of their work.


Comparing SARS-CoV-2 antigen-detection rapid diagnostic tests for COVID-19 self-testing/self-sampling with molecular and professional-use tests: a systematic review and meta-analysis.
Self-testing is an effective tool to bridge the testing gap for several infectious diseases; however, its performance in detecting SARS-CoV-2 using antigen-detection rapid diagnostic tests (Ag-RDTs) has not been systematically reviewed. This study aimed to inform WHO guidelines by evaluating the accuracy of COVID-19 self-testing and self-sampling coupled with professional Ag-RDT conduct and interpretation. Articles on this topic were searched until November 7th, 2022. Concordance between self-testing/self-sampling and fully professional-use Ag-RDTs was assessed using Cohen's kappa. Bivariate meta-analysis yielded pooled performance estimates. Quality and certainty of evidence were evaluated using QUADAS-2 and GRADE tools. Among 43 studies included, twelve reported on self-testing, and 31 assessed self-sampling only. Around 49.6% showed low risk of bias. Overall concordance with professional-use Ag-RDTs was high (kappa 0.91 [95% confidence interval (CI) 0.88-0.94]). Comparing self-testing/self-sampling to molecular testing, the pooled sensitivity and specificity were 70.5% (95% CI 64.3-76.0) and 99.4% (95% CI 99.1-99.6), respectively. Higher sensitivity (i.e., 93.6% [95% CI 90.4-96.8] for Ct < 25) was estimated in subgroups with higher viral loads using Ct values as a proxy. Despite high heterogeneity among studies, COVID-19 self-testing/self-sampling exhibits high concordance with professional-use Ag-RDTs. This suggests that self-testing/self-sampling can be offered as part of COVID-19 testing strategies.Trial registration: PROSPERO: CRD42021250706.


Outcomes of endovascular repair for patients with blunt traumatic aortic injury.
Traumatic aortic injury (TAI) remains a leading cause of death after blunt force. Thoracic endovascular aortic repair (TEVAR) has been widely adopted as an alternative to open repair for the treatment of TAI. Although significant short-term benefits have been demonstrated for patients undergoing TEVAR, longer-term follow-up data are lacking. Trauma registry data were analyzed. Follow-up data were gathered from a combination of medical records, imaging, telephone interviews, and Social Security Death Index. Primary outcomes were in-hospital mortality, stroke, and paraplegia. Secondary outcomes included device-related adverse events (rupture, migration, or endoleak), secondary procedures, open conversion, and all-cause mortality. Between September 2005 and July 2012, 82 consecutive patients (57 males, mean [SD] age, 39.5 [20] years; mean [SD] Injury Severity Score [ISS], 34 [9.5]) underwent TEVAR for TAI. A total of 87 devices were implanted: TAG (n = 36), CTAG (n = 12) (WL Gore, Flagstaff, AZ); Talent (n = 29), Valiant (n = 5) (Medtronic, Santa Rosa, CA); TX2 (n = 2) (Cook, Bloomington, IN); and other (n = 3). Left subclavian artery coverage was required in 32 patients (39%). Technical success rate was 100%. Rates of in-hospital mortality, stroke, and paraplegia were 5.0%, 2.4%, and 0%, respectively.Median follow-up time was 2.3 years (range, 0-7 years). The availability of follow-up data was as follows: Social Security Death Index (100%), telephone interview (68%), clinic visit (61%), and imaging (82%). The incidence of device-related adverse events was 2.4%. There were four secondary procedures: two patients underwent a carotid-subclavian bypass, and two had an open conversion for device-related complications. Survival was 95% at 30 days, 88% at 1 year, 87% at 2 years, and 82% at 5 years. At midterm follow-up, TEVAR is an effective and durable option for the treatment of TAI in properly selected patients. Device-related adverse events, secondary procedures, and open conversion are rare. Follow-up remains a challenge. Therapeutic study, level V.


Allelic variant in the anti-Müllerian hormone gene leads to autosomal and temperature-dependent sex reversal in a selected Nile tilapia line.
Owing to the demand for sustainable sex-control protocols in aquaculture, research in tilapia sex determination is gaining momentum. The mutual influence of environmental and genetic factors hampers disentangling the complex sex determination mechanism in Nile tilapia (Oreochromis niloticus). Previous linkage analyses have demonstrated quantitative trait loci for the phenotypic sex on linkage groups 1, 3, and 23. Quantitative trait loci for temperature-dependent sex reversal similarly reside on linkage group 23. The anti-Müllerian hormone gene (amh), located in this genomic region, is important for sexual fate in higher vertebrates, and shows sexually dimorphic expression in Nile tilapia. Therefore this study aimed at detecting allelic variants and marker-sex associations in the amh gene. Sequencing identified six allelic variants. A significant effect on the phenotypic sex for SNP ss831884014 (p<0.0017) was found by stepwise logistic regression. The remaining variants were not significantly associated. Functional annotation of SNP ss831884014 revealed a non-synonymous amino acid substitution in the amh protein. Consequently, a fluorescence resonance energy transfer (FRET) based genotyping assay was developed and validated with a representative sample of fish. A logistic linear model confirmed a highly significant effect of the treatment and genotype on the phenotypic sex, but not for the interaction term (treatment: p<0.0001; genotype: p<0.0025). An additive genetic model proved a linear allele substitution effect of 12% in individuals from controls and groups treated at high temperature, respectively. Moreover, the effect of the genotype on the male proportion was significantly higher in groups treated at high temperature, giving 31% more males on average of the three genotypes. In addition, the groups treated at high temperature showed a positive dominance deviation (+11.4% males). In summary, marker-assisted selection for amh variant ss831884014 seems to be highly beneficial to increase the male proportion in Nile tilapia, especially when applying temperature-induced sex reversal.


In vitro processing and secretion of mutant insulin proteins that cause permanent neonatal diabetes.
Permanent neonatal diabetes mellitus is a rare form of insulin-requiring diabetes presenting within the first few weeks or months of life. Mutations in the insulin gene are the second most common cause of this form of diabetes. These mutations are located in critical regions of preproinsulin and are likely to prevent normal processing or folding of the preproinsulin/proinsulin molecule. To characterize these mutations, we transiently expressed proinsulin-GFP fusion proteins in MIN6 mouse insulinoma cells. Our study revealed three groups of mutant proteins: 1) mutations that result in retention of proinsulin in the endoplasmic reticulum (ER) and attenuation of secretion of cotransfected wild-type insulin: C43G, F48C, and C96Y; 2) mutations with partial ER retention, partial recruitment to granules, and attenuation of secretion of wild-type insulin: G32R, G32S, G47V, G90C, and Y108C; and 3) similar to (2) but with no significant attenuation of wild-type insulin secretion: A24D and R89C. The mutant insulin proteins do not prevent targeting of wild-type insulin to secretory granules, but most appear to lead to decreased secretion of wild-type insulin. Each of the mutants triggers the expression of the proapoptotic gene Chop, indicating the presence of ER stress.


Registered nurses' knowledge about diabetes mellitus.
Level of knowledge was tested in 137 volunteer registered nurses in three hospitals in the Midwest. A 34-item multiple choice Diabetes Knowledge Test (DKT) was developed by the first author (S.D.S.) working with a panel of expert nurse diabetes educators. Reliability using coefficient alpha was 0.61. Staff nurses obtained a mean score of 25.3, or 74% correct. Thirty-four nurses (25%) scored above 80% correct; 62 (45%) scored between 70% and 79% correct; and 41 (30%) scored below 70% correct. Higher-scoring nurses did well on items requiring use of exchange lists, but they missed items on physiologic actions of insulin, side effects of sulfonylureas, where insulin should be stored, and areas of the body suitable for injections of insulin. Nurses who scored below 60% on the test consistently missed items requiring use of exchange lists, effects of regular exercise and illness on blood glucose, and symptoms and causes of hypoglycemia and hyperglycemia. A strong trend (P = 0.055) was found for surgical nurses to score lower than medical unit nurses, and significant differences (P less than 0.05) were found among scores between hospitals. Staff nurses employed in a hospital where clinical specialists also were employed to teach diabetic patients had the lowest scores of the three hospitals. Test content subareas should be developed in the future to test knowledge reliably about urine testing, use of oral medications, home blood glucose monitoring, effects of exercise, and Somogyi phenomenon. A curriculum for regular inservice should be developed for nurses to assure a high level of knowledge for patient teaching with diabetes patients.


Rural Status, Suicide Ideation, and Telemental Health: Risk Assessment in a Clinical Sample.
Individuals living in rural areas die by suicide at higher rates than those living in metropolitan areas. Telemental health interventions provide rural residing individuals with access to needed care. Identifying telemental health clients at risk for suicide is an important task for clinicians and policymakers. This study evaluated to what degree rural status and other demographic variables predicted suicide ideation in clients seeking services at a telemental health clinic. Study participants included 457 low-income clients residing in the medically underserved, geographically diverse Brazos Valley region of Texas. Clients completed the patient health questionnaire during their initial counseling appointment, which assessed depression severity and suicide ideation in the 2 weeks prior to assessment. Suicide ideation was common among telemental health clients, with approximately 40% of clients in all demographic groups reporting some recent thoughts of suicide. Rates of suicide ideation did not significantly differ by geographic designation (ie, rural/metropolitan status), gender, or race/ethnicity. However, depression was a strong predictor of recent suicide ideation. Telemental health programs can effectively connect clinicians with rural residing clients who are otherwise isolated from health care services. However, clinicians working in high-need, historically underserved areas should be prepared to encounter a high prevalence of suicide ideation and depression. In these regions, clinical and diagnostic features may be better indicators of suicide ideation than demographic variables.


Subglacial hydrothermal alteration minerals in Jökulhlaup deposits of Southern Iceland, with implications for detecting past or present habitable environments on Mars.
Jökulhlaups are terrestrial catastrophic outfloods, often triggered by subglacial volcanic eruptions. Similar volcano-ice interactions were likely important on Mars where magma/lava may have interacted with the planet's cryosphere to produce catastrophic floods. As a potential analogue to sediments deposited during martian floods, the Holocene sandurs of Iceland are dominated by basaltic clasts derived from the subglacial environment and deposited during jökulhlaups. Palagonite tuffs and breccias, present within the deposits, represent the primary alteration lithology. The surface abundance of palagonite on the sandurs is 1-20%. X-ray diffraction (XRD) analysis of palagonite breccias confirms a mineral assemblage of zeolites, smectites, low-quartz, and kaolinite. Oriented powder X-ray diffractograms (< 2 microm fraction) for palagonite breccia clasts and coatings reveal randomly ordered smectite, mixed layer smectite/illite, zeolites, and quartz. Visible light-near infrared (VNIR) and shortwave infrared (SWIR) lab spectroscopic data of the same palagonite samples show H2O/OH(-) absorptions associated with clays and zeolites. SWIR spectra derived from Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) images of the sandurs reveal Al-OH(-) and Si-OH(-) absorption features. The identified alteration mineral assemblage is consistent with low temperature (100-140 degrees C) hydrothermal alteration of basaltic material within the subglacial environment. These results suggest that potential martian analog sites that contain a similar suite of hydrated minerals may be indicative of past hydrothermal activity and locations where past habitable environments for microbial life may be found.


The association of positive emotion and first smoking lapse: An ecological momentary assessment study.
Individuals attempting to quit smoking typically have poor success rates, and the majority fail to maintain long-term abstinence. Although a large body of evidence documents the impact of negative affect on reducing abstinence, there is a much smaller body of research on positive emotions, which could be an important mechanism that is associated with successful cessation. As such, this study examined positive emotions in real-time via ecological momentary assessment (EMA) to determine whether discrete positive emotions were uniquely related to 2 cessation milestones: quit day lapse and first lapse. Participants were 391 smokers who received tobacco cessation treatment. EMAs were completed pre- and postquit, and positive emotion was assessed with 3 items (enthusiastic, happy, and relaxed) rated on 5-point Likert scales. Analyses examined the associations of the means and slopes of each emotion on the current day with the likelihood of lapse on the following day. When controlling for relevant covariates, prequit positive emotions were not related to quit day lapse. However, postquit positive emotions were associated with first lapse. Specifically, high levels of happiness and relaxation, as well as increasing levels of enthusiasm, happiness, and relaxation were related to a lower likelihood of next day lapse. These are some of the first real-time, real-world data to demonstrate that distinct positive emotions are associated with a lower risk of lapse during the postquit period among smokers attempting to quit. (PsycINFO Database Record


Use of image cytometry to classify biliary and ampullary adenocarcinomas.
To create an objective classification system to perform TNM classification of ampullary adenocarcinoma and cholangiocarcinoma using image cytometric data derived from Feulgen-stained tumor nuclei. Surgically resected cases of ampullary adenocarcinoma and cholangiocarcinoma with established TNM classifications were selected on the basis of available formalin-fixed, paraffin-embedded tissue. Fifteen numerical variables related to morphometric, densitometric and textural features of each tumor nucleus were recorded. We employed a methodology based on multivariate statistical tools to characterize the association of morphonuclear variables with TNM classification. The first step consisted of identifying and selecting representative nuclei of each T class. From this "purified" data set an objective classification system was created. The classification system was assessed using internal and external validation. Employing ANOVA, all 15 variables were significantly associated with T classification, 11 of 15 with N and 4 with M. Multivariate analysis was employed to distinguish between T1, T2 and T3 lesions. Our methodology correctly classified 76% of T1 nuclei, 47% of T2 nuclei and 84% of T3 nuclei. Heterogeneity within an individual tumor was defined in 61% of cases included in the training set. Complete concordance between pathologic classification and the classification system was observed in 71% of an independent validation.


Lithium in drinking water and the incidences of crimes, suicides, and arrests related to drug addictions.
Using data for 27 Texas counties from 1978-1987, it is shown that the incidence rates of suicide, homicide, and rape are significantly higher in counties whose drinking water supplies contain little or no lithium than in counties with water lithium levels ranging from 70-170 micrograms/L; the differences remain statistically significant (p less than 0.01) after corrections for population density. The corresponding associations with the incidence rates of robbery, burglary, and theft were statistically significant with p less than 0.05. These results suggest that lithium has moderating effects on suicidal and violent criminal behavior at levels that may be encountered in municipal water supplies. Comparisons of drinking water lithium levels, in the respective Texas counties, with the incidences of arrests for possession of opium, cocaine, and their derivatives (morphine, heroin, and codeine) from 1981-1986 also produced statistically significant inverse associations, whereas no significant or consistent associations were observed with the reported arrest rates for possession of marijuana, driving under the influence of alcohol, and drunkenness. These results suggest that lithium at low dosage levels has a generally beneficial effect on human behavior, which may be associated with the functions of lithium as a nutritionally-essential trace element. Subject to confirmation by controlled experiments with high-risk populations, increasing the human lithium intakes by supplementation, or the lithiation of drinking water is suggested as a possible means of crime, suicide, and drug-dependency reduction at the individual and community level.


Plasmid vectors encoding cholera toxin or the heat-labile enterotoxin from Escherichia coli are strong adjuvants for DNA vaccines.
Two plasmid vectors encoding the A and B subunits of cholera toxin (CT) and two additional vectors encoding the A and B subunits of the Escherichia coli heat-labile enterotoxin (LT) were evaluated for their ability to serve as genetic adjuvants for particle-mediated DNA vaccines administered to the epidermis of laboratory animals. Both the CT and the LT vectors strongly augmented Th1 cytokine responses (gamma interferon [IFN-gamma]) to multiple viral antigens when codelivered with DNA vaccines. In addition, Th2 cytokine responses (interleukin 4 [IL-4]) were also augmented by both sets of vectors, with the effects of the LT vectors on IL-4 responses being more antigen dependent. The activities of both sets of vectors on antibody responses were antigen dependent and ranged from no effect to sharp reductions in the immunoglobulin G1 (IgG1)-to-IgG2a ratios. Overall, the LT vectors exhibited stronger adjuvant effects in terms of T-cell responses than did the CT vectors, and this was correlated with the induction of greater levels of cyclic AMP by the LT vectors following vector transfection into cultured cells. The adjuvant effects observed in vivo were due to the biological effects of the encoded proteins and not due to CpG motifs in the bacterial genes. Interestingly, the individual LT A and B subunit vectors exhibited partial adjuvant activity that was strongly influenced by the presence or absence of signal peptide coding sequences directing the encoded subunit to either intracellular or extracellular locations. Particle-mediated delivery of either the CT or LT adjuvant vectors in rodents and domestic pigs was well tolerated, suggesting that bacterial toxin-based genetic adjuvants may be a safe and effective strategy to enhance the potency of both prophylactic and therapeutic DNA vaccines for the induction of strong cellular immunity.


Global adoption of robotic technology into neurosurgical practice and research.
Recent technological advancements have led to the development and implementation of robotic surgery in several specialties, including neurosurgery. Our aim was to carry out a worldwide survey among neurosurgeons to assess the adoption of and attitude toward robotic technology in the neurosurgical operating room and to identify factors associated with use of robotic technology. The online survey was made up of nine or ten compulsory questions and was distributed via the European Association of the Neurosurgical Societies (EANS) and the Congress of Neurological Surgeons (CNS) in February and March 2018. From a total of 7280 neurosurgeons who were sent the survey, we received 406 answers, corresponding to a response rate of 5.6%, mostly from Europe and North America. Overall, 197 neurosurgeons (48.5%) reported having used robotic technology in clinical practice. The highest rates of adoption of robotics were observed for Europe (54%) and North America (51%). Apart from geographical region, only age under 30, female gender, and absence of a non-academic setting were significantly associated with clinical use of robotics. The Mazor family (32%) and ROSA (26%) robots were most commonly reported among robot users. Our study provides a worldwide overview of neurosurgical adoption of robotic technology. Almost half of the surveyed neurosurgeons reported having clinical experience with at least one robotic system. Ongoing and future trials should aim to clarify superiority or non-inferiority of neurosurgical robotic applications and balance these potential benefits with considerations on acquisition and maintenance costs.


White paper on herbal products. American College of Clinical Pharmacy.
Individuals increasingly are taking a more active role in their health care, and herbal products have emerged as a common choice among self-care therapies. Pharmacists are active participants in the care of patients who are taking herbal products. Currently, most pharmacists are not educated adequately about herbal products and other types of alternative medicine. Furthermore, good information about many of these products is not available. These combined factors present a challenge for pharmacists as they seek to provide optimal care and counseling to patients who use herbs or supplements. We recommend the following actions to place pharmacists in better positions as effective agents protecting public safety: Regulations should be implemented at a federal level to require basic levels of standardization and quality control in the manufacture of herbal products. Indexing terms in medical bibliographic systems should be expanded to target herbal products. Funding should be increased for scientific research evaluating herbal products. Pharmacy schools should include a competency statement in their curricula regarding herbal medicines. Continuing education in herbal products should be available and encouraged for all pharmacists. Pharmacists should approach the use of all therapeutic interventions with scientific rigor, whether they are traditional or complementary in nature. Patients will benefit as more information is known and widely disseminated. By actively embracing the responsibility for counseling individuals on the appropriate use of herbal products, pharmacists will become a recognized source of expert information in this rapidly growing area, yielding important improvements in the quality of care.


Age related changes of rib cortical bone matrix and the application to forensic age-at-death estimation.
Forensic anthropology includes, amongst other applications, the positive identification of unknown human skeletal remains. The first step in this process is an assessment of the biological profile, that is: sex, age, stature and ancestry. In forensic contexts, age estimation is one of the main challenges in the process of identification. Recently established admissibility criteria are driving researchers towards standardisation of methodological procedures. Despite these changes, experience still plays a central role in anthropological examinations. In order to avoid this issue, age estimation procedures (i) must be presented to the scientific community and published in peer reviewed journals, (ii) accurately explained in terms of procedure and (iii) present clear information about the accuracy of the estimation and possible error rates. In order to fulfil all these requirements, a number of methods based on physiological processes which result in biochemical changes in various tissue structures at the molecular level, such as modifications in DNA-methylation and telomere shortening, racemization of proteins and stable isotopes analysis, have been developed. The current work proposes a new systematic approach in age estimation based on tracing physicochemical and mechanical degeneration of the rib cortical bone matrix. This study used autopsy material from 113 rib specimens. A set of 33 parameters were measured by standard bio-mechanical (nanoindentation and microindentation), physical (TGA/DSC, XRD and FTIR) and histomorphometry (porosity-ImageJ) methods. Stepwise regressions were used to create equations that would produce the best 'estimates of age at death' vs real age of the cadavers. Five equations were produced; in the best of cases an equation counting 7 parameters had an R2 = 0.863 and mean absolute error of 4.64 years. The present method meets all the admissibility criteria previously described. Furthermore, the method is experience-independent and as such can be performed without previous expert knowledge of forensic anthropology and human anatomy.


Effect of chronic lithium treatment on twenty four hour variation in plasma and red blood cell lithium and sodium concentrations, drinking behavior, body weight, kidney weight, and corticosterone levels.
This study tested the hypothesis that lithium alters the phase relationships of various 24-hour rhythms. Six point 24-hour patterns were measured throughout a 12 hour light/12 hour dark cycle from separate groups of individually housed adult male wistar rats maintained for six weeks on ad lib water and either 1) Normal lab chow, 2) Lab chow supplemented with 50mM/KG of lithium chloride, or 3) Lab chow supplemented with 50mM/KG of sodium chloride. Plasma lithium levels were 0.7-1.0 mEq/1. The sodium diet had no effect on any of the variables measured relative to normal controls. Plasma but not red blood cell lithium levels demonstrated a 24-hour rhythm with higher levels during darkness. Serum and red blood cell sodium levels did not differ among the diets and showed no 24-hour variation. Lithium treated rats weighed significantly less than controls and had significantly heavier kidneys per 100 grams of body weight than controls. Resting plasma corticosterone levels demonstrated the expected 24-hour pattern in all groups, however, the lithium group evidenced higher levels during the middle of the dark hours than either control group. Water consumption also demonstrated a 24-hour rhythm. Lithium animals consumed far greater quantities of water than controls and this behaviour became increasingly exaggerated over the duration of the study. The data are interpreted as suggesting that lithium broadens the peak of twenty four hour rhythms such that normal elevation in these measures appear earlier and last longer.


USP3 promotes breast cancer cell proliferation by deubiquitinating KLF5.
The Krüppel-like factor 5 (KLF5) transcription factor is highly expressed in basal type breast cancer and promotes breast cancer cell proliferation, survival, migration, and tumorigenesis. KLF5 protein stability is regulated by ubiquitination. In this study, ubiquitin-specific protease 3 (USP3) was identified as a new KLF5 deubiquitinase by genome-wide siRNA library screening. We demonstrated that USP3 interacts with KLF5 and stabilizes KLF5 via deubiquitination. USP3 knockdown inhibits breast cancer cell proliferation in vitro and tumorigenesis in vivo, which can be partially rescued by ectopic expression of KLF5. Furthermore, we observed a positive correlation between USP3 and KLF5 protein expression levels in human breast cancer samples. These findings suggest that USP3 is a new KLF5 deubiquitinase and that USP3 may represent a potential therapeutic target for breast cancer.


Comparative Effectiveness of Tacrolimus-Based Steroid Sparing versus Steroid Maintenance Regimens in Kidney Transplantation: Results from Discrete Event Simulation.
Corticosteroids used as immunosuppressants to prevent acute rejection (AR) and graft loss (GL) following kidney transplantation are associated with serious cardiovascular and other adverse events. Evidence from short-term randomized controlled trials suggests that many patients on a tacrolimus-based immunosuppressant regimen can withdraw from steroids without increased AR or GL risk. To measure the long-term tradeoff between GL and adverse events for a heterogeneous-risk population and determine the optimal timing of steroid withdrawal. A discrete event simulation was developed including, as events, AR, GL, myocardial infarction (MI), stroke, cytomegalovirus, and new onset diabetes mellitus (NODM), among others. Data from the United States Renal Data System were used to estimate event-specific parametric regressions, which accounted for steroid-sparing regimen (avoidance, early 7-d withdrawal, 6-mo withdrawal, 12-mo withdrawal, and maintenance) as well as patients' demographics, immunologic risks, and comorbidities. Regression-equation results were used to derive individual time-to-event Weibull distributions, used, in turn, to simulate the course of patients over 20 y. Patients on steroid avoidance or an early-withdrawal regimen were more likely to experience AR (45.9% to 55.0% v. 33.6%, P < 0.05) and GL (51.5% to 68.8% v. 37.8%, P < 0.05) compared to patients on steroid maintenance. Patients in 6-mo and 12-mo steroid withdrawal groups were less likely to experience MI (11.1% v. 13.3%, P < 0.05), NODM (30.7% to 34.4% v. 37.7%, P < 0.05), and cardiac death (29.9% to 30.5% v. 32.4%, P < 0.05), compared to steroid maintenance. Strategies of 6- and 12-mo steroid withdrawal post-kidney transplantation are expected to reduce the rates of adverse cardiovascular events and other outcomes with no worsening of AR or GL rates compared with steroid maintenance.


Ten-year rank-order stability of personality traits and disorders in a clinical sample.
This study compares the 10-year retest stability of normal traits, pathological traits, and personality disorder dimensions in a clinical sample. Ten-year rank-order stability estimates for the Revised NEO Personality Inventory, Schedule for Nonadaptive and Adaptive Personality, and Diagnostic Interview for DSM-IV Personality Disorders were evaluated before and after correcting for test-retest dependability and internal consistency in a clinical sample (N = 266). Dependability-corrected stability estimates were generally in the range of.60-.90 for traits and.25-.65 for personality disorders. The relatively lower stability of personality disorder symptoms may indicate important differences between pathological behaviors and relatively more stable self-attributed traits and imply that a full understanding of personality and personality pathology needs to take both traits and symptoms into account. The five-factor theory distinction between basic tendencies and characteristic adaptations provides a theoretical framework for the separation of traits and disorders in terms of stability in which traits reflect basic tendencies that are stable and pervasive across situations, whereas personality disorder symptoms reflect characteristic maladaptations that are a function of both basic tendencies and environmental dynamics.