Molecular abnormalities of p53, MDM2, and H-ras in synovial sarcoma.
Forty-nine cases of synovial sarcoma were evaluated for mutation of the p53 gene, amplification of the MDM2 gene and mutation of the H-ras gene, and for the relation of these factors to overall survival and clinicopathologic parameters. All investigations were carried out on formalin-fixed paraffin-embedded materials. Furthermore, we evaluated the expression of p53 protein, MDM2, and p21(WAF1/CIP1) immunohistochemically in these cases, together with an assessment of proliferative activities using monoclonal antibody MIB-1. Nine of the 49 cases (18.4%) had p53 gene alteration detected by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) and direct sequencing. Eleven cases (24%) showed nuclear accumulation of p53 protein in more than 10% of the tumor cells. Among them, only three cases contained gene mutations. There was no correlation between p53 nuclear accumulation and p53 gene alteration. MDM2 gene amplification, as shown by differential PCR, was observed in 19 out of 47 cases (40%). Nineteen out of 49 cases (38.8%) showed immunoreactivity for MDM2. MDM2 gene amplification and the expression of MDM2 protein showed a significant positive relationship (P = 0.0004). Moreover, MDM2 immunoreaction was significantly correlated with nuclear accumulation of p53 protein (P = 0.023). Positive immunoreaction for p21(WAF1/CIP1) was observed in 21 out of 48 cases (43.8%). p21(WAF1/CIP1) expression was correlated with p53 protein expression. H-ras gene mutations were seen in only three cases (6.1%). All mutations were in codon 12 (one GGC-to-AGC [Gly-to-Ser] mutation and two GGC-to-GAC [Gly-to-Ap] mutations). The gene alteration of p53, MDM2, and H-ras did not affect the patients' prognosis. Although the cases with positive immunoreaction for p53 tended to have a worse prognosis, the difference was not statistically significant (P = 0.13). No correlation was observed between MIB-1 LI and the immunohistochemical expression of p53, MDM2, and p21(WAF1/CIP1) or the mutation status of p53 and H-ras. On the other hand, high MIB-1 LI (more than 10) significantly correlated with poor prognosis (P < 0.0001). Our results suggest that p53 gene mutation does not appear to be a major prognostic factor and H-ras mutations are infrequent in synovial sarcoma.


Anatomy of Meckel's cave and the trigeminal ganglion: anatomical landmarks for a safer approach to them.
Surgical approaches to Meckel's cave (MC) are often technically difficult and sometimes associated with postoperative morbidity. The relationship of surgical landmarks to relevant anatomy is important. Therefore, we attempted to delineate quantitatively their anatomy and the relationships between MC and surrounding structures. With the aid of a surgical microscope, MC and its contents were studied in 15 formalin-fixed cadaver head specimens. Measurements were made and their relationships were observed. The distance from the zygomatic arch and the lateral end of the petrous ridge to MC was 26.5 and 34.4 mm, respectively. The distance from the arcuate eminence, the facial nerve hiatus, and the foramen spinosum to MC was 16.6, 12.8 and 7.46 mm respectively. The TG lay 5.81 mm posterior to the foramen ovale. The distance from the abducens, trochlear and oculomotor nerves to the trigeminal ganglion was 1.87, 5.53 and 6.57 mm respectively. The distance from the posterior and the anterior walls of the sigmoid sinus to the trigeminal porus was 43.6 and 33.1 mm respectively. The trigeminal porus was on average 7.19 mm from the anterior wall of the internal acoustic meatus. The anatomical landmarks as presented herein regarding MC may be used for a safer skull base approach to the region.


TGF-β Upregulated Mitochondria Mass through the SMAD2/3→C/EBPβ→PRMT1 Signal Pathway in Primary Human Lung Fibroblasts.
Tissue remodeling of subepithelial mesenchymal cells is a major pathologic condition of chronic obstructive pulmonary disease and asthma. Fibroblasts contribute to fibrotic events and inflammation in both airway diseases. Recent mechanistic studies established a link between mitochondrial dysfunction or aberrant biogenesis leading to tissue remodeling of the airway wall in asthma. Protein arginine methyltransferase-1 (PRMT1) participated in airway wall remodeling in pulmonary inflammation. This study investigated the mechanism by which PRMT1 regulates mitochondrial mass in primary human airway wall fibroblasts. Fibroblasts from control or asthma patients were stimulated with TGF-β for up to 48 h, and the signaling pathways controlling PRMT1 expression and mitochondrial mass were analyzed. PRMT1 activity was suppressed by the pan-PRMT inhibitor AMI-1. The SMAD2/3 pathway was blocked by SB203580 and C/EBPβ by small interference RNA treatment. The data obtained from unstimulated cells showed a significantly higher basal expression of PRMT1 and mitochondrial markers in asthmatic compared with control fibroblasts. In all cells, TGF-β significantly increased the expression of PRMT1 through SMAD2/3 and C/EBPβ. Subsequently, PRMT1 upregulated the expression of the mitochondria regulators PGC-1α and heat shock protein 60. Both the inhibition of the SAMD2/3 pathway or PRMT1 attenuated TGF-β-induced mitochondrial mass and C/EBPβ and α-SMA expression. These findings suggest that the signaling sequence controlling mitochondria in primary human lung fibroblasts is as follows: TGF-β→SMAD2/3→C/EBPβ→PRMT1→PGC-1α. Therefore, PRMT1 and C/EBPβ present a novel therapeutic and diagnostic target for airway wall remodeling in chronic lung diseases.


Private speech improves cognitive performance in young adults.
The current study investigated the relationship between private speech usage and cognitive performance in young adults. Participants (n = 103, mean age = 20.21 years) were instructed to complete a visual-spatial working memory task while talking out loud to themselves as much as possible (Private Speech condition). We found that participants performed better on trials for which they produced a greater amount of private speech. To establish causality, we further found that participants performed better in the Private Speech condition than in a condition in which they were instructed to remain silent (Quiet condition). These beneficial effects of private speech were not moderated by task difficulty, which was manipulated by varying image labelability. However, participants who used more private speech during the task, as well as those who reported greater use of self-management private speech in everyday life, showed the greatest benefits. These findings have implications for real-world educational/instructional settings.


Deficiency of kallikrein activity in plasma of patients with cystic fibrosis.
Total kallikrein activity and kallikrein activity inhibited by soybean trypsin inhibitor are significantly reduced in the plasma of patients with cystic fibrosis compared to age-matched controls. The level of the STI inhibited kallikrein activity in the plasma of heterozygotes was significantly different from that in either controls or affected children. However, the individual heterozygote could not be reliably identified in each case.


Automated classification of hyperlucency, fibrosis, ground glass, solid, and focal lesions in high-resolution CT of the lung.
An automatic method for textural analysis of complete HRCT lung slices is presented. The system performs classification of regions of interest (ROIs) into one of six classes: normal, hyperlucency, fibrosis, ground glass, solid, and focal. We propose a novel method of automatically generating ROIs that contain homogeneous texture. The use of such regions rather than square regions is shown to improve performance of the automated system. Furthermore, the use of two different, previously published, feature sets is investigated. Both feature sets are shown to yield similar results. Classification performance of the complete system is characterized by ROC curves for each of the classes of abnormality and compared to a total of three expert readings by two experienced radiologists. The different types of abnormality can be automatically distinguished with areas under the ROC curve that range from 0.74 (focal) to 0.95 (solid). The kappa statistics for intraobserver agreement, interobserver agreement, and computer versus observer agreement were 0.70, 0.53+/-0.02, and 0.40+/-0.03, respectively. The question whether or not a class of abnormality was present in a slice could be answered by the computer system with an accuracy comparable to that of radiologists.


[Hypercalcemia in coexistent parathyroid adenoma and multiple myeloma. Problems of differential diagnosis].
In a chance observation, a 74-year-old woman was found to have hypercalcaemia (3.0 mmol/l) and multiple skeletal osteolyses. A diagnosis of multiple myeloma was made after the demonstration of paraproteins in serum (IgG-kappa) and a 10% proportion of plasma cells in a pelvic crest biopsy. Oral chemotherapy with melphalan and prednisone failed to alter the calcium level. Simultaneous increase in alkaline phosphatase and reduction in serum phosphate concentration led to further tests: determination of peripheral venous parathormone concentration, ultrasound examination of the neck, thallium-technetium subtraction scintigraphy and selective venous parathormone measurements. The results demonstrated the coexistence of primary hyperparathyroidism. The calcium level became normal after surgical removal of a parathyroid adenoma.


Semi-parametric regression models for cost-effectiveness analysis: improving the efficiency of estimation from censored data.
In a cost-effectiveness analysis using clinical trial data, estimates of the between-treatment difference in mean cost and mean effectiveness are needed. Several methods for handling censored data have been suggested. One of them is inverse-probability weighting, and has the advantage that it can also be applied to estimate the parameters from a linear regression of the mean. Such regression models can potentially estimate the treatment contrast more precisely, since some of the residual variance can be explained by baseline covariates. The drawback, however, is that inverse-probability weighting may not be efficient. Using existing results on semi-parametric efficiency, this paper derives the semi-parametric efficient parameter estimates for regression of mean cost, mean quality-adjusted survival time and mean survival time. The performance of these estimates is evaluated through a simulation study. Applying both the new estimators and the inverse-probability weighted estimators to the results of the EVALUATE trial showed that the new estimators achieved a halving of the variance of the estimated treatment contrast for cost. Some practical suggestions for choosing an estimator are offered.


Poly(ethylene glycol)s in Semidilute Regime: Radius of Gyration in the Bulk and Partitioning into a Nanopore.
Using two approaches, small-angle neutron scattering (SANS) from bulk solutions and nanopore conductance-fluctuation analysis, we studied structural and dynamic features of poly(ethylene glycol) (PEG) water/salt solutions in the dilute and semidilute regimes. SANS measurements on PEG 3400 at the zero-average contrast yielded the single chain radius of gyration (Rg) over 1-30 wt %. We observed a small but statistically reliable decrease in Rg with increasing PEG concentration: at 30 wt % the chain contracts by a factor of 0.94. Analyzing conductance fluctuations of the α-hemolysin nanopore in the mixtures of PEG 200 with PEG 3400, we demonstrated that polymer partitioning into the nanopore is mostly due to PEG 200. Specifically, for a 1:1 wt/wt mixture the smaller polymer dominates to the extent that only about 1/25 of the nanopore volume is taken by the larger polymer. These findings advance our conceptual and quantitative understanding of nanopore polymer partitioning; they also support the main assumptions of the recent "polymers-pushing-polymers" model.


Solvolyses of 2-Deoxy-alpha- and beta-D-Glucopyranosyl 4'-Bromoisoquinolinium Tetrafluoroborates.
The solvolyses of 2-deoxy-alpha- and beta-D-glucopyranosyl 4'-bromoisoquinolinium tetrafluoroborates (1 and 2) were monitored in aqueous methanol, ethanol, trifluoroethanol, and binary mixtures of ethanol and trifluoroethanol. The observed rate constants are consistent with the solvolyses of 1 and 2 proceeding via dissociative (D(N) A(N)) transition states. In comparison to the alpha-anomer, solvolysis of the beta-compound gives a greater transition state charge delocalization onto the ring oxygen atom. Analysis of the solvolysis product ratios indicates that the 2-deoxyglucosyl oxacarbenium ion is not solvent-equilibrated in the solvent mixtures studied. In the solvolysis of compound 1, the solvent trifluoroethanol facilitates diffusional separation of the leaving group and, in so doing, promotes the formation of the retained trifluoroethyl glycoside.


Conditional or unconditional logistic regression for frequency matched case-control design?
Frequency matching is commonly used in epidemiological case control studies to balance the distributions of the matching factors between the case and control groups and to improve the efficiency of case-control designs. Applied researchers have held a common opinion that unconditional logistic regression should be used to analyze frequency matched designs and conditional logistic regression is unnecessary. However, the justification of this view is unclear. To compare the performances of ULR and CLR in terms of simplicity, unbiasedness, and efficiency in a more intuitive way, we viewed frequency matching from the perspective of weighted sampling and derived the outcome models describing how the exposure and matching factors are associated with the outcome in the matched data separately in two scenarios: (1) only categorical variables are used for matching; (2) continuous variables are categorized for matching. In either scenario the derived outcome model is a logit model with stratum-specific intercepts. Correctly specified unconditional logistic regression can be more efficient than conditional logistic regression, particularly when continuous matching factors are used, whereas conditional logistic regression is a more practical approach because it is less dependent on modeling choices.


Vortioxetine reduces BOLD signal during performance of the N-back working memory task: a randomised neuroimaging trial in remitted depressed patients and healthy controls.
Cognitive dysfunction is common in depression during both acute episodes and remission. Vortioxetine is a novel multimodal antidepressant that has improved cognitive function including executive function in depressed patients in randomised placebo-controlled clinical trials. However, it is unclear whether vortioxetine is able to target directly the neural circuitry implicated in the cognitive deficits in depression. Remitted depressed (n=48) and healthy volunteers (n=48) were randomised to receive 14 days treatment with 20 mg vortioxetine or placebo in a double-blind design. The effects of treatment on functional magnetic resonance imaging responses during an N-back working memory task were assessed at baseline and at the end of treatment. Neuropsychological measures of executive function, speed and information processing, attention and learning and memory were examined with the Trail Making Test (TMT), Rey Auditory Learning Test and Digit Symbol Substitution Test before and after treatment; subjective cognitive function was assessed using the Perceived Deficits Questionnaire (PDQ). Compared with placebo, vortioxetine reduced activation in the right dorsolateral prefrontal cortex and left hippocampus during the N-back task compared with placebo. Vortioxetine also increased TMT-A performance and self-reported cognitive function on the PDQ. These effects were seen across both subject groups. Vortioxetine modulates neural responses across a circuit subserving working memory in a direction opposite to the changes described in depression, when performance is maintained. This study provides evidence that vortioxetine has direct effects on the neural circuitry supporting cognitive function that can be dissociated from its effects on the mood symptoms of depression.


[Digestive tract hemorrhages of cirrhotic patients. Relation between hepatic insufficiency and the hemorrhagic lesion].
The cause of upper gastrointestinal bleeding was studied in 85 cirrhotic patients by emergency endoscopy. In every patient, one or several lesions were observed and the site of bleeding was ascertained in 59. The two main causes were oesophago-gastric varices (46 p.cent) and acute mucosal lesions(42 p.cent). The source of bleeding appeared to be related to the degree of liver function impairment. In patients with no or moderate liver function impariment, bleeding usually originated from varices or from drug-associated mucosal erosions. Patients with severe impairment of liver function most often bled from spontaneous acute oeso-gastro-duodenal ulcerations. These ulcerations resembled what has been described in "stress" hemorrhage. Because of the relationship between liver function and the cause of hemorrhage, mortality was lower in variceal bleeders (29 p.cent) than in patients with spontaneous ulcerations (83 p.cent). In patients with severely impaired liver function, portacaval shunt was rarely indicated since hemorrhage was generally due to acute mucosal ulcerations.


Effects of alcoholism typology on response to naltrexone in the COMBINE study.
This study investigated whether subgroups of alcohol-dependent patients responded differently to naltrexone versus placebo in the NIAAA COMBINE study. In particular, the A versus B and the Early Onset versus Late Onset typologies were examined. Relative to Type A alcoholics, Type B alcoholics are characterized by greater severity, earlier onset, stronger family history, more childhood risk factors (e.g., conduct disorder), and greater frequency of comorbid psychiatric and substance use disorders. COMBINE study participants were categorized as Type A or Type B using k-means cluster analysis and variables from 5 domains that have been shown to replicate the original Babor typology efficiently. Early Onset was defined as alcohol dependence beginning before age 25. For the planned analyses, the sample was reduced to the 618 participants receiving naltrexone alone or placebo, either with medical management (MM) alone or with MM plus the Combined Behavioral Intervention (CBI). The a priori primary outcome was percent heavy drinking days during treatment in the groups receiving MM without CBI. Among those receiving MM without CBI, Type A alcoholics had better drinking outcomes with naltrexone than placebo, whereas medication condition did not influence outcomes significantly in the Type Bs. Age of onset was not significantly related to outcome. For those receiving CBI, no significant effects were found for either typology. In this sample, the beneficial effects of opioid antagonism were limited to Type A alcoholics receiving treatment in a MM model. Future studies should investigate the relationship between clinically relevant genotypes, phenotypes such as typologies, and treatment response. More work is also needed to develop practical algorithms for phenotypic assignment.


Transcriptional analyses of baculovirus polyhedrin and foreign gene expression relative to baculovirus p10 mRNA levels.
Comparisons have been made between the p10 and polyhedrin mRNA levels recovered from Spodoptera frugiperda cells infected with Autographa californica nuclear polyhedrosis virus (AcNPV). In molar terms and from 18 h post-infection (p.i.), the polyhedrin mRNA species increased to levels one and a half times to twice as high as the p10 levels. The influence of the polyhedrin leader sequence on the expression of a foreign gene under the control of the polyhedrin promoter was investigated using a series of four recombinant baculoviruses expressing the lymphocytic choriomeningitis virus nucleocapsid (N) protein gene. The different recombinants varied in the length and composition of the upstream polyhedrin mRNA leader sequence. The recombinant containing the full-length polyhedrin leader sequence gave levels of N mRNA comparable to those of AcNPV polyhedrin mRNA. These levels were either equal to (12 h p.i.) or higher (18 to 42 h p.i.) than the p10 levels at corresponding times. Three other recombinants, with different lengths of leader sequence, accumulated significantly lower quantities of N mRNA in comparison to the p10 mRNA levels. However the mRNA levels for the three recombinants were similar (20 to 50% of the p10 level) and did not correspond to their N protein expression levels. By comparing the mRNA and protein levels, it is concluded that the sequence between -8 to +1 of the AcNPV polyhedrin translation-initiating ATG has an important function for mRNA transcription (or accumulation), while the sequences between -32 to -8 affect the overall translation efficiencies.


A decline in earning losses associated with a community-based cardiovascular disease prevention project.
Permanent and temporary disability pension award data and survey data were used to estimate the lower bound of earning losses related to cardiovascular disease during a community-based cardiovascular disease prevention program in Eastern Finland. Earning losses due to death totaled $39.94 million but were not affected by the project. Earning losses due to permanent disability totalled +29.01 million and were $4.25 million less than expected (p less than 0.025). Earning losses due to temporary disability were $10.91 million and were not affected by the project. Total earning losses attributable to cardiovascular disease during the project period were $79.86 million, and total decline in earning losses was +4.25 million. Project implementation costs were less than one per cent of total earning losses and were equal to approximately 17 per cent of the decline in these losses attributable to the project. The findings suggest that community-based heart disease prevention programs have the potential of more than paying for themselves through an associated decline in lost earnings.


Enhanced uptake of doxorubicin into bronchial carcinoma: beta-glucuronidase mediates release of doxorubicin from a glucuronide prodrug (HMR 1826) at the tumor site.
Lack of tumor selectivity is a severe limitation of cancer chemotherapy. Consequently, reducing dose-limiting organ toxicities such as the cardiac toxicity of doxorubicin (Dox) is of major clinical relevance. Approaches that would facilitate a more tumor-selective anticancer therapy by using nontoxic prodrugs that are converted to active anticancer agents at the tumor site have been the subject of intensive research. One potential method to overcome the cardiac toxicity of Dox is to apply a nontoxic, glucuronide prodrug (HMR 1826) from which Dox is released by the action of beta-glucuronidase, an enzyme present at high levels in many tumors. Using a recently developed, isolated, perfused human lung model, we compared the uptake of Dox into normal lung and lung tumors after a 2.5-h lung perfusion with doxorubicin (n = 8) and with the novel doxorubicin glucuronide prodrug (n = 8). Dox showed a poor uptake into lung tumors as compared with normal lung [mean Dox concentration at the end of perfusion, 1.78 +/- 3.11 (median, 0.66) microg/g versus 22.03 +/- 10.4 (median, 18.5) microg/g; P < 0.001]. However, after perfusion with HMR 1826, the level of Dox in tumor tissue was about 7-fold higher than after perfusion with Dox itself [14.04 +/- 12.9 (median, 12.9) microg/g versus 1.78 +/- 3.11 (median, 0.66) microg/g, P < 0.05, n = 8]. In vitro experiments showed a significantly higher beta-glucuronidase expression and activity in the tumors. The extent of in vitro cleavage of HMR 1826 by homogenized lung tissue was closely related to the content of beta-glucuronidase (r = 0.9834, P < 0.0001). When D-saccharolactone, a specific inhibitor of beta-glucuronidase, was added to the perfusate containing HMR 1826, no accumulation of Dox in lung tissue was seen. These data indicate that the high Dox levels achieved in the tumors with HMR 1826 resulted from cleavage of the prodrug by beta-glucuronidase at the tumor site. Thus, the problem of poor Dox uptake into lung tumors could be circumvented by applying the doxorubicin glucuronide prodrug. Several lines of evidence based on both ex vivo and in vitro results indicate that the approach described using a glucuronide prodrug may be useful in facilitating more selective delivery of chemotherapy to tumors in humans.


Multi-scale Unrolled Deep Learning Framework for Accelerated Magnetic Resonance Imaging.
Accelerating data acquisition in magnetic resonance imaging (MRI) has been of perennial interest due to its prohibitively slow data acquisition process. Recent trends in accelerating MRI employ data-centric deep learning frameworks due to its fast inference time and 'one-parameter-fit-all' principle unlike in traditional model-based acceleration techniques. Unrolled deep learning framework that combines the deep priors and model knowledge are robust compared to naive deep learning based framework. In this paper, we propose a novel multi-scale unrolled deep learning framework which learns deep image priors through multi-scale CNN and is combined with unrolled framework to enforce data-consistency and model knowledge. Essentially, this framework combines the best of both learning paradigms:model-based and data-centric learning paradigms. Proposed method is verified using several experiments on numerous data sets.


Traction of lateral cricoarytenoid muscle for unilateral vocal fold paralysis: comparison with Isshiki' s original technique of arytenoid adduction.
Between 1995 and 1997, we performed Isshiki's original method of arytenoid adduction alone or as an adjunct to type I thyroplasty for the treatment of unilateral vocal fold paralysis. From 1997 onward, we performed arytenoid adduction by traction of the lateral cricoarytenoid muscle (Iwamura's method), because it reduces discomfort to the patient and avoids rotation of the thyroid cartilage. Preliminary experiments and surgical procedures involving traction of the lateral cricoarytenoid muscle are described. Of 21 patients with a maximum phonation time of less than 9 seconds, 14 underwent type I thyroplasty as an adjunct to our method of arytenoid adduction and 7 underwent arytenoid adduction alone. Sixteen patients (76%) were able after surgery to extend their maximum phonation time beyond 10 seconds; this result compares favorably with the results of Isshiki's original adduction technique. We describe useful anatomic landmarks for approaching the lateral cricoarytenoid muscle in the hope that more voice surgeons will adopt this approach in the treatment of unilateral vocal fold paralysis.


Magnetic resonance imaging of the arc of contact of extraocular muscles: implications regarding the incidence of slipped muscles.
Slipped muscles are complications of strabismus surgery that are encountered more frequently after recessions of the inferior and medial rectus muscles. We obtained multipositional high-resolution magnetic resonance imaging of 10 orbits of 6 normal subjects, 9 orbits of 5 patients with thyroid-associated eye disease, and 4 orbits of 2 patients with thyroid-associated eye disease on the day after rectus muscle recessions using a suspension technique. The arc of contact and the distance between the insertion and the point of tangency of each of the extraocular muscles to the globe were measured in primary position as well as in the cardinal fields. The data confirm that the inferior and medial rectus muscles have a significantly smaller wraparound effect on the globe than the superior and lateral rectus muscles, respectively (P =.022 for the vertical rectus muscles; P =.05 for the horizontal rectus muscles, paired t test), and that their insertions may be found several millimeters posterior to their points of tangency in extreme rotation of the globe in their respective field of action. The appearance of the suspended recessed inferior rectus muscle on the first postoperative day and its decreased apposition to the globe raise concerns about the muscle losing contact with the globe in extreme downgaze. The small wraparound effect of the inferior and medial rectus muscles may explain one of the mechanisms accounting for the increased incidence of slipped muscles encountered after recessions of these muscles.


Potential role of tamoxifen in prevention of breast cancer.
Despite advances in early detection and treatment of breast cancer, primary prevention has not been well explored, especially for women at increased risk of disease due to reproductive factors and family history. There are, however, suggestions that primary prevention of breast cancer may be a realistic objective. Randomized clinical trials of adjuvant therapy for early-stage breast cancer have demonstrated a 35% decrease in contralateral breast cancers among women receiving tamoxifen compared with controls, suggesting a potential role for tamoxifen in chemoprevention of breast cancer in women at increased risk of the disease. Adjuvant therapy studies also demonstrate that tamoxifen is well tolerated by most patients and suggest additional health benefits from alterations in plasma lipid levels and stabilization of bone mineral loss in women receiving tamoxifen. Aspects of tamoxifen pharmacology, laboratory research, and clinical experience which support its investigation as a chemopreventive agent for breast cancer are summarized, and potential toxic effects are discussed.


Effect of different dry period lengths on milk production and somatic cell count in subsequent lactations in commercial Dutch dairy herds.
Shortening the dry period (DP) has been proposed as a management strategy to improve energy balance in early lactation. It is well known that both shortening and complete omission of the DP reduces milk production in the subsequent lactations. In most of these studies milk production data were obtained from planned animal experiments where cows were randomly assigned to DP length treatments, and cow management and diet composition did not differ among treatments. It may therefore be hypothesized that cows on commercial herds which apply a no-DP or short-DP-strategy, and support this by management adjustments, will have a less dramatic reduction in milk production. In this study, milk production and somatic cell count (SCC) following different DP lengths was investigated under commercial circumstances. Milk production of 342 cows (2,077 test-day records) was available from 5 Dutch commercial dairy herds which started a no DP-strategy for all cows. Test days of the year before applying the no-DP strategy are used as control (323 cows, 1,717 test-day records). Six other herds applied an individual cow approach and have different preplanned DP lengths within one herd. From these herds, information on 81 cows (482 test-day records) with a DP length between 0 and 20 d, 127 cows (925 test-day records) with a DP length between 21 and 35 d, and 143 cows (1,075 test-day records) with a DP length of more than 35 d was available. A generalized linear model incorporating an autoregressive covariance structure accounting for repeated test-day yields within cow was developed to estimate the daily yield (milk, fat and protein) and SCC of all cows. Applying no DP for all cows in the herd resulted in a reduction in postpartum milk production compared with within-herd control lactations (until 305 DIM) between 3.2 and 9.1 kg/d, which was a reduction of 12 and 32%, respectively. For the 6 herds that applied an individual cow approach with different preplanned DP lengths, the cow-specific DP strategy was based on milk production and SCC approximately 2 mo before calving. Cows with a preplanned DP length ranging between 0 and 20 d had a reduction in postpartum milk production between 5.7 and 13 kg/d compared with cows with a DP length of >35 d. Cows with a preplanned DP length ranging from 21 to 35 d had a numerically lower milk production (between 0.6 and 5.3 kg/d) than cows with a preplanned DP length of >35 d, but this difference was significant in only one herd. When corrected for milk yield, no difference in postpartum SCC for cows with different DP lengths was found.


Terminal weaning or immediate extubation for withdrawing mechanical ventilation in critically ill patients (the ARREVE observational study).
The relative merits of immediate extubation versus terminal weaning for mechanical ventilation withdrawal are controversial, particularly regarding the experience of patients and relatives. This prospective observational multicentre study (ARREVE) was done in 43 French ICUs to compare terminal weaning and immediate extubation, as chosen by the ICU team. Terminal weaning was a gradual decrease in the amount of ventilatory assistance and immediate extubation was extubation without any previous decrease in ventilatory assistance. The primary outcome was posttraumatic stress symptoms (Impact of Event Scale Revised, IES-R) in relatives 3 months after the death. Secondary outcomes were complicated grief, anxiety, and depression symptoms in relatives; comfort of patients during the dying process; and job strain in staff. We enrolled 212 (85.5%) relatives of 248 patients with terminal weaning and 190 relatives (90.5%) of 210 patients with immediate extubation. Immediate extubation was associated with airway obstruction and a higher mean Behavioural Pain Scale score compared to terminal weaning. In relatives, IES-R scores after 3 months were not significantly different between groups (31.9 ± 18.1 versus 30.5 ± 16.2, respectively; adjusted difference, -1.9; 95% confidence interval, -5.9 to 2.1; p = 0.36); neither were there any differences in complicated grief, anxiety, or depression scores. Assistant nurses had lower job strain scores in the immediate extubation group. Compared to terminal weaning, immediate extubation was not associated with differences in psychological welfare of relatives when each method constituted standard practice in the ICU where it was applied. Patients had more airway obstruction and gasps with immediate extubation. ClinicalTrials.gov identifier: NCT01818895.


Toward Content Based Image Retrieval with Deep Convolutional Neural Networks.
Content-based image retrieval (CBIR) offers the potential to identify similar case histories, understand rare disorders, and eventually, improve patient care. Recent advances in database capacity, algorithm efficiency, and deep Convolutional Neural Networks (dCNN), a machine learning technique, have enabled great CBIR success for general photographic images. Here, we investigate applying the leading ImageNet CBIR technique to clinically acquired medical images captured by the Vanderbilt Medical Center. Briefly, we (1) constructed a dCNN with four hidden layers, reducing dimensionality of an input scaled to 128×128 to an output encoded layer of 4×384, (2) trained the network using back-propagation 1 million random magnetic resonance (MR) and computed tomography (CT) images, (3) labeled an independent set of 2100 images, and (4) evaluated classifiers on the projection of the labeled images into manifold space. Quantitative results were disappointing (averaging a true positive rate of only 20%); however, the data suggest that improvements would be possible with more evenly distributed sampling across labels and potential re-grouping of label structures. This prelimainry effort at automated classification of medical images with ImageNet is promising, but shows that more work is needed beyond direct adaptation of existing techniques.


[Explanatory models of anxiety from the viewpoint of biopsychology and pharmacopsychology].
To understand the biological basis of anxiety, the following psychological aspects are discussed: The difference between "trait" and "state" anxiety, types of anxiety as related to knowledge about causes and consequences, anxiety as a chronological process involving coping strategies and different levels of responses. The lack of specificity is physiological indicators of anxiety is demonstrated by experiments based on electrodermal and cardiovascular responses. Among hormones, special emphasis is placed on the constellation between catecholamines and cortisol as being relevant for anxiety research. It is emphasized that configurations of hormone parameters may be more relevant predictors for anxiety than single response values, and the study of postoperative catecholamine and cortisol responses is used for demonstrating differences between patients in a high and low preoperative state of anxiety. Differences are observed only on the emotional and pain response levels, but not in physiological parameters. The neurophysiological model representing central nervous system substrates for anxiety is the behavioural inhibitory system described in the theory by Gray [17], and the most relevant transmitters noradrenaline, serotonin, and the GABA-system are discussed with regard to their relevance for anxiety in animal studies, in studies using provocation tests with pharmacological substances, and in clinical studies with anti-anxiety drugs. Experimental anxiety research in psychology is frequently characterised by significant interactions between many mediators of responses, in particular the type of stressor, the level of trait anxiety and other personality variables, and the type of substances used. It is concluded that stressors as well as drugs frequently do not specifically induce anxiety but may nonspecifically affect general arousal and may only be operating in certain groups and certain levels of stress intensity.


Cu segregation in Au-Cu nanoparticles exposed to hydrogen atmospheric pressure: how is fcc symmetry maintained?
In a recent work [A. Nassereddine et al., Small 2021, 17, 2104571] we reported the atomic-scale structure and dynamics of sub-4 nm sized Au nanoparticles (NPs) supported on titania in H2 at atmospheric pressure obtained by using aberration-corrected environmental transmission electron microscopy (ETEM), density functional theory (DFT) optimizations and ab initio molecular dynamic (AIMD) simulations. Our results showed unstable Au NPs losing their face-centred cubic (fcc) symmetry (from fcc to non-fcc symmetries) and revealed the drastic effect of hydrogen adsorption. In this work, we use the same approach to study the dynamics of equiatomic Au-Cu NPs in the same range of size and the results show an enhanced structural stability upon alloying by Cu. In spite of the morphology evolution from facetted to rounded shapes, the observed Au-Cu NPs are found to keep their fcc symmetry under atmospheric hydrogen pressure. AIMD simulation evidences a Cu segregation process from the sub-surface toward the upper surface layer, and a reversed segregation of Au atoms from the surface towards the sub-surface sites. The analysis of the chemical ordering in the core shows a tendency to a local chemical ordering where Au-Cu hetero-atomic bindings are favoured. The segregating Cu seems to play a major role in reducing the fluxionality of Au-Cu NPs in H2 and thus, maintaining their fcc symmetry.


Systematic review of the effectiveness of primary care nursing.
This paper reports on a systematic review that sought to answer the research question: What is the impact of the primary and community care nurse on patient health outcomes compared with usual doctor-led care in primary care settings? A range of pertinent text-words with medical subject headings were combined and electronic databases were searched. Because of the volume of published articles, the search was restricted to studies with high-level evidence. Overall, 31 relevant studies were identified and included in the review. We found modest international evidence that nurses in primary care settings can provide effective care and achieve positive health outcomes for patients similar to that provided by doctors. Nurses are effective in care management and achieve good patient compliance. Nurses are also effective in a more diverse range of roles including chronic disease management, illness prevention and health promotion. Nevertheless, there is insufficient evidence about primary care nurses' roles and impact on patient health outcomes.


[Urogenic reactive arthritis morbidity in Kazakhstan].
Statistical data on osteo-muscular morbidity in Kazakhstan are presented. Their comparative analysis revealed a 5% rise in general morbidity and a 1% rise in the frequency of urogenic Chlamydial infection. The frequency of inflammatory joint diseases including urogenic reactive arthritis among the patients of a military hospital amounted to 51%.


Comparative evolutionary histories of the fungal chitinase gene family reveal non-random size expansions and contractions due to adaptive natural selection.
Gene duplication and loss play an important role in the evolution of novel functions and for shaping an organism's gene content. Recently, it was suggested that stress-related genes frequently are exposed to duplications and losses, while growth-related genes show selection against change in copy number. The fungal chitinase gene family constitutes an interesting case study of gene duplication and loss, as their biological roles include growth and development as well as more stress-responsive functions. We used genome sequence data to analyze the size of the chitinase gene family in different fungal taxa, which range from 1 in Batrachochytrium dendrobatidis and Schizosaccharomyces pombe to 20 in Hypocrea jecorina and Emericella nidulans, and to infer their phylogenetic relationships. Novel chitinase subgroups are identified and their phylogenetic relationships with previously known chitinases are discussed. We also employ a stochastic birth and death model to show that the fungal chitinase gene family indeed evolves non-randomly, and we identify six fungal lineages where larger-than-expected expansions (Pezizomycotina, H. jecorina, Gibberella zeae, Uncinocarpus reesii, E. nidulans and Rhizopus oryzae), and two contractions (Coccidioides immitis and S. pombe) potentially indicate the action of adaptive natural selection. The results indicate that antagonistic fungal-fungal interactions are an important process for soil borne ascomycetes, but not for fungal species that are pathogenic in humans. Unicellular growth is correlated with a reduction of chitinase gene copy numbers which emphasizes the requirement of the combined action of several chitinases for filamentous growth.


Serum Interleukin-33 is a Predictor of Depression in Patients with Acute Ischemic Stroke.
The study aimed to investigate the relationship between serum interleukin-33 (IL-33) concentrations and poststroke depression (PSD) in patients with acute ischemic stroke (AIS). Serum IL-33 concentrations were determined using an enzyme-linked immunosorbent assay. Patients were assigned to the PSD group after a six-month follow-up if their score on the 17- item Hamilton Rating Scale for Depression was ≥7 or to the non-PSD group if their score was <7. IL-33 was used to predict the risk of PSD using multivariate logistic regression analysis, while a receiver operating characteristic (ROC) curve was used to analyze the accuracy of PSD prediction. In addition, the modified Rankin scale (mRS) was used for follow-up scoring six months after disease onset. A total of 151 AIS patients and 40 healthy controls were included in this study. ROC curve results showed that the area under the curve was 0.684 (95% confidence interval: 0.594-0.774,Ρ=0.001) for IL-33 as a predictor of PSD. When the IL-33 concentration was ≤71.85 ng/L, prediction sensitivity and specificity were 77.5% and 57.3%, respectively. Multivariate logistic regression analysis showed that IL-33 concentration of ≤71.85 ng/L was an independent predictor of PSD (95% CI: 1.129-7.515, P=0.027). The follow-up mRS data showed that serum IL-33 is a protective prognosis factor in patients with AIS (95% CI: 0.954-0.997, P=0.024). Serum IL-33 is an independent predictor of PSD and a protective prognosis factor in patients with AIS.


On the stability of the n:m phase synchronization index.
Synchronization analysis of multitrial EEG or (magneto encephalogram) MEG signals is an excellent approach to detect functional connectivity between different neuronal oscillators. In our current research, the n:m phase synchronization index (n:m PSI ) is of special interest. We prove the existence of stable and unstable synchronies dependent upon the analysis frequencies and show that they lie closely together in the frequency domain. Thus, a plot of the time-frequency plane of the n:m PSI automatically violates the sampling theorem and accordingly, the method cannot be considered as a black box. A frequency-tiling approach is presented that can detect robust synchronies while ignoring the unstable ones. The improved synchrony detection is evaluated in numerical experiments on using both simulated and real-life data. It can be demonstrated that the transient synchronization events between MEG oscillations in distant frequency ranges can be detected and that compactly textured EEG synchronization patterns can be reliably characterized.


Whole body physiologically-based pharmacokinetic models: their use in clinical drug development.
Whole-body physiologically-based pharmacokinetic (WB-PBPK) models mathematically describe an organism as a closed circulatory system consisting of compartments that represent the organs important for compound absorption, distribution, metabolism and elimination. To review the current state of WB-PBPK model use in the clinical phases of drug development. A qualitative description of the WB-PBPK model structure is included along with a review of the varying methods available for input parameterisation. Current and potential WB-PBPK model application in clinical development is discussed. This modelling tool is at present used for small and large molecule drug development primarily as a means to scale pharmacokinetics from animals to humans based on physiology. The pharmaceutical industry is active in employing these models to clinical drug development although the applications in use now are narrow in comparison to the potential. Expanded integration of WB-PBPK models into the drug development process will only be achieved with staff training, managerial will, success stories and regulatory agency openness.


Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index.
Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10-8 ; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10-14 ). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.


Further studies on the effect of radiation during the storage of frozen 8-cell mouse embryos at -196 degrees C.
Frozen 8-cell mouse embryos were treated with radiation doses of 0, 10, 50, 100 or 200 cGy gamma-rays at a dose rate of congruent to 5 cGy/day. After thawing the embryos were scored for normal morphological appearance and for development to morulae and blastocysts after 24 h in culture. Embryos from each treatment were then separately transferred to the uteri of pseudopregnant foster mothers which were killed at Day 14 of pregnancy. There was no effect of radiation on morphological appearance, development to morulae and blastocysts, implantation rate, or on the ratio of live fetuses to the number of transferred embryos. As there appeared to be no detrimental effect of up to 200 cGy on frozen 8-cell mouse embryos and, as this is the equivalent of congruent to 2000 years of background radiation, it is concluded that normal levels of background radiation would not be a hazard to the long-term storage of mammalian embryos.


Modelling white matter with spherical deconvolution: How and why?
Since the realization that diffusion MRI can probe the microstructural organization and orientation of biological tissue in vivo and non-invasively, a multitude of diffusion imaging methods have been developed and applied to study the living human brain. Diffusion tensor imaging was the first model to be widely adopted in clinical and neuroscience research, but it was also clear from the beginning that it suffered from limitations when mapping complex configurations, such as crossing fibres. In this review, we highlight the main steps that have led the field of diffusion imaging to move from the tensor model to the adoption of diffusion and fibre orientation density functions as a more effective way to describe the complexity of white matter organization within each brain voxel. Among several techniques, spherical deconvolution has emerged today as one of the main approaches to model multiple fibre orientations and for tractography applications. Here we illustrate the main concepts and the reasoning behind this technique, as well as the latest developments in the field. The final part of this review provides practical guidelines and recommendations on how to set up processing and acquisition protocols suitable for spherical deconvolution.


A Negative Index Nonagonal CSRR Metamaterial-Based Compact Flexible Planar Monopole Antenna for Ultrawideband Applications Using Viscose-Wool Felt.
In this paper, a compact textile ultrawideband (UWB) planar monopole antenna loaded with a metamaterial unit cell array (MTMUCA) structure with epsilon-negative (ENG) and near-zero refractive index (NZRI) properties is proposed. The proposed MTMUCA was constructed based on a combination of a rectangular- and a nonagonal-shaped unit cell. The size of the antenna was 0.825 λ0 × 0.75 λ0 × 0.075 λ0, whereas each MTMUCA was sized at 0.312 λ0 × 0.312 λ0, with respect to a free space wavelength of 7.5 GHz. The antenna was fabricated using viscose-wool felt due to its strong metal-polymer adhesion. A naturally available polymer, wool, and a human-made polymer, viscose, that was derived from regenerated cellulose fiber were used in the manufacturing of the adopted viscose-wool felt. The MTMUCA exhibits the characteristics of ENG, with a bandwidth (BW) of 11.68 GHz and an NZRI BW of 8.5 GHz. The MTMUCA was incorporated on the planar monopole to behave as a shunt LC resonator, and its working principles were described using an equivalent circuit. The results indicate a 10 dB impedance fractional bandwidth of 142% (from 2.55 to 15 GHz) in simulations, and 138.84% (from 2.63 to 14.57 GHz) in measurements obtained by the textile UWB antenna. A peak realized gain of 4.84 dBi and 4.4 dBi was achieved in simulations and measurements, respectively. A satisfactory agreement between simulations and experiments was achieved, indicating the potential of the proposed negative index metamaterial-based antenna for microwave applications.


IFNγ-IL-17-IL-22+CD4+ subset and IL-22-producing cells in tumor draining lymph nodes of patients with breast cancer.
A recently introduced CD4+ T subset that mainly secretes interleukin (IL-) 22 has been reported to be associated with a variety of tumors, including colon, gastric, hepatocellular, and small- and large-cell lung carcinoma. Both tumor-promoting and - suppressing roles have been suggested for these cells. In the present study, we aimed to investigate the frequency of IL-22-producing subsets in tumor-draining lymph nodes (TDLNs) of the patients with breast cancer and determine their association with the clinicopathological characterizations of the disease. Thirty untreated women diagnosed with breast cancer were enrolled and their axillary lymph nodes were dissected during surgery. Mononuclear cells were isolated using Ficoll density gradient, activated, permeabilized, and stained by fluorochrome-conjugated antibodies against CD4, IL-22, IL-17, and IFNγ. The cells were then acquired on the FACSCalibur flow cytometer, and raw data was analyzed by the FlowJo software package (V10). Our results demonstrated that 2.39% ± 0.39 of CD4+ lymphocytes in TDLNs of patients with breast cancer produced IL-22. Among them, 0.64% ± 0.8 just produced IL-22 but were negative for IFNγ and IL-17. Statistical analysis indicated that the frequency of CD4+IL-22+ cells was significantly higher in the patients with stage III and the ones with 3-9 tumor involved lymph nodes (N2) compared to those with stage II and those having 1-3 tumor involved lymph nodes (N1) (P = 0.008 and P = 0.004, respectively). The higher frequency of IL-22-producing cells in draining lymph nodes of patients with more advanced tumors (higher stage (stage III) and more involved lymph nodes) suggests a role for IL-22-producing cells in the tumor progression and invasion. However, further studies with larger sample size and more functional studies are needed to clarify the role of IL-22-producing cells in breast cancer pathogenesis.


Species-level predation network uncovers high prey specificity in a Neotropical army ant community.
Army ants are among the top arthropod predators and considered keystone species in tropical ecosystems. During daily mass raids with many thousand workers, army ants hunt live prey, likely exerting strong top-down control on prey species. Many tropical sites exhibit a high army ant species diversity (>20 species), suggesting that sympatric species partition the available prey niches. However, whether and to what extent this is achieved has not been intensively studied yet. We therefore conducted a large-scale diet survey of a community of surface-raiding army ants at La Selva Biological Station in Costa Rica. We systematically collected 3,262 prey items from eleven army ant species (genera Eciton, Nomamyrmex and Neivamyrmex). Prey items were classified as ant prey or non-ant prey. The prey nearly exclusively consisted of other ants (98%), and most booty was ant brood (87%). Using morphological characters and DNA barcoding, we identified a total of 1,103 ant prey specimens to the species level. One hundred twenty-nine ant species were detected among the army ant prey, representing about 30% of the known local ant diversity. Using weighted bipartite network analyses, we show that prey specialization in army ants is unexpectedly high and prey niche overlap very small. Besides food niche differentiation, we uncovered a spatiotemporal niche differentiation in army ant raid activity. We discuss competition-driven multidimensional niche differentiation and predator-prey arms races as possible mechanisms underlying prey specialization in army ants. By combining systematic prey sampling with species-level prey identification and network analyses, our integrative approach can guide future research by portraying how predator-prey interactions in complex communities can be reliably studied, even in cases where morphological prey identification is infeasible.


High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons.
The effect of high-frequency stimulation (HFS) of the subthalamic nucleus (STN) was analyzed with patch-clamp techniques (whole cell configuration, current- and voltage-clamp modes) in rat STN slices in vitro. A brief tetanus, consisting of 100-micros bipolar stimuli at a frequency of 100--250 Hz during 1 min, produced a full blockade of ongoing STN activity whether it was in the tonic or bursting mode. This HFS-induced silence lasted around 6 min after the end of stimulation, was frequency dependent, could be repeated without alteration, and was not synaptically induced as it was still observed in the presence of blockers of ionotropic GABA and glutamate receptors or in the presence of cobalt at a concentration (2 mM) that blocks voltage-gated Ca(2+) channels and synaptic transmission. During HFS-induced silence, the following alterations were observed: the persistent Na(+) current (I(NaP)) was totally blocked (by 99%), the Ca(2+)-mediated responses were strongly reduced including the posthyperpolarization rebound (-62% in amplitude) and the plateau potential (-76% in duration), suggesting that T- and L-type Ca(2+) currents are transiently depressed by HFS, whereas the Cs(+)-sensitive, hyperpolarization-activated cationic current (I(h)) was little affected. Thus a high-frequency tetanus produces a blockade of the spontaneous activities of STN neurons as a result of a strong depression of intrinsic voltage-gated currents underlying single-spike and bursting modes of discharge. These effects of HFS, which are completely independent of synaptic transmission, provide a mechanism for interrupting ongoing activities of STN neurons.


Inhibition of erythroid colony-forming cells by a Mr 15,000 protein of feline leukemia virus.
The effects of concentrated ultraviolet-inactivated feline leukemia virus (FeLV), the purified Mr 15,000 envelope protein (p15E) of FeLV, or the purified Mr 27,000 structural protein (p27) of FeLV on feline bone marrow mononuclear cells were studied in vitro in methylcellulose cultures. Whole virus and purified viral proteins were from the Kawakami-Theilen isolate of FeLV, which induces erythroid aplasia in cats. Bone marrow mononuclear cells from FeLV-negative young adult cats were preincubated with a medium control, ultraviolet-inactivated whole virus, or the p15E or p27 of FeLV, incubated in methylcellulose cultures for 2 days, and then observed for the formation of colony-forming units-erythroid (CFU-E) and colony-forming units-granulocyte/macrophage. The ultraviolet-inactivated Kawakami-Theilen isolate of FeLV at concentrations of 10 or 20 micrograms of viral protein/5 X 10(4) cells suppressed CFU-E to 66 to 56% of control values but had no significant effect on proliferation of colony-forming units-granulocyte/macrophage. p15E at concentrations of 0.1 to 0.2 micrograms/5 X 10(4) cells decreased CFU-E numbers to 0 to 1% of control values, whereas the same concentration of p27 did not alter CFU-E growth when compared with controls. Neither p15E nor p27 had a significant effect on growth of colony-forming units-granulocyte/macrophage. The erythrosuppressive effects of whole virus and an envelope-derived protein but not a structural core protein suggest that FeLV envelope proteins are important in the selective inhibition of erythrogenesis observed in vivo in FeLV-infected cats.


Inhibition of Rho-kinase attenuates hypoxia-induced angiogenesis in the pulmonary circulation.
Pulmonary hypertension (PH) is a common complication of chronic hypoxic lung diseases, which increase morbidity and mortality. Hypoxic PH has previously been attributed to structural changes in the pulmonary vasculature including narrowing of the vascular lumen and loss of vessels, which produce a fixed increase in resistance. Using quantitative stereology, we now show that chronic hypoxia caused PH and remodeling of the blood vessel walls in rats but that this remodeling did not lead to structural narrowing of the vascular lumen. Sustained inhibition of the RhoA/Rho-kinase pathway throughout the period of hypoxic exposure attenuated PH and prevented remodeling in intra-acinar vessels without enlarging the structurally determined lumen diameter. In chronically hypoxic lungs, acute Rho kinase inhibition markedly decreased PVR but did not alter the alveolar to arterial oxygen gap. In addition to increased vascular resistance, chronic hypoxia induced Rho kinase-dependent capillary angiogenesis. Thus, hypoxic PH was not caused by fixed structural changes in the vasculature but by sustained vasoconstriction, which was largely Rho kinase dependent. Importantly, this vasoconstriction had no role in ventilation-perfusion matching and optimization of gas exchange. Rho kinase also mediated hypoxia-induced capillary angiogenesis, a previously unrecognized but potentially important adaptive response.


Management of computed tomography-detected pneumothorax in patients with blunt trauma: experience from a community-based hospital.
Diagnoses of pneumothorax, especially occult pneumothorax, have increased as the use of computed tomography (CT) for imaging trauma patients becomes near-routine. However, the need for chest tube insertion remains controversial. We aimed to study the management of pneumothorax detected on CT among patients with blunt trauma, including the decision for tube thoracostomy, in a community-based hospital. Chest CT scans of patients with blunt trauma treated at Al Rahba Hospital, Abu Dhabi, United Arab Emirates, from October 2010 to October 2014 were retrospectively studied. Variables studied included demography, mechanism of injury, endotracheal intubation, pneumothorax volume, chest tube insertion, Injury Severity Score, hospital length of stay and mortality. CT was performed in 703 patients with blunt trauma. Overall, pneumothorax was detected on CT for 74 (10.5%) patients. Among the 65 patients for whom pneumothorax was detected before chest tube insertion, 25 (38.5%) needed chest tube insertion, while 40 (61.5%) did not. Backward stepwise likelihood regression showed that independent factors that significantly predicted chest tube insertion were endotracheal intubation (p = 0.01), non-United Arab Emirates nationality (p = 0.01) and pneumothorax volume (p = 0.03). The receiver operating characteristic curve showed that the best pneumothorax volume that predicted chest tube insertion was 30 mL. Chest tube was inserted in less than half of the patients with blunt trauma for whom pneumothorax was detected on CT. Pneumothorax volume should be considered in decision-making regarding chest tube insertion. Conservative treatment may be sufficient for pneumothorax of volume < 30 mL.


Risk factors for advanced colonic neoplasia and hyperplastic polyps in asymptomatic individuals.
Knowledge of risk factors for colorectal neoplasia could inform risk reduction strategies for asymptomatic individuals. Few studies have evaluated risk factors for advanced colorectal neoplasia in asymptomatic individuals, compared risk factors between persons with and without polyps, or included most purported risk factors in a multivariate analysis. To determine risk factors associated with advanced colorectal neoplasia in a cohort of asymptomatic persons with complete colonoscopy. Prospective, cross-sectional study of 3121 asymptomatic patients aged 50 to 75 years from 13 Veterans Affairs medical centers conducted between February 1994 and January 1997. All participants had complete colonoscopy to determine the prevalence of advanced neoplasia, defined as an adenoma that was 10 mm or more in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer. Variables examined included history of first-degree relative with colorectal cancer, prior cholecystectomy, serum cholesterol level, physical activity, smoking, alcohol use, and dietary factors. An age-adjusted analysis was performed for each variable to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) associated with having advanced neoplasia compared with having no polyps. We developed a multivariate logistic regression model to identify the most informative risk factors. A secondary analysis examined risk factors for having hyperplastic polyps compared with having no polyps and compared with having advanced neoplasia. Three hundred twenty-nine participants had advanced neoplasia and 1441 had no polyps. In multivariate analyses, we found positive associations for history of a first-degree relative with colorectal cancer (OR, 1.66; 95% CI, 1.16-2.35), current smoking (OR, 1.85; 95% CI, 1.33-2.58), and current moderate to heavy alcohol use (OR, 1.02; 95% CI, 1.01-1.03). Inverse associations were found for cereal fiber intake (OR, 0.95; 95% CI, 0.91-0.99), vitamin D intake (OR, 0.94; 95% CI, 0.90-0.99), and use of nonsteroidal anti-inflammatory drugs (NSAIDs) (OR, 0.66; 95% CI, 0.48-0.91). In the univariate analysis, the inverse association was found with cereal fiber intake greater than 4.2 g/d, vitamin D intake greater than 645 IU/d, and daily use of NSAIDs. Marginal factors included physical activity, daily multivitamin use, and intake of calcium and fat derived from red meat. No association was found for body mass index, prior cholecystectomy, or serum cholesterol level. Three hundred ninety-one patients had hyperplastic polyps as the worst lesion found at colonoscopy. Risk variables were similar to those for patients with no polyps, except that past and current smoking were associated with an increased risk of hyperplastic polyps. Our data endorse several important risk factors for advanced colonic neoplasia and provide a rationale for prudent risk reduction strategies. Further study is needed to determine if lifestyle changes can moderate the risk of colorectal cancer.


Evaluation of Brain Edema Formation Defined By MRI After LINAC-based Stereotactic Radiosurgery.
Peri-lesional edema is a serious and well-known complication of stereotactic radiosurgery (SRS). Here we evaluated edema risk after SRS and assessed its formation and resolution dynamics. 107 patients underwent SRS for heterogeneous diagnoses: 34 (29%) with arteriovenous malformations, 38 (35%) with meningiomas, 16 (15%) with metastatic tumors, 16 (15%) with acoustic neuromas, 3 with (3%) cavernomas, and 2 (2%) each with anaplastic astrocytomas and anaplastic oligoastrocytomas. Edema area was delineated in MRI T2-FLAIR sequences 0, 6, 12, 18, 24, 30, and 38 months after treatment. Lesion location was defined as either above (n = 80) or below (n = 32) the "Frankfurt modified line" (FML). 17% of patients developed or had worsening post-treatment edema. Edema volume was maximal at 6 months (mean 7.2, SD 1.2) post radiosurgery. Post-SRS edema was 5.1 (1.06 - 24.53) times more likely in patients with lesions above the FML. There was no association between edema development and age, PTV size, number of beams, and diagnosis (p = 0.07). Radiosurgery-associated edema develops within 6 months of treatment and decreases over time. Edema occurrence is strongly related to lesion location, and its presence is much more likely when the treated lesions are situated above the Frankfurt line.


The proapoptotic effect of formononetin in human osteosarcoma cells: involvement of inactivation of ERK and Akt pathways.
Previous studies have shown that some phytoestrogens inhibits proliferation and induces apoptosis in estrogen-dependent cancers via estrogen receptor (ER)-mediated signaling pathway. In view of the expression of ER in human osteosarcoma cells, the purpose of this study is to investigate whether formononetin and calycosin, two of the major isoflavones in Radix astragali, could also elicit anti-tumor activity against osteosarcoma, along with the underlying mechanism. Human osteosarcoma cells U2OS were respectively treated with various concentrations of formononetin or calycosin. Cell proliferation was determined by MTT assay, while apoptosis by flow cytometry. Next, the expression levels of apoptosis-related genes ERK, Akt, Bcl-2, Bax and caspase-3 were quantified by real-time PCR and Western blotting. Formononetin exhibited higher anti-proliferative activities toward human osteosarcoma cells U2OS, when compared with calycosin. Therefore, U2OS cells were then respectively treated with various concentrations of formononetin, in order to elucidate the isoflavones-related signaling pathway. It was found that formononetin dose-dependently triggered apoptosis of U2OS cells in vitro. Furthermore, treatment of formononetin led to significant inactivation of ERK and Akt, followed by downregulation of Bcl-2, upregulation of Bax and finally increased expression of caspase-3. Formononetin is more effective than calycosin at promoting cell death of U2OS cells by induction of apoptosis, which is mediated by inactivation of ERK and Akt signaling pathways. Thus isoflavones, especially formononetin, may be useful as anti-cancer drugs for osteosarcoma through their apoptosis-inducing effects.


Psychiatric education in an era of rapidly occurring scientific advances.
Scientific advances in the fields of molecular biology, neurobiology, pharmacology, epidemiology, genetics, neuroimaging, and cognitive neuroscience are influencing psychiatric diagnosis and treatment, and this influence will grow substantially in the future. The current shortage of psychiatrists will increase over the next several decades, resulting in the need to train primary care physicians in basic psychiatric care and the use of non-physician mental health professionals to administer time-intensive, formal psychotherapies. The juxtaposition of these two trends-an increasing scientific influence on the clinical practice of psychiatry and fewer psychiatrists to deliver that treatment-is cause for changes in the approach to psychiatric education. In addressing these issues, the authors suggest that (1) psychiatry should be more integrated into undergraduate medical education in both basic science and clinical curricula, (2) residents in primary care disciplines should have more direct exposure to psychiatric training, (3) joint instructional experiences involving psychiatry and primary care residents should be encouraged, (4) psychiatry residency programs should maintain flexibility in order to incorporate rapid advances in diagnostic procedures and treatments into residency training, (5) research experience should be integrated into psychiatry residency programs, and (6) departments of psychiatry must develop the leadership and expertise necessary to implement the incorporation of rapidly advancing scientific discoveries into the psychiatric curriculum.


Cell Cycle Analysis in the C. elegans Germline with the Thymidine Analog EdU.
Cell cycle analysis in eukaryotes frequently utilizes chromosome morphology, expression and/or localization of gene products required for various phases of the cell cycle, or the incorporation of nucleoside analogs. During S-phase, DNA polymerases incorporate thymidine analogs such as EdU or BrdU into chromosomal DNA, marking the cells for analysis. For C. elegans, the nucleoside analog EdU is fed to the worms during regular culture and is compatible with immunofluorescent techniques. The germline of C. elegans is a powerful model system for the studies of signaling pathways, stem cells, meiosis, and cell cycle because it is transparent, genetically facile, and meiotic prophase and cellular differentiation/gametogenesis occur in a linear assembly-like fashion. These features make EdU a great tool to study dynamic aspects of mitotically cycling cells and germline development. This protocol describes how to successfully prepare EdU bacteria, feed them to wild-type C. elegans hermaphrodites, dissect the hermaphrodite gonad, stain for EdU incorporation into DNA, stain with antibodies to detect various cell cycle and developmental markers, image the gonad and analyze the results. The protocol describes the variations in the method and analysis for the measurement of S-phase index, M-phase index, G2 duration, cell cycle duration, rate of meiotic entry, and rate of meiotic prophase progression. This method can be adapted to study the cell cycle or cell history in other tissues, stages, genetic backgrounds, and physiological conditions.


Li-ion battery shut-off at high temperature caused by polymer phase separation in responsive electrolytes.
For the purpose of realizing inherently safe high-power Li-ion batteries, a model Li4Ti5O12/LiFePO4 rechargeable battery is investigated using the thermally responsive polymer, poly(benzyl methacrylate), in an ionic liquid. At high temperature, battery operation is inhibited as a result of increased internal resistance caused by polymer and ionic liquid phase separation. Li-ion concentration is shown to affect the phase transition temperature and the extent to which batteries are deactivated.


[Thermostable Yersinia pseudotuberculosis toxin: its isolation, purification and the characteristics of its properties].
Heat-stable toxin, lethal for mice when administered parenterally (LD50 was equal to 4.5 micrograms/mouse), was isolated from Y. pseudotuberculosis grown at a temperature of 8-10 degrees C. The toxin was found to be species-specific protein with a molecular weight of 45 kD, resistant to the action of elevated temperature (boiling for 5 minutes), 0.1-1.0% anionic detergent (sodium dodecyl sulfate) and stable at the pH range between 6.0-8.0. The amino acid sequence of the N-end fragment of the toxin was determined: H2N-Ala-Glu-Val-Asp-Ser-Ser-Glu-Phen-Pro. The toxin was inactivated after treatment with trypsin, chemotrypsin, papain. Antibodies to this toxin were detected in the blood sera of pseudotuberculosis patients.


The Mdm2 oncoprotein interacts with the cell fate regulator Numb.
The Mdm2 oncoprotein is a well-known inhibitor of the p53 tumor suppressor, but it may also possess p53-independent activities. In search of such p53-independent activities, the yeast two-hybrid screen was employed to identify Mdm2-binding proteins. We report that in vitro and in transfected cells, Mdm2 can associate with Numb, a protein involved in the determination of cell fate. This association causes translocation of overexpressed Numb into the nucleus and leads to a reduction in overall cellular Numb levels. Through its interaction with Numb, Mdm2 may influence processes such as differentiation and survival. This could potentially contribute to the altered properties of tumor cells which overexpress Mdm2.


Proteins and molecular palaeontology.
Protein taxonomy has existed as a concept at least since 1958, but despite the efforts of the past 30 years, comparative studies of protein sequence, structure and distribution have not revolutionized any areas of systematics. The most interesting results of single gene phylogenies have been the anomalies, such as insulin in hystricomorphs or cytochrome c in the rattlesnake. It is likely that protein sequence information can be obtained in sufficient quality and quantity from ancient material as to change this finding? The paper will assess possibilities and the likely limitations of chemical studies of ancient protein material.


In vitro and in silico anticancer activity of amygdalin on the SK-BR-3 human breast cancer cell line.
In spite of several studies that have shown the cytotoxic effects of amygdalin on the different cancer cell lines, however, the chemopreventive potential of amygdalin on the breast cancer cell line is not completely understood. We investigated the effect of amygdalin on the cell death and the level of pro-apoptotic Bax protein and anti-apoptotic Bcl-2 protein in SK-BR-3 human breast cancer cell line. The cell viability of SK-BR-3 cells was evaluated by MTT assay in different concentration of amygdalin. The level of Bax and Bcl-2 in SK-BR-3 cells were measured by western blot analysis. For statistical analysis, One-way ANOVA was used for the comparison of Bax and Bcl-2 protein level and percent of cell viability between groups. The molecular docking studies of amygdalin within the Bcl-2 (PDB ID: 4LVT) and HER2 (PDB ID: 3RCD) active site, were performed using AutoDock 4.2.5. Amygdalin induced a significant reduction of cell viability in SK-BR-3 after 24-h treatment in a dose-dependent manner. Also, amygdalin causes an increase in pro-apoptotic Bax protein and a decrease in anti-apoptotic Bcl-2 protein expression in the SK-BR-3 cells. Molecular docking studies showed that amygdalin interacts with the active site amino acids of Bcl-2 and HER2 through hydrogen bonding and some hydrophobic interactions. Amygdalin can induce apoptotic death in SK-BR-3 cells by increasing pro-apoptotic Bax protein and decreasing anti-apoptotic Bcl-2 protein expression. The results suggest that amygdalin may be a valuable candidate for the treatment of breast cancer, especially in HER2 positive cells.


Population-standardized genetic risk score: the SNP-based method of choice for inherited risk assessment of prostate cancer.
Several different approaches are available to clinicians for determining prostate cancer (PCa) risk. The clinical validity of various PCa risk assessment methods utilizing single nucleotide polymorphisms (SNPs) has been established; however, these SNP-based methods have not been compared. The objective of this study was to compare the three most commonly used SNP-based methods for PCa risk assessment. Participants were men (n = 1654) enrolled in a prospective study of PCa development. Genotypes of 59 PCa risk-associated SNPs were available in this cohort. Three methods of calculating SNP-based genetic risk scores (GRSs) were used for the evaluation of individual disease risk such as risk allele count (GRS-RAC), weighted risk allele count (GRS-wRAC), and population-standardized genetic risk score (GRS-PS). Mean GRSs were calculated, and performances were compared using area under the receiver operating characteristic curve (AUC) and positive predictive value (PPV). All SNP-based methods were found to be independently associated with PCa (all P < 0.05; hence their clinical validity). The mean GRSs in men with or without PCa using GRS-RAC were 55.15 and 53.46, respectively, using GRS-wRAC were 7.42 and 6.97, respectively, and using GRS-PS were 1.12 and 0.84, respectively (all P < 0.05 for differences between patients with or without PCa). All three SNP-based methods performed similarly in discriminating PCa from non-PCa based on AUC and in predicting PCa risk based on PPV (all P > 0.05 for comparisons between the three methods), and all three SNP-based methods had a significantly higher AUC than family history (all P < 0.05). Results from this study suggest that while the three most commonly used SNP-based methods performed similarly in discriminating PCa from non-PCa at the population level, GRS-PS is the method of choice for risk assessment at the individual level because its value (where 1.0 represents average population risk) can be easily interpreted regardless of the number of risk-associated SNPs used in the calculation.


Purification and partial characterization of a beta-glucan fragment that elicits phytoalexin accumulation in soybean.
The synthesis of phytoalexins (antibiotics) in plant cells is induced by molecules called elicitors. Partial acid hydrolysis of mycelial walls of Phytophthora megasperma f. sp. glycinea solubilized a multicomponent mixture of elicitor-active and elicitor-inactive oligoglucosides. One elicitor-active and seven elicitor-inactive hexa(beta-D-glucopyranosyl)-D-glucitols were purified by gel-filtration, normal-phase partition, and reversed-phase liquid chromatography after reduction with NaBH4. The elicitor-active and all but one of the elicitor-inactive hexa(beta-D-glucopyranosyl)-D-glucitols consisted of 3-, 6-, and 3,6-linked glucopyranosyl residues. The eighth hexa (beta-D-glucopyranosyl)-D-glucitol consisted of beta-4-linked glucopyranosyl residues. The similarity of the structural characteristics of six of the elicitor-inactive hexa(beta-D-glucopyranosyl)-D-glucitols to the elicitor-active hexa(beta-D-glucopyranosyl)-D-glucitol suggested that a highly specific carbohydrate structure was required for elicitor activity.


Bloodstream infection-associated sepsis and septic shock in critically ill adults: a population-based study.
Few studies have investigated the epidemiology of sepsis and septic shock in a large population and none have been from Canada. The objective of this study was to define the epidemiology of bloodstream infection (BSI)-associated sepsis and septic shock among all critically ill patients in a large, fully integrated health region in Canada. All critically ill adults admitted to multidisciplinary intensive care units (ICU) in the Calgary Health Region during May 1, 1999 to April 30, 2000 were included. Clinical, microbiologic and outcome information was obtained from regional databases. We surveyed 1981 patients having at least one ICU admission. Systemic inflammatory response syndrome (SIRS) was diagnosed in 92%, BSI-associated sepsis (BSI with SIRS) in 6% and BSI-associated septic shock (BSI with SIRS and hypotension) in 3%; respective hospital mortality rates were 36%, 40% and 49%. The most common BSI etiologies were Staphylococcus aureus, Escherichia coli and Streptococcus species; only one isolate (1%) was highly antibiotic resistant. Independent risk factors for death among patients with SIRS included age (>or= 65), hypothermia (< 35 degrees C), and higher APACHE II and TISS scores. A surgical diagnosis was associated with decreased mortality risk. Neither a positive blood culture nor hypotension at presentation independently predicted death. Knowledge of the epidemiology of these syndromes is important for assessing the burden of disease and providing background information for investigating new therapies.


Novel imaging approaches to cerebrovascular disease.
Imaging techniques available to the physician treating neurovascular disease have substantially grown over the past several decades. New techniques as well as advances in imaging modalities continuously develop and provide an extensive array of modalities to diagnose, characterize, and understand neurovascular pathology. Modern noninvasive neurovascular imaging is generally based on computed tomography (CT), magnetic resonance (MR) imaging, or nuclear imaging and includes CT angiography, CT perfusion, xenon-enhanced CT, single-photon emission CT, positron emission tomography, magnetic resonance angiography, MR perfusion, functional magnetic resonance imaging with global and regional blood oxygen level dependent imaging, and magnetic resonance angiography with the use of the noninvasive optional vessel analysis software (River Forest, Ill). In addition to a brief overview of the technique, this review article discusses the clinical indications, advantages, and disadvantages of each of those modalities.


Direct Interaction of PP2A Phosphatase with GABAB Receptors Alters Functional Signaling.
Addictive drugs usurp the brain's intrinsic mechanism for reward, leading to compulsive and destructive behaviors. In the ventral tegmental area (VTA), the center of the brain's reward circuit, GABAergic neurons control the excitability of dopamine (DA) projection neurons and are the site of initial psychostimulant-dependent changes in signaling. Previous work established that cocaine/methamphetamine exposure increases protein phosphatase 2A (PP2A) activity, which dephosphorylates the GABABR2 subunit, promotes internalization of the GABAB receptor (GABABR) and leads to smaller GABABR-activated G-protein-gated inwardly rectifying potassium (GIRK) currents in VTA GABA neurons. How the actions of PP2A become selective for a particular signaling pathway is poorly understood. Here, we demonstrate that PP2A can associate directly with a short peptide sequence in the C terminal domain of the GABABR1 subunit, and that GABABRs and PP2A are in close proximity in rodent neurons (mouse/rat; mixed sexes). We show that this PP2A-GABABR interaction can be regulated by intracellular Ca2+ Finally, a peptide that potentially reduces recruitment of PP2A to GABABRs and thereby limits receptor dephosphorylation increases the magnitude of baclofen-induced GIRK currents. Thus, limiting PP2A-dependent dephosphorylation of GABABRs may be a useful strategy to increase receptor signaling for treating diseases.SIGNIFICANCE STATEMENT Dysregulation of GABAB receptors (GABABRs) underlies altered neurotransmission in many neurological disorders. Protein phosphatase 2A (PP2A) is involved in dephosphorylating and subsequent internalization of GABABRs in models of addiction and depression. Here, we provide new evidence that PP2A B55 regulatory subunit interacts directly with a small region of the C-terminal domain of the GABABR1 subunit, and that this interaction is sensitive to intracellular Ca2+ We demonstrate that a short peptide corresponding to the PP2A interaction site on GABABR1 competes for PP2A binding, enhances phosphorylation GABABR2 S783, and affects functional signaling through GIRK channels. Our study highlights how targeting PP2A dependent dephosphorylation of GABABRs may provide a specific strategy to modulate GABABR signaling in disease conditions.


Vaginal vault prolapse.
Introduction. Vaginal vault prolapse is a common complication following vaginal hysterectomy with negative impact on women's quality of life due to associated urinary, anorectal and sexual dysfunction. A clear understanding of the supporting mechanism for the uterus and vagina is important in making the right choice of corrective procedure. Management should be individualised, taking into consideration the surgeon's experience, patients age, comorbidities, previous surgery and sex life. Result. Preexisting pelvic floor defect prior to hysterectomy is the single most important risk factor for vault prolapse. Various surgical techniques have been advanced at hysterectomy to prevent vault prolapse. Studies have shown the McCall's culdoplasty under direct visualisation to be superior. Vault prolapse repair rely on either the use of patient's tissue or synthetic materials and can be carried out abdominally or vaginally. Sacrospinous fixation and abdominal sacrocolpopexy are the commonly performed procedures, with literature in favour of abdominal sacrocolpopexy over sacrospinous fixation due to its reported higher success rate of about 90%. Other less commonly performed procedures include uterosacral ligament suspension and illiococcygeal fixation, both of which are equally effective, with the former having a high risk of ureteric injury. Colpoclesis will play a greater role in the future as the aging population increases. Mesh procedures are gaining in popularity, and preliminary data from vaginal mesh procedures is encouraging. Laparoscopic techniques require a high level of skill and experience. There are many controversies on the mechanism of prolapse and management techniques, which we have tried to address in this article. Conclusion. As the aging population increases, the incidence of prolapse will also rise, older techniques using native tissue will continue, while new techniques using the mesh needs to be studied further. The later may well be the way forward in future.


Exercise response after rapid intravenous infusion of saline in healthy humans.
Patients with chronic heart failure have an abnormal pattern of exercise ventilation (Ve), characterized by small tidal volumes (Vt), increased alveolar ventilation, and elevated physiological dead space (Vd/Vt). To investigate whether increased lung water in isolation could reproduce this pattern of exercise ventilation, 30 ml/kg of saline were rapidly infused into nine normal subjects, immediately before a symptom-limited incremental exercise test. Saline infusion significantly reduced forced vital capacity, 1-s forced expiratory volume, and alveolar volume (P < 0.01 for all). After saline, exercise ventilation assessed by the Ve/Vco(2) slope increased from 24.9 +/- 2.4 to 28.0 +/- 2.9 l/l, (P < 0.0002), associated with a small decrease in arterial Pco(2), but without changes in Vt, Vd/Vt, or alveolar-arterial O(2) difference. A reduction in maximal O(2) uptake of 175 +/- 184 ml/min (P < 0.02) was observed in the postsaline infusion exercise studies, associated with a consistent reduction in maximal exercise heart rate (8.1 +/- 5.9 beats/min, P < 0.01), but without a change in the O(2) pulse. Therefore, infusion of saline to normal subjects before exercise failed to reproduce either the increase in Vd/Vt or the smaller exercise Vt described in heart failure patients. The observed increase in Ve can be attributed to dilution acidosis from infusion of the bicarbonate-free fluid and/or to afferent signals from lung and exercising muscles. The reduction in maximal power output, maximal O(2) uptake, and heart rate after saline infusion may be linked to accumulation of edema fluid in exercising muscle, impairing the diffusion of O(2) to muscle mitochondria.


Cephacetrile: clinical evaluation in 27 patients.
Cephacetrile, a new derivative of 7-aminocephalosporanic acid, was evaluated in 27 patients. Soft tissue infections due primarily to gram-positive cocci were treated in 16 patients; 12 had bacteriological and clinical cure, and 4 improved but the lesions resolved incompletely or cultures remained positive. Seven of eight patients with respiratory tract infections were cured, including three with pneumococcal pneumonia; the eighth proved to have a noninfectious process and failed to respond. Two patients with acute urinary tract infections due to Escherichia coli had prompt clinical and bacteriological improvement, but follow-up was incomplete. One patient with sepsis due to Staphylococcus aureus expired. Laboratory abnormalities observed during cephacetrile therapy included mild eosinophilia in four patients, thrombocytosis in nine, direct Coombs' test positivity in four, and an elevated serum glutamic pyruvic transaminase in eight patients. No evidence of nephrotoxicity was detected. Severe superinfection due to Enterobacter species was observed in one patient. Mean peak serum concentrations of cephacetrile were 22, 69, and 104 mug/ml after 1 g intramuscularly, 1 g intravenously, and 1.5 g intravenously, respectively. Thus, in early studies cephacetrile was efficacious for selected bacterial infections, but determination of its comparative value within the cephalosporin group of antibiotics requires further clinical investigation.


Nutritional and health benefits of dried beans.
Dried beans (often referred to as grain legumes) may contribute to some of the health benefits associated with plant-based diets. Beans are rich in a number of important micronutrients, including potassium, magnesium, folate, iron, and zinc, and are important sources of protein in vegetarian diets. In particular, they are among the only plant foods that provide significant amounts of the indispensable amino acid lysine. Commonly consumed dried beans are also rich in total and soluble fiber as well as in resistant starch, all of which contribute to the low glycemic index of these foods. They also provide ample amounts of polyphenols, many of which are potent antioxidants. Intervention and prospective research suggests that diets that include beans reduce low-density lipoprotein cholesterol, favorably affect risk factors for metabolic syndrome, and reduce risk of ischemic heart disease and diabetes. The relatively low bean intakes of North Americans and northern Europeans can be attributed to a negative culinary image as well as to intestinal discomfort attributable to the oligosaccharide content of beans. Cooking practices such as sprouting beans, soaking and discarding soaking water before cooking, and cooking in water with a more alkaline pH can reduce oligosaccharide content. Promotional efforts are needed to increase bean intake.


Paclitaxel and Cisplatin-induced neurotoxicity: a protective role of acetyl-L-carnitine.
Antineoplastic drugs belonging to platinum or taxane families are severely neurotoxic, inducing the onset of disabling peripheral neuropathies with different clinical signs. Acetyl-L-carnitine (ALC) is a natural occurring compound with a neuroprotective activity in several experimental paradigms. In this study we have tested the hypothesis that ALC may have a protective role on cisplatin and paclitaxel-induced neuropathy. Sensory nerve conduction velocity (SNCV) was measured in rats before, at end, and after an additional follow-up period from treatments with cisplatin, paclitaxel, or with the respective combination with ALC. In addition, serum from treated animals was collected to measure the levels of circulating NGF, and left sciatic nerves were processed for light and electron microscope observations. ALC interference on cisplatin and paclitaxel antitumor activity and protective mechanisms were investigated using several in vitro and in vivo models. ALC cotreatment was able to significantly reduce the neurotoxicity of both cisplatin and paclitaxel in rat models, and this effect was correlated with a modulation of the plasma levels of NGF in the cisplatin-treated animals. Moreover, experiments in different tumor systems indicated the lack of interference of ALC in the antitumor effects of cisplatin and paclitaxel. The transcriptional profile of gene expression in PC12 cells indicated that ALC, in the presence of NGF, was able to positively modulate NGFI-A expression, a gene relevant in the rescue from tissue-specific toxicity. Finally, the transcriptionally ALC-mediated effects were correlated to increase histone acetylation. In conclusion, our results indicate that ALC is a specific protective agent for chemotherapy-induced neuropathy after cisplatin or paclitaxel treatment without showing any interference with the antitumor activity of the drugs.


The transcondylar approach to craniocervical meningiomas.
Surgical removal of foramen magnum meningiomas poses great challenges due their deep location within the central skull base and their proximity to vital neurovascular structures. This video depicts the operative nuances of surgical management for a 59-year-old female who presented with a right-sided spinocranial meningioma. Simpson Grade I resection was achieved through a right transcondylar approach. The patient's postoperative period was unremarkable, and she was discharged home on postoperative Day 5 for periodic follow-up. The transcondylar approach safely exposes the craniocervical junction at the anterior aspect of the neuraxis and still allows the surgeon to access the tumor through a parallel plane, with minimum morbidity. The video can be found here: https://youtu.be/P0-kXjAkw9U .


Patient-reported outcome assessment in vasculitis may provide important data and a unique perspective.
To assess patients' self-estimates of the burden of disease in vasculitis and to compare data across patient populations from the US, Germany, and the UK. Outcome assessment in vasculitis primarily focuses on physician evaluations of disease activity and damage. Little is known about the patients' perspectives regarding the burden of disease. Patients ranked (scale 0-5) a list of vasculitis-related items to estimate a combination of pain, interference with daily function, discomfort and/or annoyance, anxiety/psychological impact, and medical importance. Patients were also asked to list the 5 most troublesome aspects of the disease. Data from 264 patients with vasculitis from 3 countries were collected. Wegener's granulomatosis was the predominant disease, comprising 63% of the cohort. Diagnoses were confirmed by physicians in 98% of cases. The most common item from the free-text sections was fatigue (75%), followed by pain (31%), musculoskeletal symptoms (24%), difficulty breathing (19%), financial aspects (13%), nasal discharge/crusting (14%), and weight gain (10%). Rankings of individual items varied substantially: fatigue (3.5), loss of energy (3.4), weight gain (3.1), joint pain (3.0), and sinusitis (3.0) were the highest-ranked symptoms among those manifestations experienced by at least 50% of patients. Several severe manifestations (e.g., dialysis, seizures, oxygen dependency) were ranked lower (<3.0). Fatigue and reduced energy level are considered the most important disease burdens by patients with vasculitis; manifestations associated with organ damage were rated lower. The patients' perspectives of the impact of vasculitis differ from the physicians' ratings. Future outcome assessment in vasculitis should include the patients' perspectives.


Naturally-occurring genetic variants in human DC-SIGN increase HIV-1 capture, cell-transfer and risk of mother-to-child transmission.
Mother-to-child transmission (MTCT) is the main cause of HIV-1 infection in children worldwide. Dendritic cell-specific ICAM-3 grabbing-nonintegrin (DC-SIGN, also known as CD209) is an HIV-1 receptor that enhances its transmission to T cells and is expressed on placental macrophages. We have investigated the association between DC-SIGN genetic variants and risk of MTCT of HIV-1 among Zimbabwean infants and characterized the impact of the associated mutations on DC-SIGN expression and interaction with HIV-1. DC-SIGN promoter (p-336C and p-201A) and exon 4 (198Q and 242V) variants were all significantly associated with increased risk of intrauterine (IU) HIV-1 infection. Promoter variants decreased DC-SIGN expression both in vitro and in placental CD163(+) macrophages (Hofbauer cells) of HIV-1 unexposed infants but not of HIV-1 exposed infants. The exon 4 protein-modifying mutations increased HIV-1 capture and transmission to T cells in vitro. This study provides compelling evidence to support an important role of DC-SIGN in IU HIV-1 infection.