Toe-walking attributable to venous malformation of the calf muscle.
Soft tissue venous malformations of muscles may produce musculoskeletal deformities caused by contracture of the involved muscle. When the venous malformation involves the flexor muscles of the leg, equinus deformity and toe-walking may occur. Three patients with unilateral toe-walking secondary to venous malformation of the calf muscle, showing the classic presentation of this unusual condition, are presented. Several methods of treating the deformity and the underlying venous malformation are discussed, and the current literature on intramuscular venous malformations, including their natural history, diagnoses, treatment options, and outcomes, is reviewed. Based on our experience and review of the literature, percutaneous sclerotherapy may be a viable option for treatment of venous malformations of the calf musculature that result in a toe-walking deformity.


[137Cs distribution and accumulation in organs and tissues of sheep in the event of chronic consumption of contaminated fodder in the area of the Chernobyl NPP accident].
The regularities of 137Cs distribution and accumulation in organs and tissues of sheep on a farm located in the Chernobyl accidental zone were experimentally estimated. The distribution pattern of 137Cs concentration in organs and tissues is found to depend on the duration of the radionuclide uptake with the ration. During the first 24 h the highest 137Cs concentration is reported in the parenchymal organs; starting from day 30 muscular tissue and kidneys rank first, whereas in the other organs and tissues 137Cs concentration is 1.5-2 times lower. By 137Cs content and accumulation rate the study organs are arranged in a declining order as follows: muscles > > skin > liver > kidneys > heart > spleen. The mathematical models were devised describing the dynamics of increasing with time in 137Cs concentration in muscles, liver and skin. The methodology is suggested for the prediction of levels of 137Cs contamination of the muscular tissue of sheep. The time periods were regulated for sheep feeding with 137Cs contaminated fodder that ensure the production of mutton the radionuclide concentration in which meets the sanitary-hygienic standards.


Transmission of Escherichia coli O157:H7 to internal tissues and its survival on flowering heads of wheat.
Escherichia coli O157:H7 is a human pathogen that can cause bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. E. coli O157:H7 illnesses are mainly associated with undercooked beef; however, in recent years, outbreaks have been linked to fresh produce, such as spinach, lettuce, and sprouts. In 2009, flour was implicated as the contamination source in an outbreak involving consumption of raw cookie dough that resulted in 77 illnesses. The objectives of this research were to determine (i) whether E. coli O157:H7 could be translocated into the internal tissues of wheat (Triticum aestivum) seedlings from contaminated seed, soil, or irrigation water and (ii) whether the bacterium could survive on flowering wheat heads. The levels of contamination of kanamycin-resistant E. coli O157:H7 strains in seed, soil, and irrigation water were 6.88 log CFU/g, 6.60 log CFU/g, and 6.76 log CFU/ml, respectively. One hundred plants per treatment were sown in pot trays with 50 g of autoclaved soil or purposely contaminated soil, watered every day with 5 ml of water, and harvested 9 days postinoculation. In a fourth experiment, flowering wheat heads were spray inoculated with water containing 4.19 log CFU/ml E. coli O157:H7 and analyzed for survival after 15 days, near the harvest period. To detect low levels of internalization, enrichment procedures were performed and Biotecon real-time PCR detection assays were used to determine the presence of E. coli O157:H7 in the wheat, using a Roche Applied Science LightCycler 2.0 instrument. The results showed that internalization was possible using contaminated seed, soil, and irrigation water in wheat seedlings, with internalization rates of 2, 5, and 10%, respectively. Even though the rates were low, to our knowledge this is the first study to demonstrate the ability of this strain to reach the phylloplane in wheat. In the head contamination experiment, all samples tested positive, showing the ability of E. coli O157:H7 to survive on the wheat head.


[Effect of continuous illumination and disruption of monoaminergic innervation on the hypothalamus of the female rat].
Hypothalamic suprachiasmatic nucleus (Schn) and Arquate nucleus (AN) were studied in female rats kept under constant illumination (rats with persistent estrus) or under light-dark cyclic illumination (normal estrus cycle). To destroy monoaminergic terminals, some rats from each group were injected with neurotoxic agents into the lateral cerebral ventricle. 6-hydroxydophamine which disturbs catecholaminergic terminals induced activation of the Schn and AN in rats with persistent estrus only. Destruction of serotoninergic terminals with 5,6-hydroxytryptophan induced activation of the Schn in rats with normal sex cycle and in those with a persistent estrus; the AN was also activated but only in rats with normal estrous cycle. As reported earlier, destruction of serotoninergic terminals withstands the decrease of plasma LH under constant illumination although persistent estrus still lasts. It seems there are different parallel ways to disturb normal sex cycle under constant light illumination.


Airway inflammation in exercise-induced bronchospasm occurring in athletes without asthma.
Exercise-induced bronchospasm (EIB) occurs in athletes with and without asthma. Studies have suggested an inflammatory basis for EIB in asthmatics; however whether inflammation plays a similar role in EIB in athletes without asthma remains unclear. Our objective was to determine whether there is evidence of an inflammatory basis for exercise-induced bronchospasm occurring in non-asthmatic athletes. Ninety-six athletes without asthma from varsity college teams underwent eucapnic voluntary hyperventilation testing. Sputum was induced from subjects with hypertonic saline inhalation post-eucapnic voluntary hyperventilation testing and was analyzed with enzyme-linked immunosorbent assays for IL-5, IL-8, IL-13, cysteinyl-leukotrienes, prostaglandin E2, histamine, leukotriene B4, and thromboxane B2. In addition, inflammatory (neutrophils, lymphocytes, eosinophils, and macrophages) and epithelial cell counts in sputum were recorded. Multivariate regression modeling showed a significant correlation between concentrations of select inflammatory mediators after eucapnic voluntary hyperventilation testing and severity of EIB. Means of the log-transformed concentrations of inflammatory mediators in EIB-positive athletes were significantly higher post-eucapnic voluntary hyperventilation than in EIB-negative athletes. Similar findings were not demonstrated with inflammatory cells. Concentrations of inflammatory mediators are higher in EIB-positive athletes than in EIB-negative athletes without asthma after eucapnic voluntary hyperventilation testing. The severity of EIB in our cohort also is significantly correlated with increased concentrations of select inflammatory mediators suggesting a potential inflammatory basis for EIB in athletes without asthma.


In vivo alpha-V beta-3 integrin expression in human aortic atherosclerosis.
Intraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αvβ3) integrin pathway. We investigated the applicability of the αvβ3-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis. Vascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217-237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBRmax). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring. 18F-Fluciclatide uptake co-localised with regions of increased αvβ3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.29 vs 1.21, p=0.02). In vivo expression of αvβ3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αvβ3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis.


In-line hologram reconstruction using Hartley transform.
In reconstruction of in-line recorded holograms, zero-order and conjugate images appear on the same physical location as the object image. Here we propose a method, new to our knowledge, to separate the object image from the others by using two quadrature phase-shifted holograms. The method uses the Hartley transform and a phase retrieval type of algorithm on the difference hologram.


Vasodilating versus first-generation β-blockers for cardiovascular protection.
The utility of β-blockers in the treatment of hypertension has created much speculation as to their efficacy in patients with comorbid conditions, and there are concerns regarding their adverse metabolic effects. It is important to note that these findings were observed with traditional β-blockers, such as atenolol and metoprolol. The newer generation of β-blockers, namely carvedilol and nebivolol, is changing the manner in which β-blockers are viewed in hypertension management. Their ability to inhibit A1 adrenoreceptors and influence nitric oxide leads to vasodilation, which traditional β-blockers fail to do. These agents have been shown to have favorable metabolic effects while maintaining the beneficial cardiovascular effects of this drug class in post-myocardial infarction patients and the heart failure population.


Immediate noninvasive diagnosis of herpesvirus by confocal scanning laser microscopy.
In an immunocompromised host, cutaneous herpesvirus infections may be atypical and severe. Bedside microscopic imaging allows rapid diagnosis and prompt therapy. We report the case of an immunocompromised woman whose clinical differential diagnosis included herpesvirus infection. We used confocal scanning laser microscopy (CSLM) for immediate noninvasive bedside detection of histologic patterns diagnostic of cutaneous herpesvirus infection. We found that CLSM revealed the presence of pleomorphic ballooned keratinocytes and multinucleated giant cells in a loose aggregate of keratinocytes, inflammatory cells, and debris. Findings on CSLM were identical to those of conventional histologic examination. Prompt treatment of the immunocompromised patient produced clearing of cutaneous lesions. We conclude that CLSM may be a useful tool in the diagnosis of cutaneous herpesvirus infections.


High quality genome assemblies reveal evolutionary dynamics of repetitive DNA and structural rearrangements in the Drosophila virilis sub-group.
High-quality genome assemblies across a range of non-traditional model organisms can accelerate the discovery of novel aspects of genome evolution. The Drosophila virilis group has several attributes that distinguish it from more highly studied species in the Drosophila genus, such as an unusual abundance of repetitive elements and extensive karyotype evolution, in addition to being an attractive model for speciation genetics. Here we used long-read sequencing to assemble five genomes of three virilis group species and characterized sequence and structural divergence and repetitive DNA evolution. We find that our contiguous genome assemblies allow characterization of chromosomal arrangements with ease and can facilitate analysis of inversion breakpoints. We also leverage a small panel of resequenced strains to explore the genomic pattern of divergence and polymorphism in this species and show that known demographic histories largely predicts the extent of genome-wide segregating polymorphism. We further find that a neo-X chromosome in D. americana displays X-like levels of nucleotide diversity. We also found that unusual repetitive elements were responsible for much of the divergence in genome composition among species. Helitron-derived tandem repeats tripled in abundance on the Y chromosome in D. americana compared to D. novamexicana, accounting for most of the difference in repeat content between these sister species. Repeats with characteristics of both transposable elements and satellite DNAs expanded by three-fold, mostly in euchromatin, in both D. americana and D. novamexicana compared to D. virilis. Our results represent a major advance in our understanding of genome biology in this emerging model clade.


Soaking up the oil: Biological impacts of dispersants and crude oil on the sponge Halichondria panicea.
Used during an oil spill to minimise the formation of an oil slick, dispersants have negative biological effects on marine model organisms. However, no study has investigated the impacts of dispersants on adult sponge individuals. Here, we examine the effects of water accommodated oil fraction (WAF - oil in seawater), chemically enhanced WAF (CEWAF - oil and dispersant in seawater) and Benzo[A]Pyrene on sponge Halichondria panicea at physiological and molecular levels. Sponge clearance rate decreased sharply when exposed to WAF and CEWAF but the oil loading at which the clearance rate was reduced by 50% (ED50) was 39-fold lower in CEWAF than in WAF. Transcriptomic analysis revealed a homogenous molecular response with the greatest number of differentially expressed genes identified in CEWAF samples (1,461 genes). Specifically, genes involved in stress responses were up-regulated. This study presents evidence that the use of dispersants should be considered carefully in areas where sponges are present.


[Klobusitsky's hemocoagulase in plastic surgery].
Klobusitzsky haemocoagulase, a haemostatic drug obtained from snake poison, was administered prior to surgery in 35 cases of harelin, cleft palate, hypospadias and deviation of the nasal septum. Treatment was carried out from 2 to 6 days, doses and i.m. or i.v. administration being determined on the basis of age. Objective and subjective results were good, particularly in cases of cleft palate and septum deviation. In all cases, there was a significant shortening of bleeding time after treatment with the drug.


Semantic preview benefit and cost: Evidence from parafoveal fast-priming paradigm.
How is semantic information in the mental lexicon accessed and selected during reading? Readers process information of both the foveal and parafoveal words. Recent eye-tracking studies hint at bi-phasic lexical activation dynamics, demonstrating that semantically related parafoveal previews can either facilitate, or interfere with lexical processing of target words in comparison to unrelated previews, with the size and direction of the effect depending on exposure time to parafoveal previews. However, evidence to date is only correlational, because exposure time was determined by participants' pre-target fixation durations. Here we experimentally controlled parafoveal preview exposure duration using a combination of the gaze-contingent fast-priming and boundary paradigms. We manipulated preview duration and examined the time course of parafoveal semantic activation during the oral reading of Chinese sentences in three experiments. Semantic previews led to faster lexical access of target words than unrelated previews only when the previews were presented briefly (80 ms in Experiments 1 and 3). Longer exposure time (100 ms or 150 ms) eliminated semantic preview effects, and full preview without duration limit resulted in preview cost, i.e., a reversal of preview benefit. Our results indicate that high-level semantic information can be obtained from parafoveal words and the size and direction of the parafoveal semantic effect depends on the level of lexical activation.


Co-occurrence Among Intraguild Predators: Avoidance or Aggregation?
Intraguild predation (IGP) may interact with prey availability to structure predator communities. However, if predators are able to avoid each other, its effect on predator community structure may be minimized or absent. To determine whether co-occurrence among IG predators is limited, we estimated co-occurrence among predators in experimental plots of maize and soybean. These crops provide high densities of shared resources (aphids) as well as known IG predators (primarily coccinellids). Despite documented intraspecific and interspecific avoidance behaviors, aggregation to patchy resources could bring IG predators into contact. We, therefore, hypothesized that despite documented intraspecific avoidance behaviors, aphidophagous IG coccinellid predators would not significantly avoid co-occurrence, making IGP likely. Co-occurrence was estimated from visual counts of aphid predators and their prey on randomly selected plants over the course of the growing season. For each habitat, we used maximum likelihood analysis to determine whether observed co-occurrence deviated significantly from that expected for each possible pairwise combination of IG predators. We repeated this analysis using published data on co-occurrence among aphid predators on tansy. We found that most co-occurrence among IG predators was random, suggesting that avoidance does not limit co-occurrence. Failure to limit co-occurrence could be the result of ineffective avoidance mechanisms or because predators balance aggregating on shared resources with avoiding IG predators.


Sedative drug-use in Denmark, 2000 to 2019: a nationwide drug utilization study.
To describe trends in and characteristics of sedative drug use from 2000 through 2019 in relation to the introduction of central regulations and new drugs. In this descriptive study, we used individual prescription data on the entire Danish population from the Danish National Prescription Registry to calculate yearly incidence and prevalence of use of benzodiazepines, benzodiazepine-related drugs (Z-drugs), melatonin, olanzapine, low-dose quetiapine, mianserin/mirtazapine, pregabalin, and promethazine from 2000 through 2019. From the Danish National Patient Registry, we obtained data on drug users' psychiatric and somatic comorbidity. The use of benzodiazepines and Z-drugs declined gradually from 2000 through 2019, whereas the newer alternatives, melatonin, low-dose quetiapine, pregabalin and promethazine, increased in use, while the use of olanzapine and mianserin/mirtazapine was relatively stable. This development was seen in both men and women and across all age groups except for hypnotic benzodiazepines which showed a steep increase in the oldest age group from 2010. For all sedative drugs depression, anxiety, alcohol and misuse disorder, pain and cancer were the most prevalent comorbidities. During our study period, the number of individuals without any of the selected diagnoses increased. In Denmark different central regulations have influenced prescription practice toward more restrictive use of Z-drugs and benzodiazepines, except for hypnotic benzodiazepine prescriptions increased after the introduction of special palliative care. An increase in use of newer sedative drugs, however, indicates that the regulations do not remove the need for sedative drugs in the population.


An evaluation of depth enhancing perceptual cues for vascular volume visualization in neurosurgery.
Cerebral vascular images obtained through angiography are used by neurosurgeons for diagnosis, surgical planning, and intraoperative guidance. The intricate branching of the vessels and furcations, however, make the task of understanding the spatial three-dimensional layout of these images challenging. In this paper, we present empirical studies on the effect of different perceptual cues (fog, pseudo-chromadepth, kinetic depth, and depicting edges) both individually and in combination on the depth perception of cerebral vascular volumes and compare these to the cue of stereopsis. Two experiments with novices and one experiment with experts were performed. The results with novices showed that the pseudo-chromadepth and fog cues were stronger cues than that of stereopsis. Furthermore, the addition of the stereopsis cue to the other cues did not improve relative depth perception in cerebral vascular volumes. In contrast to novices, the experts also performed well with the edge cue. In terms of both novice and expert subjects, pseudo-chromadepth and fog allow for the best relative depth perception. By using such cues to improve depth perception of cerebral vasculature, we may improve diagnosis, surgical planning, and intraoperative guidance.


Evaluation of a new pulse oximeter sensor.
A new forehead noninvasive oxygen saturation sensor may improve signal quality in patients with low cardiac index. To examine agreement between oxygen saturation values obtained by using digit-based and forehead pulse oximeters with arterial oxygen saturation in patients with low cardiac index. A method-comparison study was used to examine the agreement between 2 different pulse oximeters and arterial oxygen saturation in patients with low cardiac index. Readings were obtained from a finger and a forehead sensor and by analysis of a blood sample. Bias, precision, and root mean square differences were calculated for the digit and forehead sensors. Differences in bias and precision between the 2 noninvasive devices were evaluated with a t test (level of significance P<.05). Nineteen patients with low cardiac index (calculated as cardiac output in liters per minute divided by body surface area in square meters; mean 1.98, SD 0.34) were studied for a total of 54 sampling periods. Mean (SD) oxygen saturations were 97% (2.4) for blood samples, 96% (3.2) for the finger sensor, and 97% (2.8) for the forehead sensor. By Bland Altman analysis, bias +/- precision was -1.16 +/- 1.62% for the digit sensor and -0.36 +/- 1.74% for the forehead sensor; root mean square differences were 1.93% and 1.70%, respectively. Bias and precision differed significantly between the 2 devices; the forehead sensor differed less from the blood sample. In patients with low cardiac index, the forehead sensor was better than the digit sensor for pulse oximetry.


Association of Educational Attainment and Cardiovascular Risk in Hispanic Individuals: Findings From the Cooper Center Longitudinal Study.
Hispanic individuals are the fastest growing ethnic group in the United States and face lower socioeconomic status compared with non-Hispanic white (NHW) individuals. However, Hispanic individuals tend to experience better health outcomes than expected, a phenomenon known as the Hispanic paradox. Little is known about how higher socioeconomic status is associated with Hispanic cardiovascular risk factor burden and outcomes. To determine cardiovascular risk and outcomes among highly educated Hispanic vs NHW individuals in a preventive medicine clinic. Retrospective cohort analysis of participants from the Cooper Center Longitudinal Study who underwent preventive medical examinations at the Cooper Clinic in Dallas, Texas, from October 1972 to November 2017. Analysis began April 2018. Ethnicity, self-defined as Hispanic or NHW. Prevalence of major metabolic risk factors and cardiorespiratory fitness were compared, as were changes among participants with at least 2 visits. Ethnic differences adjusted for age, examination year, and educational attainment were estimated using regression models. Age-matched comparisons of coronary artery calcium scores were performed. All-cause mortality was summarized using the Kaplan-Meier method. This study included 1351 Hispanic and 43 736 NHW participants aged 20 to 80 years, body mass index between 18.5 and 50.0, and were not missing key cardiometabolic or fitness variables. Both Hispanic and NHW participants had high educational attainment, with a mean of more than 15 years of total education. Hispanic women and men had a higher prevalence of metabolic syndrome (71 of 518 [13.1%] vs 1477 of 13 732 [10.8%] for women and 255 of 833 [30.6%] vs 7902 of 30 004 [26.3%] for men, respectively). Although Hispanic individuals were twice as likely to have diabetes, there was no difference in calculated 10-year atherosclerotic cardiovascular disease risk scores by ethnicity. Both Hispanic and NWH individuals experienced a statistically significant worsening in cardiometabolic parameters during follow-up, although this was not statistically significantly different between groups. In age-matched analyses, there were no significant differences in the prevalence of coronary artery calcium scores between Hispanic and NWH individuals. During a mean (SD) follow-up of 12.9 (7.5) years, there was no difference in mortality between Hispanic and NHW individuals. Hispanic and NHW men and women with high educational attainment had similar atherosclerotic cardiovascular disease risk, subclinical coronary atherosclerosis, and mortality during follow-up. These findings do not support the Hispanic paradox in a highly educated Hispanic population.


Cellular Interaction of Human Skin Cells towards Natural Bioink via 3D-Bioprinting Technologies for Chronic Wound: A Comprehensive Review.
Skin substitutes can provide a temporary or permanent treatment option for chronic wounds. The selection of skin substitutes depends on several factors, including the type of wound and its severity. Full-thickness skin grafts (SGs) require a well-vascularised bed and sometimes will lead to contraction and scarring formation. Besides, donor sites for full-thickness skin grafts are very limited if the wound area is big, and it has been proven to have the lowest survival rate compared to thick- and thin-split thickness. Tissue engineering technology has introduced new advanced strategies since the last decades to fabricate the composite scaffold via the 3D-bioprinting approach as a tissue replacement strategy. Considering the current global donor shortage for autologous split-thickness skin graft (ASSG), skin 3D-bioprinting has emerged as a potential alternative to replace the ASSG treatment. The three-dimensional (3D)-bioprinting technique yields scaffold fabrication with the combination of biomaterials and cells to form bioinks. Thus, the essential key factor for success in 3D-bioprinting is selecting and developing suitable bioinks to maintain the mechanisms of cellular activity. This crucial stage is vital to mimic the native extracellular matrix (ECM) for the sustainability of cell viability before tissue regeneration. This comprehensive review outlined the application of the 3D-bioprinting technique to develop skin tissue regeneration. The cell viability of human skin cells, dermal fibroblasts (DFs), and keratinocytes (KCs) during in vitro testing has been further discussed prior to in vivo application. It is essential to ensure the printed tissue/organ constantly allows cellular activities, including cell proliferation rate and migration capacity. Therefore, 3D-bioprinting plays a vital role in developing a complex skin tissue structure for tissue replacement approach in future precision medicine.


Gut microbiota abnormalities, small intestinal bacterial overgrowth, and non-alcoholic fatty liver disease: An emerging paradigm.
Evidence accumulates to implicate a role for the gut microbiota in non-alcoholic fatty liver disease (NAFLD)-a disorder that has reached almost epidemic proportions around the globe. For some time a disturbance in the gut microbiome, small intestinal bacterial overgrowth (SIBO), has been described among patients with liver disease, in general, and in the development and progression of NAFLD to nonalcoholic steatohepatitis (NASH), decompensated liver disease and hepatocellular cancer (HCC), in particular. More recently and permitted by the advent of high-throughput sequencing and allied molecular techniques, a much more detailed analysis of gut microbiota in NAFLD and NASH has become possible. In animal models, several mechanisms have been delineated which reveal how gut bacteria and their products could promote steatosis, hepatic inflammation, fibrosis, cirrhosis, and carcinogenesis. For understandable reasons evidence from human studies is less complete, but here again a plausible case is beginning to emerge to incriminate microbiota in NAFLD and NASH pathogenesis. Therapeutic interventions based on the modulation of the microbiome have been explored to some extent, but their application to everyday medical practice is still in the future.


Enhanced growth of MCF-7 breast cancer cells overexpressing parathyroid hormone-related peptide.
PTH-related peptide (PTHrP) is a secreted protein produced by breast cancer cells both in vivo and in vitro. Because of its structural similarity to PTH at the amino terminus, the two proteins interact with a common cell surface receptor, the PTH/PTHrP receptor. When overproduced by tumor cells, PTHrP enters the circulation, giving rise to the common paraneoplastic syndrome of humoral hypercalcemia of malignancy. Although initially discovered in malignancies, PTHrP is now known to be produced by most cells and tissues in the body. It acts as an autocrine and paracrine mediator of cell proliferation and differentiation, effects which are mediated via the PTH/PTHrP receptor. Recent evidence also has shown that, directly after translation, PTHrP is able to enter the nucleus and/or nucleolus and influence cell cycle progression and apoptosis. In this study, we have either overproduced PTHrP or inhibited endogenous PTHrP production in the breast cancer cell line, MCF-7. Overexpression of PTHrP was associated with an increase in mitogenesis, whereas inhibiting endogenous PTHrP production resulted in decreased cell proliferation. The overexpressed peptide targeted to the perinuclear space. In contrast, PTHrP interaction with the cell surface PTH/PTHrP receptor resulted in decreased cell proliferation in the same cell line. This latter effect is dependent on interaction with the receptor, in that exogenously added PTHrP moieties known not to interact with the receptor had no effect on cell growth. Furthermore, neutralization of added peptide with an anti-PTHrP antiserum completely abolished the growth inhibitory effects. In contrast, this antibody has no effect on the increased proliferation rate of the MCF-7 transfectants that overexpress PTHrP, compared with control cells. The net effect of autocrine/paracrine and intracrine effects of PTHrP in MCF-7 cells overproducing the peptide is accelerated cell growth. These findings have critical implications regarding the role of PTHrP in breast cancer, and they suggest that controlling PTHrP production in breast cancer may be useful therapeutically.


The expanding role of immunopharmacology: IUPHAR Review 16.
Drugs targeting the immune system such as corticosteroids, antihistamines and immunosuppressants have been widely exploited in the treatment of inflammatory, allergic and autoimmune disorders during the second half of the 20th century. The recent advances in immunopharmacological research have made available new classes of clinically relevant drugs. These comprise protein kinase inhibitors and biologics, such as monoclonal antibodies, that selectively modulate the immune response not only in cancer and autoimmunity but also in a number of other human pathologies. Likewise, more effective vaccines utilizing novel antigens and adjuvants are valuable tools for the prevention of transmissible infectious diseases and for allergen-specific immunotherapy. Consequently, immunopharmacology is presently considered as one of the expanding fields of pharmacology. Immunopharmacology addresses the selective regulation of immune responses and aims to uncover and exploit beneficial therapeutic options for typical and non-typical immune system-driven unmet clinical needs. While in the near future a number of new agents will be introduced, improving the effectiveness and safety of those currently in use is imperative for all researchers and clinicians working in the fields of immunology, pharmacology and drug discovery. The newly formed ImmuPhar (http://iuphar.us/index.php/sections-subcoms/immunopharmacology) is the Immunopharmacology Section of the International Union of Basic and Clinical Pharmacology (IUPHAR, http://iuphar.us/). ImmuPhar provides a unique international expert-lead platform that aims to dissect and promote the growing understanding of immune (patho)physiology. Moreover, it challenges the identification and validation of drug targets and lead candidates for the treatment of many forms of debilitating disorders, including, among others, cancer, allergies, autoimmune and metabolic diseases.


Lagos state ambulance service: a performance evaluation.
The mortality rate from road traffic accidents (RTAs) in Nigeria is almost double that of the USA. In Nigeria, the first emergency medical services (EMS) system was established in March 2001, The Lagos State Ambulance Service (LASAMBUS). The objectives of this study are to (1) determine the burden of RTAs in Lagos, (2) assess RTA call outcomes, and (3) analyze LASAMBUS's response time and causes for delay. We reviewed completed LASAMBUS intervention forms spanning December 2017 to May 2018. We categorized the call outcomes into five groups: I. Addressed Crash, II. No Crash (False Call), III. Crash Already Addressed, IV. Did Not Respond, and V. Other. We further explored associations between the (1) causes for delay and outcomes and (2) response times and the outcomes. Overall, we analyzed 1352 intervention forms. We found that LASAMBUS did not address 53% of the RTA calls that they received. Of this, Outcome II. No Crash (False Call) accounted for 26% and Outcome III. Crash Already Addressed accounted for 22%. Self-reported causes for delay were recorded in 180 forms, representing 13.7% of the RTA burden. Traffic congestion accounted for 60% of this distribution. LASAMBUS response rates are significantly lower than response rates in high-income countries such as the USA and lead to increased RTA mortality rates. Eliminating causes for delay will improve both LASAMBUS effectiveness and RTA victims' health outcomes. Changing the public perception of LASAMBUS and standardizing LASAMBUS' contact information will aid this as well.


Light-limitation on predator-prey interactions: consequences for metabolism and locomotion of deep-sea cephalopods.
The present study attempts to correlate the metabolism and locomotory behavior of 25 species of midwater Cephalopoda from California and Hawaii with the maximal activities of key metabolic enzymes in various locomotory muscle tissues. Citrate synthase (CS) and octopine dehydrogenase (ODH) activities were used as indicators of aerobic and anaerobic metabolic potential respectively. CS activity in mantle muscle is highly correlated with whole-animal rates of oxygen consumption, whereas ODH activity in mantle muscle is significantly correlated with a species' ability to buffer the acidic end-products of anaerobic metabolism. Both CS and ODH activities in mantle muscle declined strongly with a species' habitat depth. For example, CS and ODH activities ranged respectively from 0.04 units g(-1) and 0.03 units g(-1) in the deep-living squid Joubiniteuthis portieri, to 8.13 units g(-1) and 420 units g(-1) in the epipelagic squid Sthenoteuthis oualaniensis. The relationships between enzymatic activities and depth are consistent with similar patterns observed for whole-animal oxygen consumption. This pattern is believed to result from a relaxation, among deep-living species, in the need for strong locomotory abilities for visual predator/prey interactions; the relaxation is due to light-limitation in the deep sea. Intraspecific scaling patterns for ODH activities may, for species that migrate ontogenetically to great depths, reflect the counteracting effects of body size and light on predator-prey detection distances. When scaled allometrically, enzymatic activities for the giant squid, Architeuthis sp., suggest a fairly active aerobic metabolism but little burst swimming capacity. Interspecific differences in the relative distributions of enzymatic activities in fin, mantle, and arm tissue suggest an increased reliance on fin and arm muscle for locomotion among deep-living species. We suggest that, where high-speed locomotion is not required, more efficient means of locomotion, such as fin swimming or medusoid arm propulsion, are more prevalent.


Joint effect of insulin-like growth factors and sex steroids on breast cancer risk.
Insulin-like growth factors (IGFs) and estrogens are essential hormones regulating the growth and differentiation of mammary cells. Studies have shown that IGFs and estrogens are strong mitogens for breast cancer cells and that high circulating IGF-I and estrogens are risk factors of breast cancer. Laboratory experiments further indicate that these hormones act synergistically on the pathogenesis of breast cancer. Estrogens increase the effect of IGF-I on breast cancer cells by stimulating the expression of IGF-I and IGF-I receptor; IGFs enhance the action of estrogens by regulating the production of estrogen receptor. Furthermore, the two systems have substantial signal transduction cross-talk. Despite the laboratory indications, there is no epidemiological evidence in support of the joint effect of IGFs and estrogens on breast cancer risk. To test this hypothesis in human populations, we compared plasma levels of IGFs and sex steroid hormones among 300 incident breast cancer patients and 300 age- and menopause-matched control women derived from a large population-based case-control study conducted in Shanghai, China between 1996 and 1998. Fasting morning blood samples were measured for plasma concentrations of IGF-I, IGF-II, IGF-binding protein (IGFBP)-3, estradiol, estrone, estrone sulfate, testosterone, and dehydroepiandrosterone sulfate using commercial immunoassay kits. Levels of these hormones were classified into two groups based on the median levels in the control group and combined between IGFs and steroid hormones. Conditional logistic regression analysis was performed to examine the association of breast cancer risk with the combined variables of sex steroids and IGFs. A synergistic effect on breast cancer risk was suggested for IGF-I or IGFBP-3 with estrone or testosterone among both pre- and postmenopausal women. Compared with premenopausal women with low circulating levels of both IGF-I and estrone, the odds ratios were 1.21 [95% confidence interval (CI), 0.61-2.40] for high estrone, 1.50 (95% CI, 0.77-2.93) for high IGF-I, and 2.30 (95% CI, 1.21-4.37) for both high estrone and high IGF-I. Similar patterns of association were also seen for IGF-I with testosterone as well as for IGFBP-3 with estrone or testosterone, and some of the interactions were statistically significant or borderline significant (P < 0.10). No joint effects were found for IGF-I or IGFBP-3 with estradiol or estrone sulfate. In conclusion, the study suggests a possible synergy between IGF peptide hormone and sex steroid hormones, including both estrogen and androgen, in relation to breast cancer risk.


Tissue digoxin concentrations at digoxin intoxication in normal, acutely hypokalemic, and acutely hyperglycemic dogs.
Thirty intact dogs were studied to determine digoxin concentration in various tissues after ventricular tachycardia had been induced by digoxin infusion. A control group was infused solely with digoxin. A second group was made acutely hypokalemic by glucose-insulin infusion before the digoxin infusion. A third group was infused with glucose and digoxin to determine the effect of increased blood glucose levels and osmalarity on the induction of ventricular tachycardia. Results were: (1) The amount of digoxin infused to produce ventricular tachycardia did not differ getween the normal and hypokalemic groups. (2) The concentration of digoxin in various parts of the heart, other muscle tissue, renal cortex, and liver did not differ between the normal and acutely hypokalemic dogs although the amount excreted in bile and urine was reduced in hypokalemia. (3) Acute hypokalemia did not sensitize the myocardium to the arrhythmogenic effects of digoxin. (4) Ventricular tachcardia occurred at a similar plasma digoxin level in normal and acutely hypokalemic dogs. (5) In dogs with a lowered plasma potassium level, junctional tachycardia occurred whereas it did not occur in normal dogs or those with only a high blood glucose level. (6) Ventricular tachycardia occurred in the hyperglycemic dogs at a plasma digoxin level of 170 ng/ml, which was significantly greater than in the other experiments (7) Acute hyperglycemia reduced the mean rate of myocaridal uptake of digoxin into atria and right and left ventricular tissue; and the concentration of digoxin in atria, left ventricle, and interventricular septum was lower at the time of ventricular tachycardia than occurred in normal dogs. (8) Lowering the plasma potassium level in the presence of acute hyperglycemia, which occurred with the glucose-insulin infusion, did increase the myocardial uptake of digoxin. Similar effects of hyperglycemia were noted on mean hepatic uptake and excretion of digoxin and also the renal uptake of the glycoside.


A Phase Ib Study of the Dual PI3K/mTOR Inhibitor Dactolisib (BEZ235) Combined with Everolimus in Patients with Advanced Solid Malignancies.
The combination of everolimus and the imidazoquinoline derivative, BEZ235 (dactolisib), a dual PI3K/mTOR inhibitor, demonstrated synergy in a preclinical model. To establish clinical feasibility, a phase Ib dose-escalation trial investigating safety and pharmacokinetics of this combination in patients with advanced tumors was performed. BEZ235 was orally administered daily in escalating doses of 200, 400, and 800 mg along with everolimus at 2.5 mg daily in 28-day cycles. Nineteen patients were enrolled. Adverse events and tumor responses were evaluated using CTCAE v4.0 and RECIST 1.1, respectively. Pharmacokinetic analyses were performed. Common toxicities observed included fatigue, diarrhea, nausea, mucositis, and elevated liver enzymes. No confirmed responses were observed. BEZ235 pharmacokinetics exhibited dose-proportional increases in Cmax and AUC0-24 over the three doses, with high inter-individual variability. Non-compartmental and population pharmacokinetic-based simulations indicated significant increases in everolimus Cmax and AUC0-24 on day 28 and decreased clearance to 13.41 L/hr. The combination of BEZ235 and everolimus demonstrated limited efficacy and tolerance. BEZ235 systemic exposure increased in a dose-proportional manner while oral bioavailability was quite low, which may be related to gastrointestinal-specific toxicity. The changes in steady-state pharmacokinetics of everolimus with BEZ235 highlight potential drug-drug interactions when these two drugs are administered together. Clinicaltrials.gov: NCT01508104.


Requirement of one functional RAS gene and inability of an oncogenic ras variant to mediate the glucose-induced cyclic AMP signal in the yeast Saccharomyces cerevisiae.
Addition of glucose to Saccharomyces cerevisiae cells grown on a nonfermentable carbon source triggers a cyclic AMP (cAMP) signal, which induces a protein phosphorylation cascade. In a yeast strain lacking functional RAS1 and RAS2 genes and containing a bcy mutation to suppress the lethality of RAS deficiency, the cAMP signal was absent. Addition of dinitrophenol, which stimulates in vivo cAMP synthesis by lowering intracellular pH, also did not enhance the cAMP level. A bcy control strain, with functional RAS genes present, showed cAMP responses similar to those of a wild-type strain. In disruption mutants containing either a functional RAS1 gene or a functional RAS2 gene, the cAMP signal was not significantly different from the one in wild-type cells, indicating that RAS function cannot be a limiting factor for cAMP synthesis during induction of the signal. Compared with wild-type cells, the cAMP signal decreased in intensity with increasing temperature in a ras2 disruption mutant. When the mutant RAS2Val-19, which carries the equivalent of the human H-rasVal-12 oncogene, was grown under conditions in which RAS1 expression is repressed, the cAMP signal was absent. The oncogene product is known to be deficient in GTPase activity. However, the amino acid change at position 19 (or 12 in the corresponding human oncogene product) might also have other effects, such as abolishing receptor interaction. Such an additional effect probably provides a better explanation for the lack of signal transmission than the impaired GTPase activity. When the RAS2Val-19 mutant was grown under conditions in which RAS1 is expressed, the cAMP signal was present but significantly delayed compared with the signal in wild-type cells. This indicates that oncogenic RAS proteins inhibit normal functioning of wild-type RAS proteins in vivo and also that in spite of the presence of the RAS2(Val-19) oncogene, adenyl cyclase is not maximally stimulated in vivo. Expression of only the RAS(Val-19) gene product also prevented most of the stimulation of cAMP synthesis by dinitrophenol, indicating that lowered intracellular pH does not act directly on adenyl cyclase but on a step earlier in the activation pathway of the enzyme. The results obtained with the control bcy strain, the RAS2(Val-19) strain under conditions in which RAS1 is expressed, and with dinitrophenol show that the inability of the oncogene product to mediate the cAMP signal is not due to feedback inhibition by the high protein kinase activity in strains containing the RAS2(Val-19) oncogene. Hence, the present results show that the RAS protein in S. cerevisiae are involved in the transmission of the glucose-induced cAMP signal and that the oncogenic RAS protein is unable to act as a signal transducer. The RAS protein in S. cerevisiae apparently act similarly to the Gs proteins of mammalian adenyl cyclase, but instead of being involved in hormone signal transmission, they function in a nutrient-induced signal transmission pathway.


[Medical, social and economics aspects in the sulphur mines in Sicily(1791 - 1964)].
In Sicily the sulphur extraction represented an occasion of economic growth and a development for the dignity of the workers. The "carusi", young boys from 6 to 14 years old, were given up by their parents in return of a hardly payed of loan; it was the so called "soccorso morto" (dead aid). They were submitted to an enormous very hard physical work that caused severe damage to the skeleton and this was the reason of their inability to military service. The anthropometric surveys of "carusi" and pupils highlight for the first ones a reduced increase of the height and for the second ones the presence of "gibbo". For this reasons the inhabitans of Racalmuto were called racalmutesi immiruti" which means that people who lives in Racalmuto were hunchbacked. Nowadays it's possible to say that dietary and nutritional causes determined metabolic damages to the skeleton. A comparison between people who have been declared unable for military service belonged to the two lower clones of farmers and miners showed a lower incidence of the first ones. The law of 1866 on child labour assigned to medical doctors the task of certifying their suitability to work: the first step of normalisation on a medical care basis.


The Prevalence of Helicobacter pylori Remains High in African American and Hispanic Veterans.
Helicobacter pylori in the United States has been declining in the 1990s albeit less so among blacks and Hispanics. As the socioeconomic status of racial groups has evolved, it remains unclear whether the prevalence or the racial and ethnic disparities in the prevalence of H. pylori have changed. This is a cross-sectional study from a Veteran Affairs center among patients aged 40-80 years old who underwent a study esophagogastroduodenoscopy with gastric biopsies, which were cultured for H. pylori irrespective of findings on histopathology. Positive H. pylori was defined as positive culture or histopathology (stained organism combined with active gastritis). We calculated age-, race-, and birth cohort-specific H. pylori prevalence rates and examined predictors of H. pylori infection in logistic regression models. We analyzed data on 1200 patients; most (92.8%) were men and non-Hispanic white (59.9%) or black (28.9%). H. pylori was positive in 347 (28.9%) and was highest among black males aged 50-59 (53.3%; 44.0-62.4%), followed by Hispanic males aged 60-69 (48.1%; 34.2-62.2%), and lowest in non-Hispanic white males aged 40-49 (8.2%; 2.7-20.5%). In multivariate analysis, age group 50-59 was significantly associated with H. pylori (adjusted odds ratio (OR), 2.32; 95% confidence interval (CI), 1.21-4.45) compared with those aged 40-49, and with black race (adjusted OR, 2.57; 95% CI, 1.83-3.60) and Hispanic ethnicity (adjusted OR, 3.01; 95% CI, 1.70-5.34) compared with non-Hispanic white. Irrespective of age group, patients born during 1960-1969 had a lower risk of H. pylori (adjusted OR, 0.45; 95% CI, 0.22-0.96) compared to those born in 1930-1939. Those with some college education were less likely to have H. pylori compared to those with no college education (adjusted OR 0.51; 95% CI, 0.37-0.69). Among veterans, the prevalence of active H. pylori remains high (28.9%) with even higher rates in blacks and Hispanics with lower education levels.


Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in healthy adults in South Africa.
The efficacy of bacille Calmette-Guérin (BCG) may be enhanced by heterologous vaccination strategies that boost the BCG-primed immune response. One leading booster vaccine, MVA85A (where "MVA" denotes "modified vaccinia virus Ankara"), has shown promising safety and immunogenicity in human trials performed in the United Kingdom. We investigated the safety and immunogenicity of MVA85A in mycobacteria-exposed--but Mycobacterium tuberculosis-uninfected--healthy adults from a region of South Africa where TB is endemic. Twenty-four adults were vaccinated with MVA85A. All subjects were monitored for 1 year for adverse events and for immunological assessment. MVA85A vaccination was well tolerated and induced potent T cell responses, as measured by interferon (IFN)-gamma enzyme-linked immunospot assay, which exceeded prevaccination responses up to 364 days after vaccination. BCG-specific CD4+ T cells boosted by MVA85A were comprised of multiple populations expressing combinations of IFN-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, and IL-17, as measured by polychromatic flow cytometry. IFN-gamma-expressing and polyfunctional IFN-gamma+TNF-gamma+IL-2+ CD4+ T cells were boosted during the peak BCG-specific response, which occurred 7 days after vaccination. The excellent safety profile and quantitative and qualitative immunogenicity data strongly support further trials assessing the efficacy of MVA85A as a boosting vaccine in countries where TB is endemic. ClinicalTrials.gov identifier: NCT00460590.


[Change of CD4(+) CD25(+) regulatory T cells and NK Cells in peripheral blood of children with acute leukemia and its possible significance in tumor immunity].
This study was purposed to investigate the changes of CD4(+) CD25(+) regulatory T cells and NK cells in peripheral blood of acute leukemia children at different stages, the function of immune system and the possible roles of the CD4(+) CD25(+) regulatory T cells as well as NK cells in leukemia immunity. The number and proportion of CD4(+) CD25(+) regulatory T cells and NK cells were detected by flow cytometry in the peripheral blood of 53 acute leukemia children, including 25 patients in new diagnosis and 28 patients in continuous complete remission (CCR), and were compared with that of 20 normal children. The results indicated that the mean proportion of CD4(+) CD25(+) CD127(+) in CD4(+) T cells of peripheral blood in newly diagnosed patients, patients with CCR and normal children were (9.55 +/- 2.41)%, (8.54 +/- 2.51)% and (6.25 +/- 0.85)% respectively, the mean proportions of CD4(+)CD25(+)CD127(+) in newly diagnosed patients and patients with CCR were higher than that in normal children, the mean proportion of CD4(+)CD25(+)CD127(+) in newly diagnosed patients were higher than that in patients with CCR (p < 0.05). At the same time, the NK cell count in patients with acute leukaemia decreased as compared with normal control, while after achieving CCR, the NK cell count in patients were also less than that in normal control (4.11 +/- 3.87% and 10.41 +/- 7.20% vs 14.06 +/- 5.95%, p < 0.05). It is concluded that the application of CD4(+), CD25(+) and CD127(+) to detect regulatory T cells is a simple, reproductive and accurate method, and the CD4(+) CD25(+) CD127(+) T cells can better reflect the proportion of CD4(+)CD25(+) regulatory T cells. The increase of regulatory T cells and decrease of NK cells in pediatric patients with acute leukemia indicate that the function of NK cells may be depressed. Treg T cells play a role in occurrence and development of leukemia, and are involved in down-regulating NK cell function.


The stereodivergent formation of 2,6-cis and 2,6-trans-tetrahydropyrans: experimental and computational investigation of the mechanism of a thioester oxy-Michael cyclization.
The origins of the stereodivergence in the thioester oxy-Michael cyclization for the formation of 4-hydroxy-2,6-cis- or 2,6-trans-substituted tetrahydropyran rings under different conditions was investigated both computationally and experimentally. Synthetic studies showed that the 4-hydroxyl group was essential for stereodivergence. When the 4-hydroxyl group was present, TBAF-mediated conditions gave the 2,6-trans-tetrahydropyran and trifluoroacetic acid-mediated conditions gave the 2,6-cis-tetrahydropyran. This stereodivergence vanished when the hydroxyl group was removed or protected. Computational studies revealed that: (i) the trifluoroacetic acid catalysed formation of 2,6-cis-tetrahydropyrans was mediated by a trifluoroacetate-hydroxonium bridge and proceeded via a chair-like transition state; (ii) the TBAF-mediated formation of 2,6-trans-tetrahydropyrans proceeded via a boat-like transition state, where the 4-hydroxyl group formed a crucial hydrogen bond to the cyclizing alkoxide; (iii) both reactions are under kinetic control. The utility of this stereodivergent approach for the formation of 4-hydroxy-2,6-substituted tetrahydropyran rings has been demonstrated by the total syntheses of the anti-osteoporotic natural products diospongin A and B.


Effect of acute pH change on mitochondrial glutamine transport.
The uptake of [3H]glutamine in submitochondrial particles (SMP) was measured at varying medium pH. Glutamine transport, but not glutamine binding, was inversely related to medium pH (range 6.5-8.5). Glutamine uptake was highest at medium pH of 6.5 (4.59 +/- 0.4 pmol.mg-1.30 s-1) and lowest at medium pH of 8.0 (1.99 +/- 0.3 pmol.mg-1.30 s-1). The effect of medium pH on glutamine transport was rapidly reversible. Changes in pH gradient (delta pH) had no influence on the rate of glutamine transport. Kinetics of mitochondrial glutamine transport was studied at pH 6.5 and 8.5 to further elucidate the mechanism by which pH alters glutamine transport. Glutamine concentration at half-maximal velocity ([S]0.5) was 9.07 and 13.32 mM at pH 6.5 and 8.5, respectively (P less than 0.02). The maximal velocity (Vmax) was 1,417.72 +/- 185.69 pmol.mg-1.15 s-1 at pH 6.5 and 910.95 +/- 192.85 pmol.mg-1.15 s-1 at pH 8.5 (P less than 0.01). Thus both the affinity and the Vmax of the transport system were enhanced in acidic pH. These data imply that intracellular pH has influence over glutamine transport into the mitochondrial matrix and, consequently, renal NH3 production. Glutamine delivery to the matrix via changes in cytosolic pH may be one of the regulators for ammoniagenesis during acute acid-base disorders.


Flexible dual-soliton manipulation for coherent anti-Stokes Raman scattering spectroscopy.
Though dual soliton is used as the Stokes source in coherent anti-Stokes Raman scattering (CARS) experiments, the mechanism behind it is still not fully investigated. In this paper, dual-soliton pulses generation with a highly birefringent photonic crystal fiber (PCF) is numerically explored and experimentally verified. The simulated pulse exhibits various characteristics in the temporal and spectral domains with respect to the input linear polarization angle, and can be classified into four regions based on distances in the temporal and spectral domain of the soliton pair. By tuning input power and polarization angle, a soliton pair with desirable spectral coverage and temporal delay for CARS applications can be flexibly generated before the two solitons overlap in time domain. The simulated results are then experimentally validated by comparing their temporal and spectral characteristics. In addition, the benefit of using dual-soliton sources, such as Stokes beam, in CARS experiments is also demonstrated. The results and methods presented in this work can improve CARS spectroscopy and microscopy techniques, and may also be beneficial to other dual-wavelength source applications.


Incongruent Teen Pregnancy Attitudes, Coparenting Conflict, and Support Among Mexican-Origin Adolescent Mothers.
The current longitudinal study examined whether differences between Mexican-origin adolescent mothers and their mother figures (N = 204 dyads) in attitudes on the status attained through teen pregnancy were associated with conflict in their coparenting relationship and whether coparenting conflict was associated with adolescent mothers' perceptions of social support. Findings revealed that when adolescents held more positive attitudes than their mother figures about the status gained through teen pregnancy, they tended to report greater coparenting conflict with their mother figures. Furthermore, greater coparenting conflict was significantly associated with decreases in adolescents' perceptions of social support (i.e., emotional, instrumental, companion support) 1 year later. Findings underscore the importance of incongruent attitudes and the quality of coparenting relationships between adolescent mothers and their mother figures in relation to support processes. Findings are discussed with respect to understanding Mexican-origin adolescent mothers' social support in the context of family subsystem attitudes and interactions.


Myasthenia gravis patients with anti-MuSK antibodies.
In myasthenia gravis (MG) patients without detectable anti-acetylcholine receptor (anti-AChR) antibody, referred to as seronegative myasthenia gravis patients, there is a variable proportion of patients with antibodies against the muscle-specific kinase (MuSK). MuSK antibodies were found in 8 (29.6%) of our 27 patients with generalized MG without anti-AChR antibodies. All these patients were female. The age at the onset ranged from 22 to 38 years. All patients had ocular and bulbar symptoms, and two patients also had generalized limb weakness. Two patients had pure ocular symptoms for 7 or 8 years before the development of bulbar symptoms. All anti-MuSK positive patients were treated with immunosuppressive drugs, three received plasmapheresis and one patient required mechanical ventilation. Our results are consistent with other literature reports.


Distributions of types I, II and III collagen by region in the human supraspinatus tendon.
The mechanical properties of the human supraspinatus tendon (SST) are highly heterogeneous and may reflect an important adaptive response to its complex, multiaxial loading environment. However, these functional properties are associated with a location-dependent structure and composition that have not been fully elucidated. Therefore, the objective of this study was to determine the concentrations of types I, II and III collagen in six distinct regions of the SST and compare changes in collagen concentration across regions with local changes in mechanical properties. We hypothesized that type I collagen content would be high throughout the tendon, type II collagen would be restricted to regions of compressive loading and type III collagen content would be high in regions associated with damage. We further hypothesized that regions of high type III collagen content would correspond to regions with low tensile modulus and a low degree of collagen alignment. Although type III collagen content was not significantly higher in regions that are frequently damaged, all other hypotheses were supported by our results. In particular, type II collagen content was highest near the insertion while type III collagen was inversely correlated with tendon modulus and collagen alignment. The measured increase in type II collagen under the coracoacromial arch provides evidence of adaptation to compressive loading in the SST. Moreover, the structure-function relationship between type III collagen content and tendon mechanics established in this study demonstrates a mechanism for altered mechanical properties in pathological tendons and provides a guideline for identifying therapeutic targets and pathology-specific biomarkers.


Adaptive Encoding of Outcome Prediction by Prefrontal Cortex Ensembles Supports Behavioral Flexibility.
The prefrontal cortex (PFC) is thought to play a critical role in behavioral flexibility by monitoring action-outcome contingencies. How PFC ensembles represent shifts in behavior in response to changes in these contingencies remains unclear. We recorded single-unit activity and local field potentials in the dorsomedial PFC (dmPFC) of male rats during a set-shifting task that required them to update their behavior, among competing options, in response to changes in action-outcome contingencies. As behavior was updated, a subset of PFC ensembles encoded the current trial outcome before the outcome was presented. This novel outcome-prediction encoding was absent in a control task, in which actions were rewarded pseudorandomly, indicating that PFC neurons are not merely providing an expectancy signal. In both control and set-shifting tasks, dmPFC neurons displayed postoutcome discrimination activity, indicating that these neurons also monitor whether a behavior is successful in generating rewards. Gamma-power oscillatory activity increased before the outcome in both tasks but did not differentiate between expected outcomes, suggesting that this measure is not related to set-shifting behavior but reflects expectation of an outcome after action execution. These results demonstrate that PFC neurons support flexible rule-based action selection by predicting outcomes that follow a particular action.SIGNIFICANCE STATEMENT Tracking action-outcome contingencies and modifying behavior when those contingencies change is critical to behavioral flexibility. We find that ensembles of dorsomedial prefrontal cortex neurons differentiate between expected outcomes when action-outcome contingencies change. This predictive mode of signaling may be used to promote a new response strategy at the service of behavioral flexibility.


[Effect size in clinical studies of patients with rheumatoid arthritis. EULAR guidelines and OMERACT core-sets].
Clinical trials in rheumatology are confronted with new challenges. The pharmaceutical industry must be more efficient in identifying and marketing new drugs, regulatory authorities require additional evidence about the effectiveness of new compounds, and the consumer including physicians require more transparency in the selection and use of appropriate outcomes in clinical trials. These challenges find their common denominator in a further standardization of clinical trials that extends beyond the application of Good Clinical Practice. For years, national and international organizations have developed recommendations for the selection of appropriate outcomes in RA clinical trials. However, these recommendations have rarely been data driven or evidence based. The international informal collaboration Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) has contributed enormously towards the application of a standardized methodology in the development of recommendations to enhance the quality of research in clinical rheumatology. The scope of this initiative goes now far beyond rheumatoid arthritis and now covers all major rheumatic conditions.


Strain-dependent lung tumor formation in mice transplacentally exposed to 3-methylcholanthrene and post-natally exposed to butylated hydroxytoluene.
The carcinogenic effects of in utero exposure to 3-methylcholanthrene (MC) have been demonstrated in the tumor-resistant C57BL/6 (B6) and DBA (D2) strains of mice. In this study, we determined the effects of in utero exposure to MC in BALB/c mice, a strain which demonstrates greater susceptibility to lung tumor induction, and compared our findings with those previously found in [D2xB6D2F(1)]F(2) mice. In addition, we assessed the molecular pathogenesis of the chemically induced tumors and examined the effects of the putative lung tumor promoter butylated hydroxytoluene (BHT) in BALB/c mice. BALB/c mice were treated on day 17 of gestation with 5, 15 or 45 mg/kg MC and 6 weeks after birth with BHT for 6 consecutive weeks. Mice were killed at 6 months of age. Ki-ras, p16Ink4a and p19ARF gene loci were amplified from paraffin-embedded lung tumor tissue and screened for the presence of point mutations via allele-specific oligonucleotide hybridization and single strand conformation polymorphism (SSCP) analyses. Ki-ras point mutations were found in 56% (20/36) of BALB/c lung tumors, with 33% (2/6) of the hyperplasias, 58% (10/19) of the adenomas and 73% (8/11) of the carcinomas exhibiting point mutations at this gene locus. Similar incidences of Ki-ras mutations were previously found following transplacental exposure of [D2xB6D2F(1)]F(2) mice to MC and treatment of adult A/J mice with urethane. Interestingly, a strain-dependent difference was observed in the mutational spectrum. Sixty-two and 38% of the lung lesions in BALB/c mice exhibited G-->C and G-->T transversions, respectively, in contrast to the 13 and 84% incidences previously observed in [D2xB6D2F(1)]F(2) mice. SSCP analysis of the tumor suppressor gene p16Ink4a showed a 6% incidence of point mutations, consistent with that found in [D2xB6D2F(1)]F(2) mice. No mutations were found in exon 1beta of the p19ARF gene of either strain. BHT, a lung tumor promoter in adult mice, had no statistically significant effects on either tumor incidence, tumor multiplicity or the mutational spectrum produced in the Ki-ras gene by in utero MC treatment. However, though not significant, there was an observable trend in increased tumor multiplicity in mice co-treated with BHT. These data demonstrate the transplacental carcinogenic effect of MC in BALB/c mice and show that mutagenic damage to Ki-ras is a critical early event mediating murine lung tumorigenesis in both the tumor-sensitive and tumor-resistant strains. Unlike what occurs when adult BALB/c mice are treated with MC, BHT does not appear to significantly promote the formation of lung tumors following transplacental exposure to MC, possibly due to the rapid growth and cell proliferation in the developing organism. Strain-dependent differences in the Ki-ras mutational spectrum may be associated with their differential susceptibility to lung tumor initiation.


Glycosaminoglycan production and distribution in cloned B16 murine melanoma cell lines exhibiting different lung colony-forming efficiencies.
Three cloned B16 murine melanoma cell lines were characterized with respect to their ability to a) detach from a plastic tissue culture substratum, b) form experimental pulmonary metastases, and c) produce and process glycosaminoglycans (GAGS). All three of the cell lines formed pulmonary metastases to different extents. Chondroitin sulfate and heparin-heparan sulfate were the major GAGS produced by all of the clones. Although the major compositional analyses of the cell lines were similar, some differences were apparent. The clone never selected for lung colony-forming efficiency and with the lowest metastatic potential (B16YL1) exhibited a reduced cell-associated glycosaminoglycan (GAG) matrix, shed the highest proportion of labeled GAGS into the medium, and was the most easily removed from the tissue culture substratum. In contrast, the other two cell lines (B16YM1 and B16YH1), derived from cultures selected for lung colony-forming efficiency, exhibited GAG-enriched cellular coats and were more resistant to EDTA-induced detachment from the plastic substratum. Both the B16YL1 and B16YM1 clones, which exhibited the lowest lung colony-forming efficiencies, shed an unsulfated chondroitin species into the extracellular fraction that was not evident in the most metastatic clone B16YH1. Despite these differences, cellular GAG matrix development and detachment from the plastic substratum showed only a partial correlation with lung colony-forming efficiency, presumably expressing the complexity of this biological phenomenon. Nonetheless, the findings suggest that GAGS may play an important role at several steps along the cascade of events leading to the successful dissemination of malignant cells.


Left-handed materials do not make a perfect lens.
By means of an analysis on evanescent waves in left-handed materials (LHM), we show that within a slab of such a medium, sandwiched between two positive refraction media, there is amplification of evanescent waves in ideal lossless, dispersiveless media; however, contrary to previous claims, this is limited to a finite width of the slab so that it prevents their restoration and perfect focusing. We illustrate this by considering their coupling to propagating waves through a tunnel barrier containing a slab of LHM. Further, we show that the effect of absorption, necessarily present in such materials, may drastically change any evanescent amplifying wave into a decaying one.


[Hepatoportal sclerosis--special variant of liver cirrhosis].
The clinical, functional, x-ray and morphological manifestations of hepatoportal sclerosis have been studied. It is assumed that involvement of the intrahepatic branches of the portal vein of the diffuse fibrosis type underlies hepatoportal sclerosis, a condition of unestablished etiology. Differential diagnosis should be made with the portal-hypertension pattern of congenital liver fibrosis and, according to the clinical manifestations, with liver cirrhosis.


Synaptic events that generate fast oscillations in piriform cortex.
Prominent, odor-evoked, fast (40-60 Hz) oscillations have been reported in the olfactory bulb and piriform (primary olfactory) cortex of both awake-behaving and anesthetized animals. The present study used current source-density analysis to examine the origin of the fast oscillations evoked by single weak shocks to afferent fibers. These shock-evoked oscillations closely resemble those evoked by odor. The results revealed that each cycle of the oscillatory field potential was generated by a stereotyped series of membrane currents similar to those previously characterized in the nonoscillatory response to strong afferent fiber shocks. Each cycle began with a strong inward current in layer la identified as an EPSC mediated by afferent fibers in distal apical dendrites of pyramidal cells. This afferent input was followed by a strong inward current in layer Ib identified as an EPSC mediated by intrinsic association fibers in middle apical dendritic segments. These excitatory events were followed by a smaller inward current at the depth of pyramidal cell somata (layers II and superficial III) that may be the depolarizing Cl(-)-mediated IPSC previously identified in the strong-shock response. Based on an analysis of the timing of the EPSCs it was concluded that the weak shock-evoked oscillation is generated in the olfactory bulb and that the resulting periodic activity in afferent fibers drives the oscillation in the piriform cortex.(ABSTRACT TRUNCATED AT 250 WORDS)


Perception of violence against women among future health professionals in an Industrial Township.
There is a growing concern that medical education does not prepare the future health professional to effectively deal with violence against women. Against this background, the present study was undertaken. To elicit perception of violence against women among medical and nursing students, and study the association of these perceptions with certain demographic and social variables. The study was conducted among students of a Medical College and a Nursing College both located at Pune, India. A cross-sectional descriptive study design was used to elicit the perceptions of the study subjects toward violence against women. A random sample of 125 medical and 125 nursing students was selected. Both quantitative and qualitative methods of data collection were employed. Qualitative data collection was done by focus group discussions with key persons such as dean and faculty of medical and nursing colleges. The syllabi of medical and nursing colleges were also reviewed for any topic related to domestic violence. The WHO/CDC Statistical and Epidemiology Software Package was used for data entry and statistical analysis. Various associations were explored by nonparametric tests (Mann-Whitney) for ordinal data and by Chi-square and ODDS ratio (with 95% confidence intervals), for categorical data. Overall 35.6% (95% CI 29.1%-42.6%) of the study participants had witnessed/were aware of violence against women among their family/acquaintances. This awareness was significantly more among female respondents (OR=2.65, 95% CI 1.37-5.16), Chi Sq=9.81, df=1, P=0.001. Other socioeconomic variables such as urban/rural background, education, and income were not associated with perception about family violence. Majority (>80%) agreed/strongly agreed that social agencies should do more to help battered women. Course content on violence against women was lacking in both medical and nursing syllabi. Female participants were generally more perceptive about the issue. Medical and nursing syllabi should incorporate strategies for dealing with violence against women.


Quantitative assessment of infusion pump-mediated haemolysis in feline packed red blood cell transfusions.
Haemolysis caused by the use of peristaltic infusion pumps (PIPs) has been described in human and canine packed red blood cells (pRBCs). The aim of this study was to evaluate the effects of two different linear PIPs on the haemolysis of feline pRBC units stored for a long time. Feline pRBC units stored with adenine, dextrose, mannitol and sodium chloride (SAGM) were manufactured. After 35-42 days of storage at 2-4°C, a line administration system with a 180 µm filter was attached to every pRBC bag, the system was drained by gravity alone (8 drops/min) and a 1.3 ml sample was collected (G). A NIKI V4 pump was then used at a flow rate of 25 ml/h, the flow was stopped when the infusion system was filled with blood coming from the infusion pump and another 1.3 ml sample was collected (NK). Finally, an Infusomat FmS pump was evaluated, collecting another 1.3 ml sample (IM). Packed cell volume (PCV) was measured in all samples by microhaematocrit centrifugation, total haemoglobin (HGB) was measured using a specific haemoglobin analyser and, after centrifugation, free HGB was determined by spectrophotometry. The percentage of haemolysis was calculated. Friedman's test was used to compare the samples. Fifteen feline pRBC units were evaluated. The average degree of haemolysis for sample G (gravity-assisted) was 1.12%. Comparison of the degree of gravity-assisted haemolysis with haemolysis in PIP NK (1.13%) and IM (1.14%) samples revealed no significant differences, with differences of only 0.01% and 0.02%, respectively. The results of this study demonstrate that the use of two common PIPs in veterinary hospitals does not produce levels of haemolysis that are significantly different than that caused by gravity alone during transfusion of feline pRBCs at a rate of 25 ml/h.


Decoding the future from past experience: learning shapes predictions in early visual cortex.
Learning the structure of the environment is critical for interpreting the current scene and predicting upcoming events. However, the brain mechanisms that support our ability to translate knowledge about scene statistics to sensory predictions remain largely unknown. Here we provide evidence that learning of temporal regularities shapes representations in early visual cortex that relate to our ability to predict sensory events. We tested the participants' ability to predict the orientation of a test stimulus after exposure to sequences of leftward- or rightward-oriented gratings. Using fMRI decoding, we identified brain patterns related to the observers' visual predictions rather than stimulus-driven activity. Decoding of predicted orientations following structured sequences was enhanced after training, while decoding of cued orientations following exposure to random sequences did not change. These predictive representations appear to be driven by the same large-scale neural populations that encode actual stimulus orientation and to be specific to the learned sequence structure. Thus our findings provide evidence that learning temporal structures supports our ability to predict future events by reactivating selective sensory representations as early as in primary visual cortex.


An inhibitor of the EGF receptor family blocks myeloma cell growth factor activity of HB-EGF and potentiates dexamethasone or anti-IL-6 antibody-induced apoptosis.
We previously found that some myeloma cell lines express the heparin-binding epidermal growth factor-like growth factor (HB-EGF) gene. As the proteoglycan syndecan-1 is an HB-EGF coreceptor as well as a hallmark of plasma cell differentiation and a marker of myeloma cells, we studied the role of HB-EGF on myeloma cell growth. The HB-EGF gene was expressed by bone marrow mononuclear cells in 8 of 8 patients with myeloma, particularly by monocytes and stromal cells, but not by purified primary myeloma cells. Six of 9 myeloma cell lines and 9 of 9 purified primary myeloma cells expressed ErbB1 or ErbB4 genes coding for HB-EGF receptor. In the presence of a low interleukin-6 (IL-6) concentration, HB-EGF stimulated the proliferation of the 6 ErbB1+ or ErbB4+ cell lines, through the phosphatidylinositol 3-kinase/AKT (PI-3K/AKT) pathway. A pan-ErbB inhibitor blocked the myeloma cell growth factor activity and the signaling induced by HB-EGF. This inhibitor induced apoptosis of patients'myeloma cells cultured with their tumor environment. It also increased patients' myeloma cell apoptosis induced by an anti-IL-6 antibody or dexamethasone. The ErbB inhibitor had no effect on the interaction between multiple myeloma cells and stromal cells. It was not toxic for nonmyeloma cells present in patients' bone marrow cultures or for the growth of hematopoietic progenitors. Altogether, these data identify ErbB receptors as putative therapeutic targets in multiple myeloma.


DNA binding and dimerization specificity and potential targets for the TCP protein family.
The TCP domain is a plant-specific DNA binding domain found in proteins from a diverse array of species, including the cycloidea (cyc) and teosinte branched1 (tb1) gene products and the PCF1 and PCF2 proteins. To understand the role in transcriptional regulation of proteins with this domain, we have analysed the DNA binding and dimerization specificity of the TCP protein family using rice PCF proteins, and further evaluated potential targets for the TCP protein. The seven PCF members including five newly isolated proteins, were able to be grouped into two classes, I and II, based on sequence similarity in the TCP domain. Random binding site selection experiments and electrophoretic mobility shift assays (EMSAs) revealed the consensus DNA binding sequences of these two classes to be distinct but overlapping; GGNCCCAC for class I and GTGGNCCC for class II. The TB1 protein from maize, which belongs to class II, had the same specificity as the rice class II proteins, suggesting the conservation of binding specificity between TCP domains from different species. The yeast 2-hybrid assay and EMSA revealed that these proteins tend to form a homodimer or a heterodimer between members of the same class. We searched predicted 5' flanking sequences of Arabidopsis genes for the consensus binding sequences and found that the consensus sites are distributed in the genome at a considerably lower frequency. We further analysed eight promoters containing the class I consensus TCP sites. The transcriptional activities of six promoters were decreased by a mutation of the TCP binding site, which is consistent with the observation that the class I TCP site can confer transactivation function on a heterologous promoter. These results suggest that the two classes of TCP protein are distinct in DNA binding specificity and transcriptional regulation.


Comparison between enhanced MALDI in-source decay by ammonium persulfate and N- or C-terminal derivatization methods for detailed peptide structure determination.
Amino acid sequencing and more detailed structure elucidation analysis of peptides and small proteins is a very difficult task even if state-of-the-art mass spectrometry (MS) is employed. To make this task easier, chemical derivatization methods of the N terminus with 4-sulfophenyl-isothiocyanate (SPITC) or the C terminus with 2-methoxy-4,5-dihydro-1H-imidazole (Lys-tag) can enhance peptide fragmentation or fragment ionizability, via proton mobility/localization mechanisms making tandem MS (MS(2)) spectra more informative and less demanding for structural interpretation. Observed disadvantages related to both derivatization methods are sample- and time-consuming procedures and the increased number of reaction byproducts. A novel, sulfate radical in-source formation method of matrix-assisted laser desorption ionization (MALDI) MS based on chemically enhanced in-source decay (ISD) can be accomplished by simple addition of ammonium persulfate (APS) in the matrix solution. This method enables effective decomposition of peptide ions already in the first stage of MS analysis where a large number of fragment ions are produced. The resultant MALDI-ISD mass spectra (MS after APS → MALDI-ISD MS) are almost equivalent to conventional, collision-induced dissociation (CID) MS(2) spectra. These fragment ions are further subjected to the second stage of the MS, and consequently, MS(3) spectra are produced, which makes the sequence analysis more informative and complete (CID MS(2) is thus equivalent to CID MS(3)). Multiply stage MS after APS addition showed enhanced sensitivity, resolution, and mass accuracy compared to peptide derivatization (SPITC and Lys-tag) or conventional MS and MS(2) analyses and offered more detailed insight into peptide structure.


Putting the Spotlight Back on Plant Suspension Cultures.
Plant cell suspension cultures have several advantages that make them suitable for the production of recombinant proteins. They can be cultivated under aseptic conditions using classical fermentation technology, they are easy to scale-up for manufacturing, and the regulatory requirements are similar to those established for well-characterized production systems based on microbial and mammalian cells. It is therefore no surprise that taliglucerase alfa (Elelyso®)-the first licensed recombinant pharmaceutical protein derived from plants-is produced in plant cell suspension cultures. But despite this breakthrough, plant cells are still largely neglected compared to transgenic plants and the more recent plant-based transient expression systems. Here, we revisit plant cell suspension cultures and highlight recent developments in the field that show how the rise of plant cells parallels that of Chinese hamster ovary cells, currently the most widespread and successful manufacturing platform for biologics. These developments include medium optimization, process engineering, statistical experimental designs, scale-up/scale-down models, and process analytical technologies. Significant yield increases for diverse target proteins will encourage a gold rush to adopt plant cells as a platform technology, and the first indications of this breakthrough are already on the horizon.


The activated complement pathway in the fibrous process of benign prostatic hyperplasia.
To elucidate the changes in activated complement pathway in the fibrous process of benign prostatic hyperplasia (BPH), we analyzed the correlation between complement component expression and histological types of fibrosis using human BPH tissue. Fifty-six histological BPH patients who underwent prostate needle biopsy at our institution (mean age 68.6 ± 6.5 years), divided into two histological groups, fibromuscular and fibrous, were compared. Inflammatory cell infiltration in BPH tissue was evaluated by immunohistochemical staining using CD45, with complement expression analysis performed using C3, factor B, and C5b-9 antibody, and the occupancy ratio of the stained region was calculated. Further, correlation between the histological types of fibrous components in BPH tissue and lower urinary tract symptoms questionnaires was analyzed. Twenty-seven (48.2%) and 29 (51.8%) cases were classified in the fibromuscular and fibrous groups, respectively. The proportion of CD45-positive cells in BPH tissue was significantly higher in the fibromuscular group. In complement component analysis, factor B did not significantly differ between groups, while C3 (fibromuscular group; 10.7 ± 8.2%, fibrous group; 16.4 ± 12.7%) and C5b-9 (fibromuscular group; 15.9 ± 6.2%, fibrous group; 17.6 ± 9.2%) were significantly higher in the fibrous group (p = 0.04, p = 0.04, respectively). International Prostate Symptom Score Q5 subscore, indicating slow stream, was significantly higher in the fibrous group (p = 0.04). In fibrous BPH with abundant fibrosis, the late complement pathway in addition to alternative pathway was activated compared to fibromuscular BPH. These results suggested that the alternative and late complement pathways were involved in the histological fibrous process of BPH.


Profile of selumetinib and its potential in the treatment of melanoma.
The mitogen-activated protein kinase (MAPK) pathway is a critical oncogenic driver signal in a number of malignancies. The discovery of activating mutations in the MAPK pathway has led to the development of MAPK pathway inhibitors. Selumetinib is a potent and selective inhibitor of MEK1 and MEK2, which are essential downstream molecules in the MAPK pathway. Several preclinical and clinical studies have demonstrated the promising antitumor activity of selumetinib. In this review, we discuss the MAPK pathway in melanoma and summarized data from preclinical and clinical studies of selumetinib for advanced melanoma.


Polyvinylpyrrolidone-assisted synthesis of ultrathin multi-nanolayered Cu2Nb34O87-x for advanced Li+ storage.
The ultrathin multi-nanolayered structure with ultrathin monolayer thickness (<10 nm) and certain interlayer spacing can significantly shorten Li+ paths and alleviate the volume effect for Li+-storage materials. However, unlike layered materials such as MXene and MoS2, shear ReO3-type niobates have difficulty forming ultrathin multi-nanolayered structures due to their crystal structures, which still remains a challenge. Herein, by a polyvinylpyrrolidone (PVP)-assisted solvothermal method, we first synthesize ultrathin multi-nanolayered Cu2Nb34O87-x with oxygen vacancies composed of ultrathin nanolayers (2-10 nm in thickness) and interlayer spacing (1-5 nm). Oxygen vacancies can radically enhance the inherent electronic/ionic conductivity and Li+ diffusion coefficient of this material. The PVP-induced formation mechanism of this material is expounded in detail. The well-preserved ultrathin multi-nanolayered structure and excellent multi-electron electrochemical reversibility (Nb5+ ↔ Nb4+ ↔N b3+ and Cu2+ ↔ Cu+) of this material during cycling are fully verified. Based on an ultrathin multi-nanolayered structure and oxygen vacancies, this material as the anode of lithium-ion batteries is highly competitive among reported shear ReO3-type Cu-Nb-O anodes, displaying a high reversible capacity (315.3 mAh g-1 after 300 cycles at 1 C), durable cycling stability (85.7 % capacity retention after 1000 cycles at 10 C), and outstanding rate performance. Moreover, the application of this material to lithium-ion capacitors generates a large energy density (97.9 Wh kg-1 at 87.5 W kg-1) and a high power density (17,500 W kg-1 at 12.6 Wh kg-1), thus further indicating its fast faradaic pseudocapacitive behavior for practical applications. The results of this work indicate a breakthrough in synthesizing ultrathin multi-nanolayered shear ReO3-type niobates.


Evolution and divergence of the MADS-box gene family based on genome-wide expression analyses.
MADS-box genes encode transcription factors involved in various important aspects of development and differentiation in land plants, metazoans, and other organisms. Three types of land plant MADS-box genes have been reported. MIKCC- and MIKC*-type genes both contain conserved MADS and K domains but have different exon/intron structures. M-type genes lack a K domain. Most MADS-box genes previously analyzed in land plants are expressed in the sporophyte (diploid plant body); few are expressed in the gametophyte (haploid plant body). Land plants are believed to have evolved from a gametophyte (haploid)-dominant ancestor without a multicellular sporophyte (diploid plant body); most genes expressed in the sporophyte probably originated from those used in the gametophyte during the evolution of land plants. To analyze the evolution and diversification of MADS-box genes in land plants, gametophytic MADS-box genes were screened using macroarray analyses for 105 MADS-box genes found in the Arabidopsis genome. Eight MADS-box genes were predominantly expressed in pollen, the male gametophyte; all but one of their expression patterns was confirmed by Northern analyses. Analyses of the exon/intron structure of these seven genes revealed that they included two MIKCC-type, one M-type, and four MIKC*-type MADS-box genes. Previously, MIKC*-type genes have been reported only from a moss and a club moss, and this is the first record in seed plants. These genes can be used to investigate the unknown ancestral functions of MADS-box genes in land plants. The macroarray analyses did not detect expression of 56 of 61 M-type MADS-box genes in any tissues examined. A phylogenetic tree including all three types of Arabidopsis MADS-box genes with representative genes from other organisms showed that M-type genes were polyphyletic and that their branch lengths were much longer than for the other genes. This finding suggests that most M-type genes are pseudogenes, although further experiments are necessary to confirm this possibility. Our global phylogenetic analyses of MADS-box genes did not support the previous classification of MADS-box genes into type I and II groups, based on smaller scale analyses. An evolutionary scenario for the evolution of MADS-box genes in land plants is discussed.


Optimizing the trajectory of deep brain stimulation leads reduces RF heating during MRI at 3 T: Characteristics and clinical translation.
Radiofrequency (RF) induced tissue heating around deep brain stimulation (DBS) leads is a well-known safety risk during magnetic resonance imaging (MRI), hindering routine protocols for patients. Known factors that contribute to variations in the magnitude of RF heating across patients include the implanted lead's trajectory and its orientation with respect to the MRI electric fields. Currently, there are no consistent requirements for surgically implanting the extracranial portion of the DBS lead. Recent studies have shown that incorporating concentric loops in the extracranial trajectory of the lead can reduce RF heating, but the optimal positioning of the loop is unknown. In this study, we evaluated RF heating of 77 unique lead trajectories to determine how different characteristics of the trajectory affect RF heating during MRI at 3 T. We performed phantom experiments with commercial DBS systems from two manufacturers to determine how consistently modifying the lead trajectory mitigates RF heating. We also presented the first surgical implementation of these modified trajectories in patients. Low-heating trajectories included small concentric loops near the surgical burr hole which were readily implemented during the surgical procedure; these trajectories generated nearly a 2-fold reduction in RF heating compared to unmodified trajectories.Clinical Relevance- Surgically modifying the DBS lead trajectory can be a cost-effective strategy for reducing RF-induced heating during MRI at 3 T.


Downregulation of B4GALT5 attenuates cardiac fibrosis through Lumican and Akt/GSK-3β/β-catenin pathway.
Virtually all forms of cardiac disease exhibit cardiac fibrosis as a common trait, which ultimately leads to adverse ventricular remodeling and heart failure. To improve the prognosis of heart disease, it is crucial to halt the progression of cardiac fibrosis. Protein function is intricately linked with protein glycosylation, a vital post-translational modification. As a fundamental member of the β1,4-galactosyltransferase gene family (B4GALT), β1,4-galactosyltransferase V (B4GALT5) is associated with various disorders. In this study, significant levels of B4GALT5 expression were observed in cardiac fibrosis induced by transverse aortic constriction (TAC) or TGFβ1 and the activation of cardiac fibroblasts (CFs). Subsequently, by administering AAV9-shB4GALT5 injections to TAC animals, we were able to demonstrate that in vivo B4GALT5 knockdown decreased the transformation of CFs into myofibroblasts (myoFBs) and reduced the deposition of cardiac collagen fibers. In vitro tests revealed the same results. Conversely, both in vivo and in vitro experiments indicated that overexpression of B4GALT5 stimulates CFs activation and exacerbates cardiac fibrosis. Initially, we elucidated the primary mechanism by which B4GALT5 regulates the Akt/GSK-3β/β-catenin pathway and directly interacts with laminin, thereby affecting cardiac fibrosis. Our findings demonstrate that B4GALT5 promotes cardiac fibrosis through the Akt/GSK-3β/β-catenin pathway and reveal laminin as the target protein of B4GALT5.


Double-proton transfer in adenine-thymine and guanine-cytosine base pairs. A post-Hartree-Fock ab initio study.
The results of a comprehensive study on the double-proton transfer in Adenine-Thymine (AT) and Guanine-Cytosine (GC) base pairs at room temperature in gas phase and with the inclusion of environmental effects are obtained. The double-proton-transfer process has been investigated in the AT and GC base pairs at the B3LYP/6-31G(d) and MP2/6-31G(d) levels of theory. It has been predicted that the hydrogen-bonded bases possess nonplanar geometries due to sp3 hybridization of nitrogen atoms and because of the soft intermolecular vibrations in the molecular complexes. An analysis of the energetic parameters of the local minima suggests that rare AT base pair conformation is not populated due to the shallowness of this minimum, which completely disappears from the Gibbs free energy surface. The stabilization of canonic or rare forms of the DNA bases by water molecules and metal cations has been predicted by calculating the optimal configuration of charges (using differential product/transition state stabilization approach) followed by calculations of the interactions between the base pair and a water/sodium cation.


Gastrointestinal tube stent plication in infants and children.
Twenty cases of intestinal obstruction in infants and children were managed by gastrointestinal tube stent plication. The mean age was 2.6 years, and ten patients were infants. Previous (often multiple) abdominal operations were performed in 18 patients with a variety of anomalies. Tube plication was used at initial operation in two neonates with malrotation. Following lysis of adhesions, a No. 12 or No. 16 tube (usually a Baker tube) was inserted by gastrostomy and advanced distally into the colon. The tube was kept in place for ten days, with caloric needs supplied by parenteral alimentation. Barium tubogram showed distal patency, and the tube was removed. Eighteen patients survived (90%), and obstruction was relieved in each instance. These observations suggest that gastrointestinal tube stent plication is a useful adjunctive procedure in carefully selected cases or recurrent adhesive intestinal obstruction in infants and children.


Orbital rhabdomyosarcoma in an adult.
Rhabdomyosarcoma is the most common primary orbital malignant tumor in children. Orbital lesions represent about 10 % of all the cases of rhabdomyosarcoma. Rhabdomyosarcoma is a rare cause of proptosis in adults. To report a case of primary orbital rhabdomyosarcoma in a 45-year-old female. Interventional case report. The main outcome measures are a rare cause ofproptosis in an adult, discussion on treatment options and prognosis ofrhabdomyosarcoma. The patient underwent total orbital exenteration and was referred for radiotherapy and chemotherapy. Rhabdomyosarcoma is a rare cause of proptosis in adults. It should be suspected in a case of rapidly-progressive proptosis in adults.