Acupuncture for hypertension.
Elevated blood pressure (hypertension) affects about one billion people worldwide. It is important as it is a major risk factor for stroke and myocardial infarction. However, it remains a challenge for the medical profession as many people with hypertension have blood pressure (BP) that is not well controlled. According to Traditional Chinese Medicine theory, acupuncture has the potential to lower BP. To assess the effectiveness and safety of acupuncture for lowering blood pressure in adults with primary hypertension. We searched the Hypertension Group Specialised Register (February 2017); the Cochrane Central Register of Controlled Trials (CENTRAL) 2017, Issue 2; MEDLINE (February 2017); Embase (February 2017), China National Knowledge Infrastructure (CNKI) (January 2015), VIP Database (January 2015), the World Health Organisation Clinical Trials Registry Platform (February 2017)and ClinicalTrials.gov (February 2017). There were no language restrictions. We included all randomized controlled trials (RCTs) that compared the clinical effects of an acupuncture intervention (acupuncture used alone or add-on) with no treatment, a sham acupuncture or an antihypertensive drug in adults with primary hypertension. Two review authors independently selected studies according to inclusion and exclusion criteria. They extracted data and assessed the risk of bias of each trial, and telephoned or emailed the authors of the studies to ask for missing information. A third review author resolved disagreements. Outcomes included change in systolic blood pressure (SBP), change in diastolic blood pressure (DBP), withdrawal due to adverse effects, and any adverse events. We calculated pooled mean differences (MD) with 95% confidence intervals (CI) for continuous outcomes using a fixed-effect or random-effects model where appropriate. Twenty-two RCTs (1744 people) met our inclusion criteria. The RCTs were of variable methodological quality (most at high risk of bias because of lack of blinding). There was no evidence for a sustained BP lowering effect of acupuncture; only one trial investigated a sustained effect and found no BP lowering effect at three and six months after acupuncture. Four sham acupuncture controlled trials provided very low quality evidence that acupuncture had a short-term (one to 24 hours) effect on SBP (change) -3.4 mmHg (-6.0 to -0.9) and DBP -1.9 mmHg (95% CI -3.6 to -0.3). Pooled analysis of eight trials comparing acupuncture with angiotensin-converting enzyme inhibitors and seven trials comparing acupuncture to calcium antagonists suggested that acupuncture lowered short-term BP better than the antihypertensive drugs. However, because of the very high risk of bias in these trials, we think that this is most likely a reflection of bias and not a true effect. As a result, we did not report these results in the 'Summary of findings' table. Safety of acupuncture could not be assessed as only eight trials reported adverse events. At present, there is no evidence for the sustained BP lowering effect of acupuncture that is required for the management of chronically elevated BP. The short-term effects of acupuncture are uncertain due to the very low quality of evidence. The larger effect shown in non-sham acupuncture controlled trials most likely reflects bias and is not a true effect. Future RCTs must use sham acupuncture controls and assess whether there is a BP lowering effect of acupuncture that lasts at least seven days.


An improved ovine reference genome assembly to facilitate in-depth functional annotation of the sheep genome.
The domestic sheep (Ovis aries) is an important agricultural species raised for meat, wool, and milk across the world. A high-quality reference genome for this species enhances the ability to discover genetic mechanisms influencing biological traits. Furthermore, a high-quality reference genome allows for precise functional annotation of gene regulatory elements. The rapid advances in genome assembly algorithms and emergence of sequencing technologies with increasingly long reads provide the opportunity for an improved de novo assembly of the sheep reference genome. Short-read Illumina (55× coverage), long-read Pacific Biosciences (75× coverage), and Hi-C data from this ewe retrieved from public databases were combined with an additional 50× coverage of Oxford Nanopore data and assembled with canu v1.9. The assembled contigs were scaffolded using Hi-C data with Salsa v2.2, gaps filled with PBsuitev15.8.24, and polished with Nanopolish v0.12.5. After duplicate contig removal with PurgeDups v1.0.1, chromosomes were oriented and polished with 2 rounds of a pipeline that consisted of freebayes v1.3.1 to call variants, Merfin to validate them, and BCFtools to generate the consensus fasta. The ARS-UI_Ramb_v2.0 assembly is 2.63 Gb in length and has improved continuity (contig NG50 of 43.18 Mb), with a 19- and 38-fold decrease in the number of scaffolds compared with Oar_rambouillet_v1.0 and Oar_v4.0. ARS-UI_Ramb_v2.0 has greater per-base accuracy and fewer insertions and deletions identified from mapped RNA sequence than previous assemblies. The ARS-UI_Ramb_v2.0 assembly is a substantial improvement in contiguity that will optimize the functional annotation of the sheep genome and facilitate improved mapping accuracy of genetic variant and expression data for traits in sheep.


Stage-specific expression of Nc SAG4 as a marker of chronic Neospora caninum infection in a mouse model.
Neospora caninum infection persists throughout the life of its intermediate host due to the conversion of tachyzoites to slowly dividing bradyzoites that encyst in the brain. This event results in persistent N. caninum infection in bovine herds and partially explains the poor efficacy of many chemotherapeutic agents and vaccine formulations. Thus, there is a need for greater understanding of the tachyzoite-to-bradyzoite conversion mechanisms. Here we studied for the first time the transcription kinetics of the N. caninum bradyzoite-specific gene NcSAG4 in brain samples from chronically infected mice by means of real-time RT-PCR. NcSAG4-messenger RNA (mRNA) levels increased significantly during the chronic phase but followed 2 different expression patterns depending on the isolate used for murine inoculation. NcSAG4-mRNA levels in brains from Nc-1-inoculated mice peaked during late chronic infection (on day 64 post-infection, p.i.), whereas those from Nc-Liv-inoculated mice peaked earlier during the chronic infection (on day 32 p.i.). This difference could be a reflection of the different abilities of these isolates to replicate and form cysts in parasitized brains. These results are consistent with our observations of anti-rNcSAG4 antibody production; low levels were present at seroconversion and slowly increased during the chronic phase. In contrast, NcSAG1 transcription levels, which mark the tachyzoite stage, were maintained without variation in both groups of mice. This suggests the presence of a significant amount of tachyzoites or intermediate zoites expressing NcSAG1 in the brain, even during the late chronic infection.


Epidemiological and clinical features of rotavirus gastroenteritis in Oman.
Two-hundred-and-seventeen children admitted with diarrhoea and 204 unmatched controls hospitalized during the 2-year period from November 1990 to October 1992 were included in this prospective study. Their stool samples were subjected to microscopy, cultures, ELISA for rotavirus and electron microscopy. Human rotavirus (HRV) was detected in 68 (31 per cent) of the stool samples in the study group and 12 (6 per cent) in the control group. There was an increased incidence in the cooler months of the year; typically, most of the affected infants and children presented with vomiting and respiratory symptoms, and had mild to moderate dehydration. Biochemical profile showed normal or hyponatraemia and normokalaemia. A more detailed community-based study of diarrhoeal diseases in Oman is to follow this pilot study.


The life cycle of Ceratomyxa shasta, a myxosporean parasite of salmonids, requires a freshwater polychaete as an alternate host.
The actinosporean life stage of Ceratomyxa shasta, a myxozoan parasite of salmonids, and the annelid worm that serves as its alternate host were identified in laboratory transmission experiments and their roles were confirmed using molecular techniques. Infection by the parasite occurred in susceptible fish that were either exposed to or force fed the freshwater polychaete, Manayunkia speciosa, infected with the actinosporean. These observations were confirmed using the polymerase chain reaction with primers designed from the C. shasta 18S rDNA sequence. DNA was amplified from polychaetes harboring the actinosporean that caused infection in the fish but not from uninfected polychaetes. Amplified DNA from an infected polychaete was sequenced and its homology with the 18S rDNA sequence of C. shasta spores verified the proposed life cycle. Ultrastructural examination of the actinosporean in the polychaete showed developmental stages in the epidermis rather than within the intestinal epithelium as described for other myxozoans. The methods described will be useful in identifying alternate hosts and morphologically diverse life stages in the complex life cycles of other myxosporea and in understanding the relationships between these parasites and their hosts.


Carotenoid composition of spinach chloroplast grana and stroma lamellae.
Stroma lamellae and grana stacks prepared by French press rupture of spinach (Spinacia oleracea) chloroplasts contain similar amounts of beta-carotene on a protein basis. The grana fraction has considerably more xanthophylls than does the stroma fraction. Total carotenoid to chlorophyll ratios are similar for both fractions.


Cholesterol Effect on the Specific Capacitance of Submicrometric DOPC Bilayer Patches Measured by in-Liquid Scanning Dielectric Microscopy.
The specific capacitance of biological membranes is a key physical parameter in bioelectricity that also provides valuable physicochemical information on composition, phase, or hydration properties. Cholesterol is known to modulate the physicochemical properties of biomembranes, but its effect on the specific capacitance has not been fully established yet. Here we use the high spatial resolution capabilities of in-liquid scanning dielectric microscopy in force detection mode to directly demonstrate that DOPC bilayer patches at 50% cholesterol concentration show a strong reduction of their specific capacitance with respect to pure DOPC bilayer patches. The reduction observed (∼35%) cannot be explained by the small increase in bilayer thickness (∼16%). We suggest that the reduction of the specific capacitance might be due to the dehydration of the polar head groups caused by the insertion of cholesterol molecules in the bilayer. The results reported confirm the potential of in-liquid SDM to study the electrical and physicochemical properties of lipid bilayers at very small scales (down to ∼200 nm here), with implications in fields such as biophysics, bioelectricity, biochemistry, and biosensing.


Long-term Follow-up of Humoral Immune Status in Adult Lung Transplant Recipients.
Lung transplant recipients have an increased risk for infections in the posttransplant period due to immunosuppressive therapy. Protection against infections can be achieved through vaccination, but the optimal vaccination schedule in lung transplant recipients is unknown. Data on long-term immunological follow up and vaccination responses after lung transplantation are scarce. Here we present long-term immunological follow up of a cohort of 55 lung transplant recipients. This includes detailed antibody responses after 23-valent pneumococcal polysaccharide vaccination (23vPPV). All patients were vaccinated with 23vPPV before transplantation. Median follow-up after transplantation was 6.6 years (379 patient-years). After transplantation, there is a significant decrease of all immunoglobulins, IgG subclasses and pneumococcal polysaccharide antibodies. After the first year posttransplantation, there is a gradual increase of all immunoglobulins and IgG subclasses, but values were always significantly lower than in the pretransplant period. After a median of 4.4 years posttransplantation, patients were revaccinated with 23vPPV. The pneumococcal polysaccharide antibody response was impaired in 87% of patients (ie, antibody titer above cutoff and twofold increase between pre and postvaccination values for <70% of serotypes). We found that impairment of humoral immunity was most outspoken in the first year after lung transplantation. Immunoglobulin levels remain decreased several years after transplantation and the response to pneumococcal polysaccharide vaccine was significantly lower posttransplantation compared to the pretransplantation response. However, most patients did show a partial response to vaccination. Based on our results, revaccination with pneumococcal vaccines after transplantation should be considered 1 year after transplantation.


Equilibrium information from nonequilibrium measurements in an experimental test of Jarzynski's equality.
Recent advances in statistical mechanical theory can be used to solve a fundamental problem in experimental thermodynamics. In 1997, Jarzynski proved an equality relating the irreversible work to the equilibrium free energy difference, DeltaG. This remarkable theoretical result states that it is possible to obtain equilibrium thermodynamic parameters from processes carried out arbitrarily far from equilibrium. We test Jarzynski's equality by mechanically stretching a single molecule of RNA reversibly and irreversibly between two conformations. Application of this equality to the irreversible work trajectories recovers the DeltaG profile of the stretching process to within k(B)T/2 (half the thermal energy) of its best independent estimate, the mean work of reversible stretching. The implementation and test of Jarzynski's equality provides the first example of its use as a bridge between the statistical mechanics of equilibrium and nonequilibrium systems. This work also extends the thermodynamic analysis of single molecule manipulation data beyond the context of equilibrium experiments.


Noninvasive assessment of cardiac output in critically ill patients by analysis of the finger blood pressure waveform.
To assess whether the measurement of cardiac output by computer-assisted analysis of the finger blood pressure waveform can substitute for the thermodilution method in critically ill patients. Prospective data collection. Emergency department in a 2000-bed inner city hospital Forty-six critically ill patients requiring invasive monitoring for clinical management were prospectively studied. Under local anesthesia a 7-Fr pulmonary artery catheter was inserted via the central subclavian or jugular vein. Cardiac output was determined by the use of a cardiac output computer and injections of 10 mL ice-cold glucose 5%. Noninvasive cardiac output was calculated from the finger blood pressure waveform by the use of the test software program. Three hundred twenty-three pairs of invasive and noninvasive hemodynamic measurements were collected in intervals of 30 mins from 46 patients (mean age 61.9 +/- 12.4 yrs; 35 male, 11 female). The average cardiac index during the study period was 2.83 L/min/m2 (range 0.97 to 5.56). The overall discrepancy between both measurements was 0.14 L/min/m2 (95% confidence interval: 0.10-.018, p < .001). Seventy-five (23.2%) measurements had an absolute discrepancy > +/- 0.50 L/min/m2. Noninvasive and invasive comparisons of mean differential cardiac output were out of phase for 9.7% of all readings. Computer-assisted analysis of finger blood pressure waveform to assess cardiac output is not a substitute for the thermodilution method due to a high percentage (23.2%) of inaccurate readings; however, it may be a useful tool for the detection of relative hemodynamic trends in critically ill patients.


Better exercise adherence after treatment for cancer (BEAT Cancer) study: rationale, design, and methods.
Most breast cancer survivors do not engage in regular physical activity. Our physical activity behavior change intervention for breast cancer survivors significantly improved physical activity and health outcomes post-intervention during a pilot, feasibility study. Testing in additional sites with a larger sample and longer follow-up is warranted to confirm program effectiveness short and longer term. Importantly, the pilot intervention resulted in changes in physical activity and social cognitive theory constructs, enhancing our potential for testing mechanisms mediating physical activity behavior change. Here, we report the rationale, design, and methods for a two-site, randomized controlled trial comparing the effects of the BEAT Cancer physical activity behavior change intervention to usual care on short and longer term physical activity adherence among breast cancer survivors. Secondary aims include examining social cognitive theory mechanisms of physical activity behavior change and health benefits of the intervention. Study recruitment goal is 256 breast cancer survivors with a history of ductal carcinoma in situ or Stage I, II, or IIIA disease who have completed primary cancer treatment. Outcome measures are obtained at baseline, 3 months (i.e., immediately post-intervention), 6 months, and 12 months and include physical activity, psychosocial factors, fatigue, sleep quality, lower extremity joint dysfunction, cardiorespiratory fitness, muscle strength, and waist-to-hip ratio. Confirming behavior change effectiveness, health effects, and underlying mechanisms of physical activity behavior change interventions will facilitate translation to community settings for improving the health and well-being of breast cancer survivors.


Corona Immunitas: study protocol of a nationwide program of SARS-CoV-2 seroprevalence and seroepidemiologic studies in Switzerland.
Seroprevalence studies to assess the spread of SARS-CoV-2 infection in the general population and subgroups are key for evaluating mitigation and vaccination policies and for understanding the spread of the disease both on the national level and for comparison with the international community. Corona Immunitas is a research program of coordinated, population-based, seroprevalence studies implemented by Swiss School of Public Health (SSPH+). Over 28,340 participants, randomly selected and age-stratified, with some regional specificities will be included. Additional studies in vulnerable and highly exposed subpopulations are also planned. The studies will assess population immunological status during the pandemic. Phase one (first wave of pandemic) estimates from Geneva showed a steady increase in seroprevalence up to 10.8% (95% CI 8.2-13.9, n = 775) by May 9, 2020. Since June, Zurich, Lausanne, Basel City/Land, Ticino, and Fribourg recruited a total of 5973 participants for phase two thus far. Corona Immunitas will generate reliable, comparable, and high-quality serological and epidemiological data with extensive coverage of Switzerland and of several subpopulations, informing health policies and decision making in both economic and societal sectors. ISRCTN Registry: https://www.isrctn.com/ISRCTN18181860 .


Plasm Metabolomics Study in Pulmonary Metastatic Carcinoma.
The lung is one of the most common metastatic sites of malignant tumors. Early detection of pulmonary metastatic carcinoma can effectively reduce relative cancer mortality. Human metabolomics is a qualitative and quantitative study of low-molecular metabolites in the body. By studying the plasm metabolomics of patients with pulmonary metastatic carcinoma or other lung diseases, we can find the difference in plasm levels of low-molecular metabolites among them. These metabolites have the potential to become biomarkers of lung metastases. Patients with pulmonary nodules admitted to our department from February 1, 2019, to May 31, 2019, were collected. According to the postoperative pathological results, they were divided into three groups: pulmonary metastatic carcinoma (PMC), benign pulmonary nodules (BPN), and primary lung cancer (PLC). Moreover, healthy people who underwent physical examination were enrolled as the healthy population group (HPG) during the same period. On the one hand, to study lung metastases screening in healthy people, PMC was compared with HPG. The multivariate statistical analysis method was used to find the significant low-molecular metabolites between the two groups, and their discriminating ability was verified by the ROC curve. On the other hand, from the perspective of differential diagnosis of lung metastases, three groups with different pulmonary lesions (PMC, BPN, and PLC) were compared as a whole, and then the other two groups were compared with PMC, respectively. The main low-molecular metabolites were selected, and their discriminating ability was verified. In terms of lung metastases screening for healthy people, four significant low-molecular metabolites were found by comparison of PMC and HPG. They were O-arachidonoyl ethanolamine, adrenoyl ethanolamide, tricin 7-diglucuronoside, and p-coumaroyl vitisin A. In terms of the differential diagnosis of pulmonary nodules, the significant low-molecular metabolites selected by the comparison of the three groups as a whole were anabasine, octanoylcarnitine, 2-methoxyestrone, retinol, decanoylcarnitine, calcitroic acid, glycogen, and austalide L. For the comparison of PMC and BPN, L-tyrosine, indoleacrylic acid, and lysoPC (16 : 0) were selected, while L-octanoylcarnitine, retinol, and decanoylcarnitine were selected for the comparison of PMC and PLC. Their AUCs of ROC are all greater than 0.80. It indicates that these substances have a strong ability to differentiate between pulmonary metastatic carcinoma and other pulmonary nodule lesions. Through the research of plasm metabolomics, it is possible to effectively detect the changes in some low-molecular metabolites among primary lung cancer, pulmonary metastatic carcinoma, and benign pulmonary nodule patients and healthy people. These significant metabolites have the potential to be biomarkers for screening and differential diagnosis of lung metastases.


Chloro({2-[mesityl(quinolin-8-yl-κN)boryl]-3,5-dimethyl-phenyl}methyl-κC)palladium(II) as a catalyst for Heck reactions.
We recently reported an air and moisture stable 16-electron borapalladacycle formed upon combination of 8-quinolyldimesitylborane with bis(benzonitrile)dichloropalladium(II). The complex features a tucked mesityl group formed upon metalation of an ortho-methyl group on a mesityl; however it is unusually stable due to contribution of the boron pz orbital in delocalizing the carbanion that gives rise to an η4-boratabutadiene fragment coordinated to Pd(II), as evidenced from crystallographic data. This complex was observed to be a highly active catalyst for the Heck reaction. Data of the catalyst activity are presented alongside data found in the literature, and initial comparison reveals that the borapalladacycle is quite active. The observed catalysis suggests the borapalladacycle readily undergoes reductive elimination; however the Pd(0) complex has not yet been isolated. Nevertheless, the ambiphilic ligand 8-quinolyldimesitylborane may be able to support palladium in different redox states.


Opportunities for theory-informed decision science in cancer control.
Cancer prevention and control involves navigation of complex clinical decisions, often laden with uncertainty and/or intricate interpersonal dynamics, which have implications for both physical health and quality of life. Cancer decision-making research in recent decades has primarily focused on working to improve the quality of decisions by providing patients with detailed information about their choices and through an increased emphasis in medicine on the importance of shared decision making. This emphasis is reflective of a model of decision making that emphasizes knowledge, options, and deliberative synthesis of information as primary to decision making; yet, decades of research in psychology, decision science, and behavioral economics have taught us that our decisions are not influenced only by our objective knowledge of facts, but by our emotions, by the influence of others, and by biased cognitive processes. We present a conceptual framework for a future of research in decision science and cancer that is informed by decision science theories. Our framework incorporates greater recognition of the interpersonal dynamics of shared decision making, including the biases (including cognitive heuristics and race-based bias) that may affect multiple actors in the decision-making process, and emphasizes study of the interaction between deliberative and affective psychological processes as they relate to decision making. This work should be conducted with an eye toward informing efforts to improve decision making across the cancer care continuum, through interventions that are also informed by theory.


Dynamics of time discrimination.
Pigeons tracked sinusoidal sequences of interfood intervals (IFIs) by pausing in each interval for a time proportional to the preceding interval. Schedules with either long (30-90 s) or short (5-15 s) values, with variable numbers of cycles and starting phase each day, were tracked about equally well. Tracking was apparently immediate and did not improve across sessions. Experiment 2, in which long and short series were presented on alternate days, showed that tracking on long was more impaired than on short. Experiment 3 showed that occasional presentation of a short IFI in a series of fixed, longer IFIs caused a reduction in waiting time in the next IFI. These effects are evidence for a fast-acting timing mechanism in which waiting time in the IFI N + 1 is strongly determined by the preceding IFI, N. Earlier IFIs have some cumulative effect, but the details remain to be elucidated.


Sample Preparation for Mass Spectrometry-based Identification of RNA-binding Regions.
Noncoding RNAs play important roles in several nuclear processes, including regulating gene expression, chromatin structure, and DNA repair. In most cases, the action of noncoding RNAs is mediated by proteins whose functions are in turn regulated by these interactions with noncoding RNAs. Consistent with this, a growing number of proteins involved in nuclear functions have been reported to bind RNA and in a few cases the RNA-binding regions of these proteins have been mapped, often through laborious, candidate-based methods. Here, we report a detailed protocol to perform a high-throughput, proteome-wide unbiased identification of RNA-binding proteins and their RNA-binding regions. The methodology relies on the incorporation of a photoreactive uridine analog in the cellular RNA, followed by UV-mediated protein-RNA crosslinking, and mass spectrometry analyses to reveal RNA-crosslinked peptides within the proteome. Although we describe the procedure for mouse embryonic stem cells, the protocol should be easily adapted to a variety of cultured cells.


Nurses' Physical and Psychological Symptoms During the first COVID-19 Lockdown in Italy: a Nationwide Cross-Sectional Study in Stem Cell Transplantation Setting.
Northern Italy was one of the first European territories to deal with the Coronavirus Disease 2019 (COVID-19) outbreak. Drastic emergency restrictions were introduced to contain the spread and limit pressure on healthcare facilities. However, nurses were at high risk of developing physical, mental, and working issues due to professional exposure. The aim of this cross-sectional study was to investigate these issues among nurses working in Italian hematopoietic stem cell transplant (HSCT) centers during the COVID-19 pandemic. Data were collected online immediately after the first "lockdown" period in order to investigate the prevalence of physical issues, sleep disorders, and burnout symptoms and explore correlations with COVID-19 territorial incidence in Northern Italian regions versus Central and Southern Italian regions. Three hundred and eight nurses working in 61 Italian HSCT Units responded to the survey. Depression, cough, and fever were more frequently reported by nurses working in geographical areas less affected by the pandemic (p=0.0013, p<0.0001, and p=0.0005 respectively) as well as worst sleep quality (p=0.008). Moderate levels of emotional exhaustion (mean±SD -17.4±13.0), depersonalization (5.3±6.1), and personal accomplishment (33.2±10.7) were reported without significant differences between territories. different COVID-19 incidence among territories did not influence nurses' burden of symptoms in the HSCT setting. However, burnout and insomnia levels should be considered by health care facilities in order to improve preventive strategies.


Age-dependent changes in MRI of motor brain stem nuclei in a mouse model of ALS.
Mice over-expressing the mutant human G93A-SOD1 are widely used as an animal model of amyotrophic lateral sclerosis (ALS). ALS is characterized by progressive degeneration of motor neurons in the motor cortex, brain stem and spinal cord. The underlying mechanisms for the selective death of motor neurons are still uncertain. To study factors that cause selective neuron degeneration or therapeutic approaches to delay the progression of the disease, a method is required to monitor the state of motor neurons under in-vivo conditions. Here, we demonstrate that in G93A-SOD1 mice the MRI signal intensities of nucleus V, VII, XII, and nucleus ambiguus show a time-dependent increase starting around day 90, parallel to first behavioral signs of a motoneuron disorder.


Personalized Transcranial Magnetic Stimulation in Psychiatry.
Transcranial magnetic stimulation (TMS) is a noninvasive brain stimulation technique that allows for modulating the activity of local neural populations and related neural networks. TMS is touted as a viable intervention to normalize brain activity and alleviate some psychiatric symptoms. However, TMS interventions are known to be only moderately reliable, and the efficacy of such therapies remains to be proven for psychiatric disorders other than depression. We review new opportunities to personalize TMS interventions using neuroimaging and computational modeling, aiming to optimize treatment to suit particular individuals and clinical subgroups. Specifically, we consider the prospect of improving the efficacy of existing TMS interventions by parsing broad diagnostic categories into biologically and clinically homogeneous biotypes. Biotypes can provide distinct treatment targets for optimized TMS interventions. We further discuss the utility of computational models in refining TMS personalization and efficiently establishing optimal cortical targets for distinct biotypes. Personalizing cortical stimulation targets, treatment frequencies, and intensities can improve the therapeutic efficacy of TMS and potentially establish noninvasive brain stimulation as a viable treatment for psychiatric symptoms.


Evidence for Kinetic Limitations as a Controlling Factor of Ge Pyramid Formation: a Study of Structural Features of Ge/Si(001) Wetting Layer Formed by Ge Deposition at Room Temperature Followed by Annealing at 600 °C.
The article presents an experimental study of an issue of whether the formation of arrays of Ge quantum dots on the Si(001) surface is an equilibrium process or it is kinetically controlled. We deposited Ge on Si(001) at the room temperature and explored crystallization of the disordered Ge film as a result of annealing at 600 °C. The experiment has demonstrated that the Ge/Si(001) film formed in the conditions of an isolated system consists of the standard patched wetting layer and large droplike clusters of Ge rather than of huts or domes which appear when a film is grown in a flux of Ge atoms arriving on its surface. We conclude that the growth of the pyramids appearing at temperatures greater than 600 °C is controlled by kinetics rather than thermodynamic equilibrium whereas the wetting layer is an equilibrium structure. Primary 68.37.Ef; 68.55.Ac; 68.65.Hb; 81.07.Ta; 81.16.Dn.


The cardiovascular safety aspects of calcium supplementations: where does the truth lie? A personal perspective.
Clinical guidelines may change with time, as more information from topline studies emerges. Calcium plus vitamin D supplementation became routine decades ago, especially in the older population, based on the assumption that it may promote bone health and prevent fractures, and perhaps induce additional favorable health outcomes. During the past years, an ongoing debate defies this paradigm, mainly because of a potential cardiovascular risk on the one hand, and uncertainty in regard to the extent of the beneficial bone effects on the other hand. The following article summarizes the main recent developments, trying to put some order into the controversial information and opinions which have been published in the medical literature. We conclude that the best current evidence supports a primary strategy of obtaining recommended intakes of calcium and vitamin D from dietary sources. But, since most western diets are inadequate in that regard, and since there is no clear evidence of harm from modest supplementation (up to 1000 mg of elemental calcium and 400 IU of vitamin D3), supplementation is appropriate when dietary intake is inadequate.


Improvement in Oxygenation Utilizing Transpulmonary Pressure Monitoring for Optimal Positive End-Expiratory Pressure in Pediatric Acute Respiratory Distress Syndrome: A Case Report.
In severe pediatric acute respiratory distress syndrome, data are lacking on methods to measure and set optimal positive end-expiratory pressure. We present a 2-year-old girl with Trisomy 21 who developed severe pediatric acute respiratory distress syndrome and refractory hypoxemia from human metapneumovirus pneumonia. Esophageal manometry was utilized to measure transpulmonary pressure, and positive end-expiratory pressure was increased to 19 cm H2O, resulting in rapid improvement in oxygenation. Hemodynamics remained adequate without intervention. The patient improved and survived without sequelae. Our case suggests that transpulmonary pressure monitoring should be studied as an adjunct to improve outcomes in pediatric acute respiratory distress syndrome.


A clinical review of statins and cancer: helpful or harmful?
The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the second most prescribed therapeutic drug class in the United States after analgesics. Although these agents are used predominantly to reduce cholesterol concentrations in patients with hyperlipidemia, numerous studies have investigated the pleiotropic effects of statins and their potential in the prevention and/or treatment of other disease states, including cancer. Many theories have been proposed as to how statins may affect the risk or development of malignancies, prompting a clinical review of the literature. Studies have revealed statins to be associated with both increased and decreased cancer risk. Most of the published studies have been observational and retrospective in nature, and most prospective trials evaluated cancer as a secondary end point or adverse event, making it difficult to determine causality. Although most of the available evidence suggests a possible beneficial effect of statins on cancer, further study is needed with better designed trials and/or increased efforts in evaluating cancer as secondary end points in all statin trials until definite conclusions regarding statin effects on cancer risk and occurrence can be made.


Metabolic stress in isolated mouse ventricular myocytes leads to remodeling of t tubules.
Cardiac ventricular myocytes possess an extensive t-tubular system that facilitates the propagation of membrane potential across the cell body. It is well established that ionic currents at the restricted t-tubular space may lead to significant changes in ion concentrations, which, in turn, may affect t-tubular membrane potential. In this study, we used the whole cell patch-clamp technique to study accumulation and depletion of t-tubular potassium by measuring inward rectifier potassium tail currents (I(K1,tail)), and inward rectifier potassium current (I(K1)) "inactivation". At room temperatures and in the absence of Mg(2+) ions in pipette solution, the amplitude of I(K1,tail) measured ~10 min after the establishment of whole cell configuration was reduced by ~18%, but declined nearly twofold in the presence of 1 mM cyanide. At ~35°C I(K1,tail) was essentially preserved in intact cells, but its amplitude declined by ~85% within 5 min of cell dialysis, even in the absence of cyanide. Intracellular Mg(2+) ions played protective role at all temperatures. Decline of I(K1,tail) was accompanied by characteristic changes in its kinetics, as well as by changes in the kinetics of I(K1) inactivation, a marker of depletion of t-tubular K(+). The data point to remodeling of t tubules as the primary reason for the observed effects. Consistent with this, detubulation of myocytes using formamide-induced osmotic stress significantly reduced I(K1,tail), as well as the inactivation of inward I(K1). Overall, the data provide strong evidence that changes in t tubule volume/structure may occur on a short time scale in response to various types of stress.


Molecular and cytogenetic analysis of the telomeric (TTAGGG)n repetitive sequences in the Nile tilapia, Oreochromis niloticus (Teleostei: Cichlidae).
The majority of chromosomes in Oreochromis niloticus, as with most fish karyotyped to date, cannot be individually identified owing to their small size. As a first step in establishing a physical map for this important aquaculture species of tilapia we have analyzed the location of the vertebrate telomeric repeat sequence, (TTAGGG)n, in O. niloticus. Southern blot hybridization analysis and a Bal31 sensitivity assay confirm that the vertebrate telomeric repeat is indeed present at O. niloticus chromosomal ends with repeat tracts extending for 4-10 kb on chromosomal ends in erythrocytes. Fluorescent in situ hybridization revealed that (TTAGGG)n is found not only at telomeres, but also at two interstitial loci on chromosome 1. These data support the hypothesis that chromosome 1, which is significantly larger than all the other chromosomes in the karyotype, was produced by the fusion of three chromosomes and explain the overall reduction of chromosomal number from the ancestral teleost karyotype of 2n=48 to 2n=44 observed in tilapia.


Low-Level Laser Therapy Effects on Rat Blood Hemostasis Via Significant Alteration in Fibrinogen and Plasminogen Expression Level.
Introduction: There are many documents about the significant role of low-level laser therapy (LLLT) in different processes such as regenerator medicine and bone formation. The aim of this study is to assess the role of LLLT in blood hemostasis in rats via bioinformatic investigation. Methods: The differentially expressed plasma proteins of treated rats via LLLT from the literature and the added 50 first neighbors were investigated via network analysis to find the critical dysregulated proteins and biological processes by using Cytoscape software, the STRING database, and ClueGO. Results: A scale-free network including 55 nodes was constructed from queried and added first neighbor proteins. Fibrinogen gamma, fibrinogen alpha, and plasminogen were highlighted as the central genes of the analyzed network. Fibrinolysis was determined as the main group of biological processes that were affected by LLLT. Conclusion: Findings indicate that LLLT affects blood hemostasis which is an important point in approving the therapeutic application of LLLT and also in preventing its possible complication.


LQTS gene LOVD database.
The Long QT Syndrome (LQTS) is a group of genetically heterogeneous disorders that predisposes young individuals to ventricular arrhythmias and sudden death. LQTS is mainly caused by mutations in genes encoding subunits of cardiac ion channels (KCNQ1, KCNH2,SCN5A, KCNE1, and KCNE2). Many other genes involved in LQTS have been described recently(KCNJ2, AKAP9, ANK2, CACNA1C, SCNA4B, SNTA1, and CAV3). We created an online database(http://www.genomed.org/LOVD/introduction.html) that provides information on variants in LQTS-associated genes. As of February 2010, the database contains 1738 unique variants in 12 genes. A total of 950 variants are considered pathogenic, 265 are possible pathogenic, 131 are unknown/unclassified, and 292 have no known pathogenicity. In addition to these mutations collected from published literature, we also submitted information on gene variants, including one possible novel pathogenic mutation in the KCNH2 splice site found in ten Chinese families with documented arrhythmias. The remote user is able to search the data and is encouraged to submit new mutations into the database. The LQTS database will become a powerful tool for both researchers and clinicians.


[The structure of urological disorders in athletes].
According to the data of preventive medical examinations since the end of 2009 to April 2012, data on the urological incidence in 654 athletes surveyed during this period were collected and analyzed. Among the diseases identified in athletes, the main place is occupied by varicocele (5.35%), urethritis (5.04%), urolithiasis without clinical manifestation of acute inflammation (1.37%).


Classification images for detection, contrast discrimination, and identification tasks with a common ideal observer.
We consider three simple forced-choice visual tasks--detection, contrast discrimination, and identification--in Gaussian white noise. The three tasks are designed so that the difference signal in all three cases is the same difference-of-Gaussians (DOG) profile. The distribution of the image noise implies that the ideal observer uses the same DOG filter to perform all three tasks. But do human observers also use the same visual strategy to perform these tasks? We use classification image analysis to evaluate the visual strategies of human observers. We find significantly different subject classification images across the three tasks. The domain of greatest variability appears to be low spatial frequencies [<5 cycles per degree (cpd)]. In this range, we find frequency enhancement in the detection task, and frequency suppression and reversal in the contrast discrimination task. In the identification task, subject classification images agree reasonably well with the ideal observer filter. We evaluate the effect of nonlinear transducers and intrinsic spatial uncertainty to explain divergence from the ideal observer found in detection and contrast discrimination tasks.


Eclampsia in rural Nigeria: The unmitigating catastrophe.
Eclampsia is one of the most dreaded causes of adverse outcomes of pregnancy worldwide. It is one of the greatest causes of maternal and perinatal morbidity and mortality world over. We do not know the prevalence, management outcome, and the devastation caused by this dreaded disease in our center hence the need for this work. This is a 7-year retrospective review of all cases of eclampsia managed in Mater Misericordiae Hospital Afikpo, a rural secondary cum referral Catholic Mission Hospital in Afikpo, Ebonyi State in Southeastern Nigeria. The prevalence of eclampsia in our center is 1.12% or one case of eclampsia for every 89 women that delivered in our facility. The majority of the women that had eclampsia in our center 56 (71.8%) were primigravidae. Seventeen women (21.8%) had various antenatal complications with 4 or 23.6% presenting with intrauterine fetal deaths and two (11.8%) each with intrauterine growth restriction, and domestic violence, respectively. Thirty-five or 44.9% of the women were delivered by emergency lower segment cesarean section. Fifteen or 17.9% babies were dead giving a perinatal mortality rate of 174 per 1,000After delivery, and 3 (3.8%) of the women had postpartum hemorrhage. Two women (2.6%) died giving a maternal mortality ratio of 2564 per 100,000 deliveries. Eclampsia is a dreaded obstetric disease with adverse fetal and maternal consequences that are not mitigating, and no effort should be spared in managing it effectively including public enlightenment.


Oligofructose alone and in combination with 2'fucosyllactose induces physiologically relevant changes in γ-aminobutyric acid and organic acid production compared to sole 2'fucosyllactose supplementation: an in vitro study.
We explored the potential for the prebiotic oligofructose and prebiotic candidate 2'fucosyllactose, alone and in combination (50:50 blend) to induce physiologically relevant increases in neurotransmitter (γ-aminobutyric acid, serotonin, tryptophan, and dopamine) and organic acid (acetate, propionate, butyrate, lactate, and succinate) production as well as microbiome changes using anaerobic pH-controlled in vitro batch culture fermentations over 48 h. Changes in organic acid and neurotransmitter production were assessed by gas chromatography and liquid chromatography and, bacterial enumeration using fluorescence in situ hybridization, respectively. Both oligofructose and oligofructose/2'fucosyllactose combination fermentations induced physiologically relevant concentrations of γ-aminobutyric acid, acetate, propionate, butyrate, and succinate at completion (all P ≤ .05). A high degree of heterogeneity was seen amongst donors in both neurotransmitter and organic acid production in sole 2'FL fermentations suggesting a large responder/nonresponder status exists. Large increases in Bifidobacterium, Lactobacillus, and Bacteroides numbers were detected in oligofructose fermentation, smallest increases being detected in 2'fucosyllactose fermentation. Bacterial numbers in the combined oligofructose/2'fucosyllactose fermentation were closer to that of sole oligofructose. Our results indicate that oligofructose and oligofructose/2'fucosyllactose in combination have the potential to induce physiologically relevant increases in γ-aminobutyric and organic acid production along with offsetting the heterogenicity seen in response to sole 2'fucosyllactose supplementation.


Pathologic findings in larval and juvenile anurans inhabiting farm ponds in Tennessee, USA.
Amphibian populations are declining globally, yet general pathologic surveys for free-ranging amphibians are uncommon. Pathologic surveys are necessary to provide insight into the impacts of humans on emergence of pathogens in amphibian populations. During 2005, 104 American bullfrog (Rana catesbeiana) and 80 green frog (Rana clamitans) larvae and 40 green frog juveniles were collected from farm ponds in Tennessee, and complete necropsies were performed. Diagnostic testing included bacterial culture, virus testing, fecal parasite analysis, and histologic examination. Gross and histologic examination revealed that all individuals, except one bullfrog tadpole, could be classified as clinically normal. The clinically abnormal tadpole had swollen erythemic legs, and was positive for Aeromonas hydrophila but negative for Ranavirus. Parasites were common (43%) among specimens, with myxosporidium and trematodes most often noted. Commensal and opportunistic microorganisms were cultured from the tissues. Ranavirus was detected in 29% of individuals but generally not associated with significant histopathologic changes. Myxosporidia and Ranavirus coinfections occurred in 7 and 26% of green and bullfrog tadpoles, respectively, with the highest coinfection rate (83%) in bullfrog tadpoles during winter. Protozoans were most common in fecal examination. These data can serve as a baseline to evaluate the presence of clinical disease in larval and juvenile amphibians.


Automated area calculation of histopathologic features using SIVQ.
Recently, with the advent of the 7th edition of the AJCC Cancer Staging manual, at least one set of criteria (e.g. breast) were modified to now require the measurement of maximal depth of stromal invasion. With the current manual interpretive morphological approaches typically employed by surgical pathologists to assess tumor extent, the specialty now potentially has stumbled upon a crossroads of practice, where the diagnostic criteria have exceeded the capabilities of our commonly available tools. While whole slide imaging (WSI) technology holds the potential to offer many improvements in clinical workflow over conventional slide microscopy including unambiguous utility for facilitating quantitative diagnostic tasks with one important example being the determination of both linear dimension and surface area. However, the availability of histology data in digital form is of little utility if time-consuming and cumbersome manual workflow steps are necessarily imposed upon the pathologist in order to generate such measurements, especially as encountered with the complex and ill-defined shapes inherent to infiltrative tumors. In this communication, we demonstrate the utility of the recently described SIVQ algorithm to serve as the basis of a highly accurate, precise and semi-automated tool for direct surface area measurement of tumor infiltration from WSI data sets. By anticipating the current trend in cancer staging that emphasizes increasingly precise feature characterization, as witnessed by the recent publication of AJCC's 7th edition of the Cancer Staging Manual, this tool holds promise to will be of value to pathologists for clinical utility.


[Mechanism of DERL3 Affecting the Proliferation, Invasion and Metastasis of Lung Adenocarcinoma A549 Cells].
Derlin 3 (DERL3) is downregulated in colorectal cancer (CRC) samples. Its level is closely linked to lymphatic metastasis or distant metastasis rate in CRC patients. However, its biological behavior in lung adenocarcinoma were rarely reported. The aim of this study is to investigate the ectopic expression of DERL3 in lung adenocarcinoma tissues and its effect on the invasion and metastasis of lung adenocarcinoma A549 cell line to reveal the possible mechanism of invasion and metastasis of lung adenocarcinoma. Lung adenocarcinoma microarray gene chip data included 3 cases of lymph node metastasis and 3 cases of lung adenocarcinoma tissue without lymph node metastasis. The GEDS and Kaplan-Meier plot queries the survival curve and expression level of DERL3. Western blot was used to detect the expression of DERL3 in lung adenocarcinoma cells. The efficiency of knockdown DERL3 gene was detected by Western blot assay. Transwell detected the number of cells passing through the basement membrane of the transwell. EDU assay detected cell proliferation ability. Western blot detected the expression of epithelial-mesenchymal transition related proteins E-cadherin and Vimentin. The microarray gene chip results showed that compared with lung adenocarcinoma tissues without lymph node metastasis, 1,314 mRNAs in lung adenocarcinoma tissues with lymph node metastasis were up-regulated, 400 mRNAs were down (P<0.05). The expression of DERL3 increased in lung adenocarcinoma (P<0.05). The results of survival curve showed that the lung cancer patients with high expression of DERL3 with poor prognosis (P<0.05). Western blot results indicated that plasmid transfection was successful. Knockdown of DERL3 suppressed the ability of proliferation, invasion and migration in A549 cells (P<0.05). After knockdown of DERL3, the expression level of Vimentin was decreased, while E-cadherin expression increased (P<0.05). Knockdown of DERL3 inhibited the proliferation, invasion and metastasis of A549 cells.


Hospitalization costs for acute ischemic stroke patients treated with intravenous thrombolysis in the United States are substantially higher than medicare payments.
It is important to know the costs for hospitalization for ischemic stroke patients treated with intravenous thrombolysis so that comparisons can be made with payments to hospitals. Using the National Inpatient Sample, we evaluated hospitalization costs for patients treated with intravenous thrombolysis for acute ischemic stroke in the United States from 2001 to 2008. Cost data were correlated with demographics and clinical outcome. Intravenous thrombolysis for acute ischemic stroke was received by 63 472 patients; 24 094 patients were younger than age 65 years and 40 780 patients were 65 years or older. Median hospital costs in 2008 dollars were $14 102 (interquartile range, $9987-$20 819) for patients with good outcome, $18 856 (interquartile range, $13 145-$30 423) for patients with severe disability, and $19 129 (interquartile range, $11 966-$30 781) for patients with in-hospital mortality. Average 2008 Medicare payments were $10 098 for intravenous thrombolysis without complication and $13 835 for intravenous thrombolysis with major complication. Hospitalization costs for patients treated with intravenous thrombolysis are substantially higher than Medicare payments.


Enhancement in the Charge-Transfer Kinetics of Pseudocapacitive Iridium-Doped Layered Manganese Oxide.
Birnessite manganese oxide is a promising candidate as an electrode material for aqueous supercapacitors owing to its pseudocapacitance associated with fast redox processes. While manganese oxides are semiconductive, the conductivity is much lower than that of typical materials used for capacitive electrodes such as activated carbon or ruthenium oxide. In an attempt to increase the electronic conductivity of birnessite, a new solid solution phase, Ky(Mn1-xIrx)O2, was synthesized, and the electrochemical charge storage capability of Ir-doped birnessite was studied in aqueous Li2SO4. Structural characterization revealed that the single-phase Ky(Mn1-xIrx)O2 could be synthesized up to x = 0.1. An increase in the pseudocapacitive charge was observed with the increase in Ir content. In addition to the increase in the pseudocapacitive charge, an unusual change in the peak potential was observed. The peak-to-peak difference for the Mn4+/Mn3+ redox decreased with increasing Ir content, indicating an increase in the reversibility of the pseudocapacitive process. The decrease in peak-to-peak difference was observed only by Ir substitution and was not observed for physical mixtures of K0.28MnO2 and IrO2, suggesting a strong electronic interaction between the host Mn ion and the substituting Ir ion.


Expression of nestin in dermatofibrosarcoma protuberans in comparison to dermatofibroma.
Making a differential diagnosis to distinguish dermatofibrosarcoma protuberans (DFSP) from dermatofibroma (DF) is occasionally difficult. In those instances, CD34 and factor XIIIa have been used as valuable differential markers. The histogenesis of DFSP, however, remains uncertain and controversial, although it is generally thought to be a neuromesenchymal neoplasm. Nestin is an intermediate filament protein that was first observed in neuroectodermal stem cells. We investigated the expression of nestin in order to distinguish between DFSP and DF in combination with the use of conventional markers, CD34 and factor XIIIa. The nestin expression was investigated in tissue specimens from 16 DFSP cases and 30 DF cases. The expression of other differential markers such as CD34, factor XIIIa, CD163 and CD10 was also observed in these samples. Fifteen (94%) of 16 cases of DFSP showed the expression of nestin, whereas only four (13%) of 30 cases of DF showed the expression of nestin. Most of the DFSP cases showed a diffuse positive reaction in more than half of the tumor cells. In contrast, DF cases with nestin expression showed a partial positive reaction. Nestin is considered to be a useful and additional marker in combination with CD34, factor XIIIa and CD163 in order to distinguish between DFSP and DF. The frequent expression of nestin in DFSP may therefore indicate that DFSP is derived from putative, multipotent neuromesenchymal cells.


Comparison of electromagnetic and hadronic models generated using Geant 4 with antiproton dose measured in CERN.
After proposing the idea of antiproton cancer treatment in 1984 many experiments were launched to investigate different aspects of physical and radiobiological properties of antiproton, which came from its annihilation reactions. One of these experiments has been done at the European Organization for Nuclear Research known as CERN using the antiproton decelerator. The ultimate goal of this experiment was to assess the dosimetric and radiobiological properties of beams of antiprotons in order to estimate the suitability of antiprotons for radiotherapy. One difficulty on this way was the unavailability of antiproton beam in CERN for a long time, so the verification of Monte Carlo codes to simulate antiproton depth dose could be useful. Among available simulation codes, Geant4 provides acceptable flexibility and extensibility, which progressively lead to the development of novel Geant4 applications in research domains, especially modeling the biological effects of ionizing radiation at the sub-cellular scale. In this study, the depth dose corresponding to CERN antiproton beam energy by Geant4 recruiting all the standard physics lists currently available and benchmarked for other use cases were calculated. Overall, none of the standard physics lists was able to draw the antiproton percentage depth dose. Although, with some models our results were promising, the Bragg peak level remained as the point of concern for our study. It is concluded that the Bertini model with high precision neutron tracking (QGSP_BERT_HP) is the best to match the experimental data though it is also the slowest model to simulate events among the physics lists.


Mechanisms of 2-butoxyethanol-induced hemangiosarcomas.
Chronic exposure to 2-butoxyethanol increased liver hemangiosarcomas in male mice. The mechanism for the selective induction of hemangiosarcomas by 2-butoxyethanol is unknown but has been suggested to occur through non-DNA-reactive mechanisms. The occurrence of liver hemangiosarcomas in male mice has been linked to oxidative damage subsequent to RBC hemolysis and iron deposition and activation of macrophages (Kupffer cells) in the liver, events that exhibit a threshold in both animals and humans. 2-Butoxyethanol is metabolized to 2-butoxyacetaldehyde and 2-butoxyacetic acid, and although the aldehyde metabolite is short lived, the potential exists for this metabolite to cause DNA damage. The present study examined whether 2-butoxyethanol and its metabolites, 2-butoxyacetaldehyde and 2-butoxyacetic acid, damaged mouse endothelial cell DNA using the comet assay. No increase in DNA damage was observed following 2-butoxyethanol (1-10mM), 2-butoxyacetaldehyde (0.1-1.0mM), or 2-butoxyacetic acid (1-10mM) in endothelial cells after 2, 4, or 24 h of exposure. Additional studies examined the involvement of hemolysis and macrophage activation in 2-butoxyethanol carcinogenesis. DNA damage was produced by hemolyzed RBCs (10 x 10(6), 4 h), ferrous sulfate (0.1-1.0 microM; 2-24 h), and hydrogen peroxide (50-100 microM; 1-4 h) in endothelial cells. Hemolyzed RBCs also activated macrophages, as evidenced by increased tumor necrosis factor (TNF) alpha, while neither 2-butoxyethanol nor butoxyacetic acid increased TNF-alpha from macrophages. The effect of activated macrophages on endothelial cell DNA damage and DNA synthesis was also studied. Coculture of endothelial cells with activated macrophages increased endothelial cell DNA damage after 4 or 24 h and increased endothelial cell DNA synthesis after 24 h. These data demonstrate that 2-butoxyethanol and related metabolites do not directly cause DNA damage. Supportive evidence also demonstrated that damaged RBCs, iron, and/or products from macrophage activation (possibly reactive oxygen species) produce DNA damage in endothelial cells and that activated macrophages stimulate endothelial cell proliferation. These events coupled together provide the events necessary for the induction of hemangiosarcomas by 2-butoxyethanol.


Functional anatomy of the equine temporomandibular joint: Collagen fiber texture of the articular surfaces.
In the last decade, the equine masticatory apparatus has received much attention. Numerous studies have emphasized the importance of the temporomandibular joint (TMJ) in the functional process of mastication. However, ultrastructural and histological data providing a basis for biomechanical and histopathological considerations are not available. The aim of the present study was to analyze the architecture of the collagen fiber apparatus in the articular surfaces of the equine TMJ to reveal typical morphological features indicating biomechanical adaptions. Therefore, the collagen fiber alignment was visualized using the split-line technique in 16 adult warmblood horses without any history of TMJ disorders. Within the central two-thirds of the articular surfaces of the articular tubercle, the articular disc and the mandibular head, split-lines ran in a correspondent rostrocaudal direction. In the lateral and medial aspects of these articular surfaces, the split-line pattern varied, displaying curved arrangements in the articular disc and punctual split-lines in the bony components. Mediolateral orientated split-lines were found in the rostral and caudal border of the articular disc and in the mandibular fossa. The complex movements during the equine chewing cycle are likely assigned to different areas of the TMJ. The split-line pattern of the equine TMJ is indicative of a relative movement of the joint components in a preferential rostrocaudal direction which is consigned to the central aspects of the TMJ. The lateral and medial aspects of the articular surfaces provide split-line patterns that indicate movements particularly around a dorsoventral axis.


A Fast and Robust Poisson-Boltzmann Solver Based on Adaptive Cartesian Grids.
An adaptive Cartesian grid (ACG) concept is presented for the fast and robust numerical solution of the 3D Poisson-Boltzmann Equation (PBE) governing the electrostatic interactions of large-scale biomolecules and highly charged multi-biomolecular assemblies such as ribosomes and viruses. The ACG offers numerous advantages over competing grid topologies such as regular 3D lattices and unstructured grids. For very large biological molecules and multi-biomolecule assemblies, the total number of grid-points is several orders of magnitude less than that required in a conventional lattice grid used in the current PBE solvers thus allowing the end user to obtain accurate and stable nonlinear PBE solutions on a desktop computer. Compared to tetrahedral-based unstructured grids, ACG offers a simpler hierarchical grid structure, which is naturally suited to multigrid, relieves indirect addressing requirements and uses fewer neighboring nodes in the finite difference stencils. Construction of the ACG and determination of the dielectric/ionic maps are straightforward, fast and require minimal user intervention. Charge singularities are eliminated by reformulating the problem to produce the reaction field potential in the molecular interior and the total electrostatic potential in the exterior ionic solvent region. This approach minimizes grid-dependency and alleviates the need for fine grid spacing near atomic charge sites. The technical portion of this paper contains three parts. First, the ACG and its construction for general biomolecular geometries are described. Next, a discrete approximation to the PBE upon this mesh is derived. Finally, the overall solution procedure and multigrid implementation are summarized. Results obtained with the ACG-based PBE solver are presented for: (i) a low dielectric spherical cavity, containing interior point charges, embedded in a high dielectric ionic solvent - analytical solutions are available for this case, thus allowing rigorous assessment of the solution accuracy; (ii) a pair of low dielectric charged spheres embedded in a ionic solvent to compute electrostatic interaction free energies as a function of the distance between sphere centers; (iii) surface potentials of proteins, nucleic acids and their larger-scale assemblies such as ribosomes; and (iv) electrostatic solvation free energies and their salt sensitivities - obtained with both linear and nonlinear Poisson-Boltzmann equation - for a large set of proteins. These latter results along with timings can serve as benchmarks for comparing the performance of different PBE solvers.


Pulmonary hemorrhage, a rare complication in a girl with Henoch-Schönlein purpura
Henoch-Schonlein purpura (HSP) is the most common vasculitis in children. Vasculitic processes can involve the lung. Although diffuse alveolar hemorrhage may be seen as one of the manifestation of HSP, it is not a frequent presentation. Here we reported the case of a 10-year-old girl with HSP nephritis who developed pulmonary hemorrhage. The patient was treated successfully with intravenous methylprednisolone. A review of the literature revealed that young age may be a good prognostic sign and that immunosuppressive drugs and supportive management are essential in the treatment.


Angiotensin-converting enzyme inhibition enhances a subthreshold stimulus to elicit delayed preconditioning in pig myocardium.
We assessed the effect of angiotensin-converting enzyme (ACE) inhibition in combination with a subthreshold preconditioning (PC) stimulus to elicit delayed preconditioning against infarction in pig myocardium. Bradykinin triggers early PC. Angiotensin-converting enzyme inhibitors increase local bradykinin levels via inhibition of kinin breakdown and have been shown in experimental studies to augment early protection afforded by PC. A role for bradykinin in eliciting delayed PC has not so far been identified. We used a two-day protocol. On day 1 (closed chest), pigs were either sham-operated (group 1) or preconditioned, using balloon catheter inflation of the left anterior descending (LAD) coronary artery, with either a full (4 x 5 min PC, group 2) or subthreshold PC stimulus (2 x 2 min PC, group 3). Additional groups were pre-treated with perindoprilat (0.06 mg/kg i.v.) before sham (group 4) or subthreshold PC (group 5). On day 2 (open chest), all pigs were subjected to 40 min occlusion of the LAD followed by 3 h of reperfusion. Infarct size was determined by tetrazolium staining. Group 1 had a mean infarct size of 42.8+/-3.2% of the risk zone. Preconditioning with 4 x 5 min reduced the infarct size to 19.5+/-3.9% (p < 0.05). Groups 3 and 4 had infarct sizes not statistically different from group 1. However, combining perindoprilat with subthreshold PC resulted in a significant limitation of the infarction (18.4+/-3.1% p < 0.05), comparable with group 2. This is the first study to show that ACE inhibition can augment a mild ischemic stimulus to induce a protected state 24 h later.


Temporal cues to onset voicing contrasts in Australian English-speaking children.
Voicing contrasts are lexically important for differentiating words in many languages (e.g., "bear" vs "pear"). Temporal differences in the voice onset time (VOT) and closure duration (CD) contribute to the voicing contrast in word-onset position. However, little is known about the acoustic realization of these voicing contrasts in Australian English-speaking children. This is essential for understanding the challenges faced by those with language delay. Therefore, the present study examined the VOT and CD values for word-initial stops as produced by 20 Australian English-speaking 4-5-year-olds. As anticipated, these children produced a systematic distinction between voiced and voiceless stops at all places of articulation (PoAs). However, although the children's VOT values for voiced stops were similar to those of adults, their VOTs for voiceless stops were longer. Like adults, the children also had different CD values for voiced and voiceless categories; however, these were systematically longer than those of adults. Even after adjusting for temporal differences by computing proportional ratios for the VOT and CD, children's voicing contrasts were not yet adultlike. These results suggest that children of this age are still developing appropriate timing and articulatory adjustments for voicing contrasts in the word-initial position.


Science and schooling for students with LD: a discussion of the symposium.
In this summative discussion, we respond to Crockett's proposals about supporting science in the schoolhouse, and we summarize and reflect on the perspectives of the commentators. Overall, they identify discussion points in issues of science in schooling, implementation of scientific practices, teacher training and professional development, and issues in educational administration and leadership. We agree with Crockett and the commentators that intensive efforts in all these areas must be made to strengthen the role of science in the schoolhouse.


Work and leisure: transcending the dichotomy.
The contribution of a balance of work and leisure to health and a sense of well-being is a common sense assumption in everyday knowledge as well as in occupational therapy. The impact of the organization and balance of occupations in daily life on health, adaptation, life satisfaction, and a sense of well-being are central issues in occupational science. One of occupational science's potential contributions to society is the ability to provide understanding and insights that transcend common sense assumptions and everyday knowledge about occupations. This article will address, through a review of the literature, some of the limitations inherent in beliefs about a healthy balance of work and leisure. It will demonstrate how distinctions between work and leisure are culturally bound and perpetuate the assumption that they are dichotomous experiences. This dichotomy is shown to be a false one and must be transcended in order to explore the question of what is a healthy balance within daily life. This article concludes with considerations for occupational therapy research and practice that may arise from transcendence of the dichotomy of work and leisure.


Torsion of Collision Tumor: Dermoid Cyst and Fibrothecoma with Postmenopausal Bleeding.
The term collision tumor refers to the coexistence of two adjacent but histological distinct tumors with no histological admixture at the interface. Collision tumors involving ovaries are extremely rare. A collision tumor composed of a dermoid cyst and fibrothecoma is extremely rare in menopausal women. The mechanism of the development of collision tumor is uncertain. During clinical evaluation, differentiation of characters of these ovarian tumors is important to decide appropriate treatment strategies and for good prognosis. We report an unusual clinical manifestation of the torsion of a dermoid cyst and fibrothecoma in the right ovary with postmenopausal bleeding.


Neuroprotective Effect of Maternal Resveratrol Supplementation in a Rat Model of Neonatal Hypoxia-Ischemia.
Neonatal hypoxia-ischemia (nHI) is a major cause of death or subsequent disabilities in infants. Hypoxia-ischemia causes brain lesions, which are induced by a strong reduction in oxygen and nutrient supply. Hypothermia is the only validated beneficial intervention, but not all newborns respond to it and today no pharmacological treatment exists. Among possible therapeutic agents to test, trans-resveratrol is an interesting candidate as it has been reported to exhibit neuroprotective effects in some neurodegenerative diseases. This experimental study aimed to investigate a possible neuroprotection by resveratrol in rat nHI, when administered to the pregnant rat female, at a nutritional dose. Several groups of pregnant female rats were studied in which resveratrol was added to drinking water either during the last week of pregnancy, the first week of lactation, or both. Then, 7-day old pups underwent a hypoxic-ischemic event. Pups were followed longitudinally, using both MRI and behavioral testing. Finally, a last group was studied in which breastfeeding females were supplemented 1 week with resveratrol just after the hypoxic-ischemic event of the pups (to test the curative rather than the preventive effect). To decipher the molecular mechanisms of this neuroprotection, RT-qPCR and Western blots were also performed on pup brain samples. Data clearly indicated that when pregnant and/or breastfeeding females were supplemented with resveratrol, hypoxic-ischemic offspring brain lesions were significantly reduced. Moreover, maternal resveratrol supplementation allowed to reverse sensorimotor and cognitive deficits caused by the insult. The best recoveries were observed when resveratrol was administered during both gestation and lactation (2 weeks before the hypoxic-ischemic event in pups). Furthermore, neuroprotection was also observed in the curative group, but only at the latest stages examined. Our hypothesis is that resveratrol, in addition to the well-known neuroprotective benefits via the sirtuin's pathway (antioxidant properties, inhibition of apoptosis), has an impact on brain metabolism, and more specifically on the astrocyte-neuron lactate shuttle (ANLS) as suggested by RT-qPCR and Western blot data, that contributes to the neuroprotective effects.


The effect of poliovirus proteinase 2Apro expression on cellular metabolism. Inhibition of DNA replication, RNA polymerase II transcription, and translation.
Infection of cells with poliovirus results in a rapid inhibition of host RNA and protein synthesis. Concordant with this shutoff, the p220 subunit of the cap-binding protein complex is cleaved, probably indirectly, by the poliovirus proteinase p2A (2Apro). To elucidate the mechanism of action of 2Apro in inhibiting protein synthesis in vivo, we studied the effect of transient expression of 2Apro in COS-1 monkey kidney cells. In cells transfected with a 2Apro expression plasmid, p220 was cleaved and the 2Apro mRNA was reduced 30-fold compared to an identical plasmid containing a translation termination codon within the 2Apro coding region. The reduced expression from the 2Apro vector results from a 4-fold reduction in DNA replication and 22-fold reduction in transcription by RNA polymerase II from the adenovirus major late promoter/SV40 enhancer utilized in this vector. In contrast, no decrease in transcription of the adenovirus virus-associated I RNA gene by RNA polymerase III was observed. The effect of 2Apro expression on cap-dependent mRNA translation was studied by producing a dicistronic beta-globin mRNA harboring the encephalomyocarditis virus leader and 2Apro coding region within the 3' end of the mRNA to mediate cap-independent translation of 2Apro. Expression of this mRNA was also reduced 25-fold compared to an identical plasmid harboring a termination codon within the 2Apro coding region. Translation of the beta-globin marker gene from this mRNA was reduced 3-fold when corrected for mRNA level. These results suggest that p220 cleavage itself is not sufficient for complete inhibition of host translation and that an important effect of 2Apro expression on host protein synthesis is a reduction in RNA polymerase II transcription and to a lesser extent, DNA replication. This reduction could be a primary effect of 2Apro, or a secondary effect caused by the inhibition of translation.


Solution structure of phosphorylase kinase studied using small-angle X-ray and neutron scattering.
Small-angle X-ray and neutron scattering have been used to characterize the solution structure of rabbit skeletal phosphorylase kinase. The radius of gyration of the unactivated holoenzyme determined from neutron scattering is 94 A, and its maximum dimension is approximately 275-295 A. A planar model has been constructed that is in general agreement with the dimensions of the transmission electron microscope images of negatively stained phosphorylase kinase and that gives values for the radius of gyration, maximum linear dimension, and a pair distribution function for the structure that are consistent with the scattering data.


[Study on morphology, quality and germination characteristics of Acanthopanax trifoliatus seeds under different habitats].
To preliminary explore the difference of the morphological, quality and germinal characteristics of Acanthopanax trifoliatus seeds under different habitats. Collect the wild seeds from different habitats in West Mountain, and then observe their external appearances and internal structure, and test the thousand seeds weight,water content and seed vigor. What's more, the influence to germination rates of the seeds from different temperatures and light intensities in artificial bioclimatic chamber was studied. Orthogonal test in experimental plots was carried out to screen the different sowing dates, matrix types and soil depths which may influence germination rate. The external appearances and quality characteristics of wild seeds from three habitats were different. Seeds could germinate in the both light and dark, the germination rate of the habitat II was as high as 70.5% at the optimum temperature 20 degrees C in artificial bioclimatic chamber. The optimal combination A1, B1, C1 was screened out through orthogonal test, namely, the germination rate would be the highest when the seeds sowed in autumn covering with 2 cm depth of matrix type which component of the ratio of soil, sand and organic fertilizer was 6: 3: 1. There was significant difference in the morphology and germination rate of the three habitats seeds. The habitat II seeds were the optimal choice when culture seedling. The influences of different temperatures on germination rate were different, and the dried seeds should sow in current autumn, better than the next spring.


Intravenous anti-D immunoglobulin in the management of immune thrombocytopenic purpura.
Approximately 70% to 80% of Rh-positive adults and children with acute or chronic immune thrombocytopenic purpura or HIV-related thrombocytopenia respond to infusions of anti-D immunoglobulin. The speed of onset of response is slower than that seen with intravenous immunoglobulin. Anti-D immunoglobulin is well tolerated, with occasional adverse reactions similar to those seen in treatment with polyclonal intravenous immunoglobulin, but anemia requiring blood transfusion can occur. Response is generally better in younger patients and those who have responded to other forms of treatment. Inhibition of Fc receptor-mediated platelet destruction by anti-D immunoglobulin-opsonized erythrocytes is the most likely mechanism of action, although the relative ineffectiveness of a monoclonal anti-D immunoglobulin preparation in treatment of immune thrombocytopenic purpura suggests that other mechanisms may exist. Hepatitis C has been transmitted by intravenous anti-D immunoglobulin preparations when used in the prevention of Rh immunization, prior to the introduction of screening donor plasma for hepatitis C virus antibodies. However, an intravenous solvent-detergent-treated preparation is now available.


ROLE OF ENDOGENOUS AND EXOGENOUS LIGANDS FOR THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR alpha IN THE DEVELOPMENT OF BLEOMYCIN-INDUCED LUNG INJURY.
The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. The aim of the present study was to examine the effects of endogenous and exogenous the PPAR-alpha ligand on the development of lung injury caused by bleomycin administration. Lung injury was induced in PPAR-alpha wild-type (WT) mice and PPAR-alpha knockout (KO) mice by intratracheal administration of bleomycin. An increase of immunoreactivity to poly-ADP-ribose, TNF-alpha, and IL-1 beta, as well as a significant loss of body weight and mortality was observed in the lung of bleomycin-treated PPAR-alpha WT mice. The absence of a functional PPAR-alpha gene in PPAR-alpha KO mice resulted in a significant augmentation of all the above-described parameters. On the contrary, the treatment of PPAR-alpha WT with WY-14643 (1 mg/kg daily) significantly reduced the degree of lung injury, the rise in myeloperoxidase activity, and the increase in staining (immunohistochemistry) for poly-ADP-ribose, TNF-alpha, and IL-1 beta caused by bleomycin administration. Thus, endogenous and exogenous PPAR-alpha ligands reduce the degree of lung injury induced by bleomycin in the mice. Therefore, we propose that the PPAR-alpha ligand may be useful in the treatment of lung injury.


Management of obstructive colon cancer: Current status, obstacles, and future directions.
Approximately 10%-18% of patients with colon cancer present with obstruction at the initial diagnosis. Despite active screening efforts, the incidence of obstructive colon cancer remains stable. Traditionally, emergency surgery has been indicated to treat patients with obstructive colon cancer. However, compared to patients undergoing elective surgery, the morbidity and mortality rates of patients requiring emergency surgery for obstructive colon cancer are high. With the advancement of colonoscopic techniques and equipment, a self-expandable metal stent (SEMS) was introduced to relieve obstructive symptoms, allowing the patient's general condition to be restored and for them undergo elective surgery. As the use of SEMS placement is growing, controversies about its application in potentially curable diseases have been raised. In this review, the short- and long-term outcomes of different treatment strategies, particularly emergency surgery vs SEMS placement followed by elective surgery in resectable, locally advanced obstructive colon cancer, are described based on the location of the obstructive cancer lesion. Controversies regarding each treatment strategy are discussed. To overcome current obstacles, a potential diagnostic method using circulating tumor DNA and further research directions incorporating neoadjuvant chemotherapy are introduced.


Magnetic Resonance Imaging Markers for Cognitive Impairment in Parkinson's Disease: Current View.
Cognitive impairment (CI) ranging from mild cognitive impairment (MCI) to dementia is a common and disturbing complication in patients with Parkinson's disease (PD). Numerous studies have focused on neuropathological mechanisms underlying CI in PD, along with the identification of specific biomarkers for CI. Magnetic resonance imaging (MRI), a promising method, has been adopted to examine the changes in the brain and identify the candidate biomarkers associated with CI. In this review, we have summarized the potential biomarkers for CI in PD which have been identified through multi-modal MRI studies. Structural MRI technology is widely used in biomarker research. Specific patterns of gray matter atrophy are promising predictors of the evolution of CI in patients with PD. Moreover, other MRI techniques, such as MRI related to small-vessel disease, neuromelanin-sensitive MRI, quantitative susceptibility mapping, MR diffusion imaging, MRI related to cerebrovascular abnormality, resting-state functional MRI, and proton magnetic resonance spectroscopy, can provide imaging features with a good degree of prediction for CI. In the future, novel combined biomarkers should be developed using the recognized analysis tools and predictive algorithms in both cross-sectional and longitudinal studies.


[Sellar fibrosarcoma following radiotherapy for prolactinoma].
A 51-year-old house woman visited the Department of Neurosurgery, Osaka University Hospital for examination of the head injury on Oct. 7, 1975. Neurological examination was normal. Endocrinological examination showed galactorrhea. The patient had a past history of premature menopause. Plain skull films revealed enlargement of sella turcica and CT scan showed sellar tumor with suprasellar expansion which was enhanced by contrast medium. The serum prolactin (PRL) level was 3,290 ng/ml. Diagnosis of PRL secreting pituitary adenoma (prolactinoma) was made. Though surgical removal of the tumor was recommended, it was refused by the patient. Therefore, careful observation was continued as an out-patient until May 1979 when she noticed a temporal hemianopsia of her left eye. She was admitted and had partial removal of the tumor via frontal route and subsequent irradiation (total dose of 5,000 rad by Lineac). The tumor was verified to be a prolactinoma by the immunohistochemical staining. Postoperative course was uneventful and she lead a normal life. In Oct. 1981, severe faceache began and she was readmitted. Sella was destructed extensively and CT scan revealed a hugh sellar tumor with multi-directional extrasellar extension which was less enhanced than that of the first study. The serum PRL level was 588 ng/ml and the regrowth of prolactinoma was suspected. High dose bromocriptine (40 mg/day) therapy was started. The serum PRL level rapidly fell to the negligible value, however, shrinkage of the tumor was not observed. On Jan. 20, 1982, suddenly she developed a left hemiparesis and her level of consciousness gradually deteriorated. On Mar. 11, 1982, the second operation was performed and a solid firm tumor in the base of the skull was partially removed. The tumor was histologically verified to be a fibrosarcoma. After the second operation bromocriptine therapy was discontinued, however expected elevation of the serum PRL level was not recognized. She died on Apr. 4, 1982.


Comparison of Direct Oral Anticoagulants Versus Warfarin in Patients With Atrial Fibrillation and Bioprosthetic Heart Valves.
There are limited data regarding direct oral anticoagulants (DOACs) for stroke prevention in patients with bioprosthetic heart valves (BHVs) and atrial fibrillation (AF). The objectives of this study were to evaluate the ambulatory utilization of DOACs and to compare the effectiveness and safety of DOACs versus warfarin in patients with AF and BHVs. We conducted a retrospective cohort study at a large integrated health care delivery system in California. Patients with BHVs and AF treated with warfarin, dabigatran, rivaroxaban, or apixaban between September 12, 2011 and June 18, 2020 were identified. Inverse probability of treatment-weighted comparative effectiveness and safety of DOACs compared with warfarin were determined. Use of DOACs gradually increased since 2011, with a significant upward in trend after a stay-at-home order related to COVID-19. Among 2,672 adults with BHVs and AF who met the inclusion criteria, 439 were exposed to a DOAC and 2233 were exposed to warfarin. For the primary effectiveness outcome of ischemic stroke, systemic embolism and transient ischemic attack, no significant association was observed between use of DOACs compared with warfarin (HR 1.19, 95% CI 0.96 to 1.48, p = 0.11). Use of DOACs was associated with lower risk of the primary safety outcome of intracranial hemorrhage, gastrointestinal bleeding, and other bleed (HR 0.69, 95% CI 0.56 to 0.85, p < 0.001). Results were consistent across multiple subgroups in the sensitivity analyses. These findings support the use of DOACs for AF in patients with BHVs.


[An autopsy case of adult respiratory distress syndrome (ARDS) with peculiar histopathological features modified by a positive end-expiratory pressure (PEEP) therapy].
A case is reported of adult respiratory distress syndrome(ARDS) combined with barotrauma due to positive end-expiratory pressure (PEEP) therapy. The patient was a 32-year-old woman with fulminant hepatitis, type B, who died of ARDS 22 days after the onset of the illness. The autopsy revealed extraordinary heavy lungs (left: 923g, right: 985g) with edema in the peripheral part and marked emphysematous changes in the central part near the hili. Histologically, scattered foci of intra-alveolar organization and interstitial fibrosis with hemorrhage were observed, which might have been the result of the proceeding pneumonia. The emphysematous lesion seen in this case was peculiar and not like any type of of ordinary pulmonary emphysema. Judging from the strange, sharply demarcated emphysematous lesion with marked destruction of alveolar structure, and the good preservation of the alveolar structure in the edematous lesion, the emphysematous lesion might be barotrauma which was induced by PEEP therapy on top of pneumonia.


The impact of anti-infective drug shortages on hospitals in the United States: trends and causes.
Anti-infective shortages pose significant logistical and clinical challenges to hospitals and may be considered a public health emergency. Anti-infectives often represent irreplaceable life-saving treatments. Furthermore, few new agents are available to treat increasingly prevalent multidrug-resistant pathogens. Frequent anti-infective shortages have substantially altered patient care and may lead to inferior patient outcomes. Because many of the shortages stem from problems with manufacturing and distribution, federal legislation has been introduced but not yet enacted to provide oversight for the adequate supply of critical medications. At the local level, hospitals should develop strategies to anticipate the impact and extent of shortages, to identify therapeutic alternatives, and to mitigate potential adverse outcomes. Here we describe the scope of recent anti-infective shortages in the United States and explore the reasons for inadequate drug supply.


[Multidisciplinary treatment of advanced invasive thymoma].
From February 1988 to September 1992, six patients with Stage III or IV invasive thymoma were enrolled onto our study of multidisciplinary treatment, which included chemotherapy, surgery, and radiotherapy. The chemotherapy consisted of cisplatin (20 mg/m2 continuous 24-hour infusion on days 1 through 4), doxorubicin (40 mg/m2 on day 1), and methylprednisolone (1,000 mg on days 1 through 4 and 500 mg days 5 and 6). Two patients received surgery (incomplete resection) and postoperative chemo/radiotherapy, and four patients received induction chemotherapy followed by surgery and chemo/radiotherapy. All patients with induction chemotherapy showed a partial response and underwent complete (n = 2) or partial (n = 2) resection. Four patients are alive with no evidence of disease for 31 to 55 months after the diagnoses. But two with partial resection after chemotherapy died of recurrent disease. Multidisciplinary treatment including chemotherapy may be a new therapeutic choice in management of advanced invasive thymoma.


Consequences of strong coupling between solvation and electronic structure in the excited state of a betaine dye.
The electronic ground and excited-state structures of the betaine dye molecule pyridinium- N-phenoxide [4-(1-pyridinio)phenolate] are investigated both in the gas phase and in aqueous solution, using the reference interaction site model self-consistent-field (RISM-SCF) procedure within a CASSCF framework. We obtain the total free energy profiles in both the ground and excited states with respect to variation in the torsion angle between the phenoxide and pyridinium rings. We analyze the effect of solvent on the variation of the solute dipole moment and on the charge transfer character in the excited state. In the gas phase, it is shown that the potential energy profile in the excited-state decreases monotonically toward a perpendicular ring orientation and the dipole moment decreases along with decreasing charge localization. In water, the free energy surface for twisting is better characterized as nearly flat along the same coordinate for sterically accessible angles. These results are analyzed in terms of contributions of the solvation free energy, the solute electronic energy, and their coupling. Correspondingly, the dependence of the charge transfer character on solute geometry and solvation are analyzed, and the important roles in the excitation and subsequent relaxation processes for the betaine dye are discussed. It is found that there is considerable solute electronic reorganization associated with the evolution of solvation in the excited state, and it is suggested that this reorganization may contribute significantly to the early time evolution of transient spectra following photoexcitation.


Adenosine regulation of cyclic AMP in corneal endothelium.
Adenosine receptor agonists increased cyclic AMP in cultures of bovine corneal endothelium up to 12-fold over control. Effects were dose-dependent between 1 microM and 0.5 mM adenosine. N6-methyladenosine produced a greater maximal effect but was approximately 10-fold less potent. Isoproterenol and N6-methyladenosine produced an additive response. Propranolol blocked the isoproterenol, but not the adenosine effect on cyclic AMP. Adenine-9-beta-D-arabinofuranoside had no effect on cyclic AMP alone, but inhibited stimulations by N6-methyladenosine, isoproterenol and forskolin. These data indicate the presence of specific adenosine receptors which stimulate adenylate cyclase in cultured bovine corneal endothelium.


Role of CT in the evaluation of congenital cardiovascular disease in children.
The purpose of this review is to describe the role of CT in the evaluation of congenital cardiovascular disease in children. Clinical indications, imaging techniques, and illustrations of relevant conditions are presented. CT accurately depicts many forms of congenital cardiovascular disease in children. It is particularly valuable in the assessment of extracardiac vascular anomalies and in the evaluation of postoperative complications.


The DNA binding-independent function of the glucocorticoid receptor mediates repression of AP-1-dependent genes in skin.
The glucocorticoid receptor (GR) mediates the biological effects of glucocorticoids (GCs) through activation or repression of gene expression, either by DNA binding or via interaction with other transcription factors, such as AP-1. Work in tissue culture cells on the regulation of AP-1-dependent genes, such as collagenase (MMP-13) and stromelysin (MMP-3) has suggested that the antitumor and antiinflammatory activity of GCs is mediated, at least in part, by GR-mediated downmodulation of AP-1. Here, we have identified phorbol ester-induced expression of MMP-3 and MMP-13 in mouse skin as the first example of an in vivo system to measure negative interference between AP-1 and GR in the animal. Cell type-specific induction of these genes by tumor promoters is abolished by GCs. Importantly, this is also the case in GR(dim) mice expressing a DNA binding-defective mutant version of GR. In contrast, the newly identified target genes in skin, plasma glutathione peroxidase and HSP-27, were induced by GC in wild-type, but not in GR(dim) mice. Thus, these data suggest that the DNA binding-independent function of the GR is dispensable for repression of AP-1 activity in vivo and responsible for the antitumor promoting activity of GCs.


Bisulfite Amplicon Sequencing Can Detect Glia and Neuron Cell-Free DNA in Blood Plasma.
Sampling the live brain is difficult and dangerous, and withdrawing cerebrospinal fluid is uncomfortable and frightening to the subject, so new sources of real-time analysis are constantly sought. Cell-free DNA (cfDNA) derived from glia and neurons offers the potential for wide-ranging neurological disease diagnosis and monitoring. However, new laboratory and bioinformatic strategies are needed. DNA methylation patterns on individual cfDNA fragments can be used to ascribe their cell-of-origin. Here we describe bisulfite sequencing assays and bioinformatic processing methods to identify cfDNA derived from glia and neurons. In proof-of-concept experiments, we describe the presence of both glia- and neuron-cfDNA in the blood plasma of human subjects following mild trauma. This detection of glia- and neuron-cfDNA represents a significant step forward in the translation of liquid biopsies for neurological diseases.


A Systematic Review and Meta-Analysis of Arthroscopic Meniscus Repair in Young Patients: Comparison of All-Inside and Inside-Out Suture Techniques.
The purposes of the present study were to review published studies that investigated arthroscopic meniscus repair to treat meniscus injury in young patients and to compare all-inside and inside-out suture techniques. Various electronic databases were queried for published articles, and this search was updated in August 2017 for evaluating the outcomes of arthroscopic meniscus surgery in young patients. Data search, extraction, analysis, and quality assessment were performed according to the Cochrane Collaboration guidelines, and the clinical outcomes were evaluated using various outcome values in young patients according to suture techniques. Three randomized controlled trials and three prospective comparative studies were included in this systematic review and meta-analysis. There were no significant differences in clinical outcomes such as meniscus healing rate (risk ratio [RR], 1.11; 95% confidence interval [CI], 0.90 to 1.37; I2=39%) and perioperative complications (RR, 0.62; 95% CI, 0.23 to 1.72; I2=43%) between all-inside and inside-out techniques for meniscus repair. The present study shows favorable results for clinical outcomes such as meniscus healing rate and perioperative complications in young patients. Furthermore, based on our results, both all-inside and inside-out meniscal suture techniques are equally effective in these patients.


Antibacterial Films Made of Ionic Complexes of Poly(γ-glutamic acid) and Ethyl Lauroyl Arginate.
The biocide agent LAE (ethyl αN-lauroyl l-arginate chloride) was coupled with poly(γ-glutamic acid) (PGGA) to form stable ionic complexes with LAE:PGGA ratios of 1 and 0.5. The nanostructure adopted by these complexes and its response to thermal changes were examined in detail by Differential scanning calorimetry (DSC) and X-ray diffraction (XRD) using synchrotron radiation in real time. A layered biphasic structure with LAE filling the space between the polypeptidic sheets was adopted in these complexes. The complexes were stable up to above 250 °C, non-water soluble, and were able to form consistent transparent films. The release of LAE from the complexes upon incubation in aqueous buffer was examined and found to depend on both pH and complex composition. The antibacterial activity of films made of these complexes against Gram-positive (L. monocytogenes and S. aureus) and Gram-negative (E. coli and S. enterica) bacteria was preliminary evaluated and was found to be very high against the formers and only moderate against the later. The bactericide activity displayed by the LAE·PGGA complexes was directly related with the amount of LAE that was released from the film to the environment.