Respiratory control in humans after 8 h of lowered arterial PO2, hemodilution, or carboxyhemoglobinemia.
In humans exposed to 8 h of isocapnic hypoxia, there is a progressive increase in ventilation that is associated with an increase in the ventilatory sensitivity to acute hypoxia. To determine the relative roles of lowered arterial PO2 and oxygen content in generating these changes, the acute hypoxic ventilatory response was determined in 11 subjects after four 8-h exposures: 1) protocol IH (isocapnic hypoxia), in which end-tidal PO2 was held at 55 Torr and end-tidal PCO2 was maintained at the preexposure value; 2) protocol PB (phlebotomy), in which 500 ml of venous blood were withdrawn; 3) protocol CO, in which carboxyhemoglobin was maintained at 10% by controlled carbon monoxide inhalation; and 4) protocol C as a control. Both hypoxic sensitivity and ventilation in the absence of hypoxia increased significantly after protocol IH (P < 0.001 and P < 0.005, respectively, ANOVA) but not after the other three protocols. This indicates that it is the reduction in arterial PO2 that is primarily important in generating the increase in the acute hypoxic ventilatory response in prolonged hypoxia. The associated reduction in arterial oxygen content is unlikely to play an important role.


Efficacy of cilofungin alone and in combination with amphotericin B in a murine model of disseminated aspergillosis.
Cilofungin, amphotericin B, and a combination of the two drugs were compared in a model of aspergillosis in immunocompetent mice in three experiments. Cilofungin was equivalent to amphotericin B in preventing death and eradicating cerebral aspergillosis, but it did not sterilize the kidneys. This is the first demonstration of the in vivo activity of cilofungin against any fungus other than Candida albicans. The mortality with combination therapy was higher than those with amphotericin B alone (P = 0.003) and cilofungin alone (P = 0.054), as was weight loss after infection, indicating antagonism between cilofungin and amphotericin B in this model. The mechanisms of action and antagonism remain to be explained.


New therapies for castration-resistant prostate cancer: efficacy and safety.
Prostate cancer (PCa) is the most common noncutaneous malignancy and the second leading cause of cancer mortality amongst men in the Western world. Up to 40% of men diagnosed with PCa will eventually develop metastatic disease, and although most respond to initial medical or surgical castration, progression to castration resistance is universal. The average survival for patients with castration-resistant prostate cancer (CRPC) is 2-3 yr. To discuss the biologic rationale and evidence supporting current management of patients with CRPC and to review promising novel agents. Electronic databases (PubMed, ClinicalTrials.gov), relevant journals, and conference proceedings were searched manually for preclinical studies, clinical trials, and biomarker analyses focused on the treatment of CRPC. Keywords included castrate resistant prostate cancer and: targeted therapy, novel therapy, immunotherapy, androgen therapy, bone therapy, mechanisms, biomarkers, and trial endpoints; no time range was specified. Information pertaining to current studies was discussed with key opinion leaders. We focus on the efficacy and safety of approved agents, promising therapies that have proceeded to phase 3 evaluation, and those that have enhanced our understanding of the biology of CRPC. Biomarkers are considered in the context of novel targeted agents and immunotherapy. CRPC has many targets. Four new agents with different mechanisms of action have recently been shown to have positive results in large phase 3 randomized trials, and have already been approved in the United States for CRPC: cabazitaxel, sipuleucel-T, denosumab, and abiraterone acetate. With our improved understanding of tumor biology and the incorporation of new prognostic and molecular biomarkers into clinical trials, we are making progress in the management of patients with CRPC.


Cycling Rate-Induced Spatially-Resolved Heterogeneities in Commercial Cylindrical Li-Ion Batteries.
Synchrotron high-energy X-ray diffraction computed tomography has been employed to investigate, for the first time, commercial cylindrical Li-ion batteries electrochemically cycled over the two cycling rates of C/2 and C/20. This technique yields maps of the crystalline components and chemical species as a cross-section of the cell with high spatiotemporal resolution (550 × 550 images with 20 × 20 × 3 µm3 voxel size in ca. 1 h). The recently developed Direct Least-Squares Reconstruction algorithm is used to overcome the well-known parallax problem and led to accurate lattice parameter maps for the device cathode. Chemical heterogeneities are revealed at both electrodes and are attributed to uneven Li and current distributions in the cells. It is shown that this technique has the potential to become an invaluable diagnostic tool for real-world commercial batteries and for their characterization under operating conditions, leading to unique insights into "real" battery degradation mechanisms as they occur.


Project ACHIEVE - using implementation research to guide the evaluation of transitional care effectiveness.
Poorly managed hospital discharges and care transitions between health care facilities can cause poor outcomes for both patients and their caregivers. Unfortunately, the usual approach to health care delivery does not support continuity and coordination across the settings of hospital, doctors' offices, home or nursing homes. Though complex efforts with multiple components can improve patient outcomes and reduce 30-day readmissions, research has not identified which components are necessary. Also we do not know how delivery of core components may need to be adjusted based on patient, caregiver, setting or characteristics of the community, or how system redesign can be accelerated. Project ACHIEVE focuses on diverse Medicare populations such as individuals with multiple chronic diseases, patients with low health literacy/numeracy and limited English proficiency, racial and ethnic minority groups, low-income groups, residents of rural areas, and individuals with disabilities. During the first phase, we will use focus groups to identify the transitional care outcomes and components that matter most to patients and caregivers to inform development and validation of assessment instruments. During the second phase, we will evaluate the comparative effectiveness of multi-component care transitions programs occurring across the U.S. Using a mixed-methods approach for this evaluation, we will study historical (retrospective) and current and future (prospective) groups of patients, caregivers and providers using site visits, surveys, and clinical and claims data. In this natural experiment observational study, we use a fractional factorial study design to specify comparators and estimate the individual and combined effects of key transitional care components. Our study will determine which evidence-based transitional care components and/or clusters most effectively produce patient and caregiver desired outcomes overall and among diverse patient and caregiver populations in different healthcare settings. Using the results, we will develop concrete, actionable recommendations regarding how best to implement these strategies. Finally, this work will provide tools for hospitals, community-based organizations, patients, caregivers, clinicians and other stakeholders to help them make informed decisions about which strategies are most effective and how best to implement them in their communities. Registered as NCT02354482 on clinicaltrials.gov on 1/29/2015.


[Various mechanisms of cytoprotective effect of omeprazole and low intensity laser radiation on the gastroduodenal mucosa in the treatment of patients with duodenal ulcer].
Clinical studies were made in 130 patients with duodenal ulcer in the phase of exacerbation of the disease. There were 98 men and 32 women who ranged from 17 to 50 years old. Results of examination of 7 essentially healthy subjects were regarded as control. The patients were divided into three groups. Group I patients (n = 48) received a conventional therapy; in group II patients, the adopted therapy was supplemented by omeprazol, 20 mg twice daily, group III patients (n = 43) were (in addition to the above therapeutic regimen) exposed to a session of endoscopic low-intensity laser irradiation (LILI) for 5 min (overall 6 to 8 LILI procedures). It has been ascertained that omeprazol exerts a cytoprotective effect on the mucozal barrier of the gastroduodenal zone brought about by increase in the synthesis of glucoproteins in the mucous membrane, improvement of the water-and-elastic properties, and enhancement of resistance of the mucosal barrier to the action of the aggressive factors. Administration of endoscopic LILI treatments in DU patients has also been found out to have a cytoprotective effect but superior to omeprazol. A protective action of LILI is believed to be caused by stimulation of synthesis of the most important components of glycoproteins. A cytoprotective effect of omeprazol and endoscopic LILI is ccompanied by a significant shortening of time for the clinical symptoms to get dispelled, the ulcer cicatrization frequency increased.


Cell cycle-dependent nuclear accumulation of the p94fer tyrosine kinase is regulated by its NH2 terminus and is affected by kinase domain integrity and ATP binding.
p94fer and p51ferT are two tyrosine kinases that are encoded by differentially spliced transcripts of the FER locus in the mouse. The two tyrosine kinases share identical SH2 and kinase domains but differ in their NH2-terminal amino acid sequence. Unlike p94fer, the presence of which has been demonstrated in most mammalian cell lines analyzed, the expression of p51ferT is restricted to meiotic cells. Here, we show that the two related tyrosine kinases also differ in their subcellular localization profiles. Although p51ferT accumulates constitutively in the cell nucleus, p94fer is cytoplasmic in quiescent cells and enters the nucleus concomitantly with the onset of S phase. The nuclear translocation of the FER proteins is driven by a nuclear localization signal (NLS), which is located within the kinase domain of these enzymes. The functioning of that NLS depends on the integrity of the kinase domain but was not affected by inactivation of the kinase activity. The NH2 terminus of p94fer dictated the cell cycle-dependent functioning of the NLS of FER kinase. This process was governed by coiled-coil forming sequences that are present in the NH2 terminus of the kinase. The regulatory effect of the p94fer NH2-terminal sequences was not affected by kinase activity but was perturbed by mutations in the kinase domain ATP binding site. Ectopic expression of the constitutively nuclear p51ferT in CHO cells interfered with S-phase progression in these cells. This was not seen in p94fer-overexpressing cells. The FER tyrosine kinases seem, thus, to be regulated by novel mechanisms that direct their different subcellular distribution profiles and may, consequently, control their cellular functioning.


The cost of antiemetic therapy for chemotherapy-induced nausea and vomiting in patients receiving platinum-containing regimens in daily practice in Japan: a retrospective study.
The objective of this study was to estimate the cost of antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) in daily practice in Japan. This was a retrospective observational study using medical records. Eligible patients were those with bladder or testicular cancer receiving platinum-containing highly emetogenic chemotherapy. The incidence of CINV on days 1-5 in single-day chemotherapy and on days 1-9 in multiple-day chemotherapy, and the costs of antiemetic therapy directly associated with the administration of antiemetics were estimated. The analysis of costs was performed from a hospital perspective. A total of 54 patients or 169 chemotherapy courses were included. In all chemotherapy courses 5-HT(3) receptor antagonists were used on the day(s) that platinum-containing agents were administered and frequently used on subsequent days. In contrast, the use of corticosteroids was infrequent. Acute CINV in single-day chemotherapy was well controlled, but the incidences of delayed CINV in single-day chemotherapy and CINV in multiple-day chemotherapy were relatively high. The costs for antiemetic therapy were $484.65 in courses with CINV and $318.56 in courses without CINV, and the difference was approximately $170 per chemotherapy course, which was considered to be mainly imputable to the prevalence of CINV. The cost of antiemetic therapy for CINV is substantial in Japan as well as in other countries, and it is suggested that the onset of CINV is a possible cost driver. The improvements in antiemetic therapy may contribute not only to improved patient well-being but also to a reduction of economic burden.


Repeated, transient lactate exposure does not "precondition" rat myocardium.
The precise mechanism of the cardioprotective effect of ischemic preconditioning (IPC) is still unclear, although various mechanisms have been suggested, including activation of ATP-dependent potassium (KATP) channels by adenosine and protein kinase C as well as increased expression of heat shock protein (HSP). Increasing evidence suggests that lactate, which accumulates during IPC periods, can activate several of these "triggers" of preconditioning. We tested whether repeated exposure to lactate, producing tissue lactate concentrations similar to those during brief ischemic periods, could contribute to IPC benefits. Five isolated rat hearts were subjected to a previously reported IPC protocol composed of two 5-min ischemia-reperfusion cycles; another five hearts served as controls; and six hearts underwent a "lactate-preconditioning" protocol, consisting of two 5-min exposures to 15 mM lactate and two 5-min periods of reflow with a lactate-free buffer. Subsequently all hearts underwent 30 min of normothermic, total ischemia followed by 30 min of reflow at a constant perfusion pressure of 80 mmHg (1 mmHg = 133.3 Pa). Lactate exposure resulted in tissue lactate levels similar to those during ischemia in ischemia-preconditioned hearts (10.5 +/- 0.6 versus 10.5 +/- 1.2 mumol/g wet weight, mean +/- SEM). However, the recovery of left ventricular developed pressure (DevP) following 30 min of total ischemia was significantly higher in the IPC hearts than in either the control or lactate-exposed hearts, reaching 56.8 +/- 3.4, 14.2 +/- 6.8, and 9.5 +/- 3.6%, respectively, of the baseline values. There was no significant difference between lactate-preconditioned and control hearts. End-diastolic pressure (EDP) was significantly lower during reperfusion in IPC hearts than in lactate-exposed and control hearts, with no significant differences between the latter two groups (36.2 +/- 3.5, 82.0 +/- 2.9, and 81.2 +/- 8.5 mmHg, respectively). In contrast with the proposed hypothesis, repeated, transient lactate exposure resulting in tissue lactate levels similar to ischemic preconditioning did not improve contractile recovery after a prolonged ischemic period in this model.


Comprehensive gene and microRNA expression profiling reveals miR-206 inhibits MET in lung cancer metastasis.
MiRNAs associated with the metastasis of lung cancer remain largely unexplored. In this study, gene and miRNA expression profiling were performed to analyze the global expression of mRNAs and miRNAs in human high- and low-metastatic lung cancer cell strains. By developing an integrated bioinformatics analysis, six miRNAs (miR-424-3p, miR-450b-5p, miR-335-5p, miR-34a-5p, miR-302b-3p and miR-206) showed higher target gene degrees in the miRNA-gene network and might be potential metastasis-related miRNAs. Using the qRT-PCR method, the six miRNAs were further confirmed to show a significant expression difference between human lung cancer and normal tissue samples. Since miR-206 showed lower expression both in lung cancer tissues and cell lines, it was used as an example for further functional verification. The wound healing assay and transwell invasion assay showed that miR-206 mimics significantly inhibited the cell migration and invasion of the high-metastatic lung cancer 95D cell strain. One of its predicted targets in our miRNA-gene network, MET, was also obviously decreased at the protein level when miR-206 was overexpressed. Instead, miR-206 inhibitors increased MET protein expression, cell migration and invasion of the low-metastatic lung cancer 95C cell strain. Meanwhile, the luciferase assay showed that MET was a direct target of miR-206. Furthermore, MET gene silence showed a similar anti-migration and anti-invasion effect with miR-206 mimics in 95D cells and could partially attenuate the migration- and invasion-promoting effect of miR-206 inhibitors in 95C cells, suggesting that miR-206 targets MET in lung cancer metastasis. Finally, we also demonstrated that miR-206 can significantly inhibit lung cancer proliferation and metastasis in mouse models. In conclusion, our study provided a miRNA-gene regulatory network in lung cancer metastasis and further demonstrated the roles of miR-206 and MET in this process, which enhances the understanding of the regulatory mechanism in lung cancer metastasis.


Interprofessional education in the care of people diagnosed with dementia: protocol for a systematic review.
Interprofessional education (IPE) offers a possible way to improve interprofessional collaboration and patient care. Current research addressing the effectiveness of IPE in dementia care is limited. A protocol is described for a systematic review to investigate the evidence for the influence of IPE on collaborative knowledge and skills; interprofessional practice and the delivery of dementia care. We will search the following electronic databases: PubMed, EMBASE, The Cochrane Library, PsycINFO CINAHL, Applied Social Sciences Index and Abstracts (ASSIA), ERIC British Education Index (BEI) and the Healthcare Management Information Consortium (HMIC). Additional studies will be identified by manually searching relevant journals and the reference list of selected studies. The selection of the studies, data collection and quality appraisal will be performed independently by two reviewers. Data will be initially analysed through a narrative synthesis method. If a subset of data we analyse appears comparable, we will investigate the possibility of pooling such data via formal meta-analysis analytical techniques. Ethics approval will not be required as this is a protocol for a systematic review. This systematic review aims to establish the effectiveness of IPE programmes on collaborative professional practice and the delivery of care for people with dementia. The findings of this systematic review may also identify specific gaps in the evidence informing a future agenda for research, policy and practice. It will be published in a peer-reviewed journal. PROSPERO CRD42014015075.


Tissue-specific activity of two manganese superoxide dismutase promoters in transgenic tobacco.
In eukaryotes, manganese superoxide dismutase is a nuclear-encoded protein that scavenges superoxide radicals in the mitochondrial matrix. We have isolated two manganese superoxide dismutase genes from Nicotiana plumbaginifolia L. and fused the 5' upstream regulatory region of these genes to the beta-glucuronidase reporter gene. The two gene fusions displayed a differential tissue specificity in transgenic tobacco (Nicotiana tabacum). Promoter activity of the SodA1 gene fusion was found in the pollen, middle layer, and stomium of anthers, but was usually undetectable in vegetative organs of mature plants. The SodA2 gene fusion was expressed in the leaves, stems, roots, and flowers. SodA2 promoter activity was most prominent in the vascular bundles, stomata, axillary buds, pericycle, stomium, and pollen. Histochemical analysis of succinate dehydrogenase activity suggested that the spatial expression of the two gene fusions is generally correlated with mitochondrial respiratory activity.


Correlation of modified Gleason grading with pT stage of prostatic carcinoma after radical prostatectomy.
To study the correlation between modified Gleason score (GS) and pT stage of radical prostatectomy (RP) specimens. Six hundred forty-nine consecutive RP specimens were graded according to the conventional and the modified Gleason grading systems. A total of 29% of the tumors were upgraded. Both variants of GS correlated with pathologic stage. Stage pT2 tumors were assigned a GS of 3-6 less often with modified grading than with conventional grading (29% and 84%, respectively). The only significant difference of stage distribution between conventional and modified GS was for GS 7, where pT2 was the most common stage with modified grading (54%) and pT3 was most common with conventional grading (67%). Of GS 3 + 4 = 7a tumors, 95% were stage pT2, while 79% of GS 4 + 3 = 7b tumors were stage pT3-4. The stage distribution of modified GSs of RP specimens differs from that of conventional GSs, but a good correlation exists between grade and pT stage. Notably, GS 4 + 3 = 7b was more often associated with high stage than was GS 3 + 4 = 7a.


Mechanism of red cell 2,3-diphosphoglycerate increase in neonatal lambs.
The tenfold increase in red cell 2,3-diphosphoglycerate (DPG) concentration that occurs during the first 5 days of life in lambs is an important adaptation to extrauterine life. In lambs, DPG reduces hemoglobin oxygen affinity by the Bohr effect. Our data on 10 neonatal lambs suggest that the biochemical mechanism underlying this DPG increase involves the following: (1) a rise in plasma glucose from 40 to 100 mg/dl in the first 48 hr of life, which allows for increased glucose consumption in the highly glucose-permeable neonatal RBC; (2) a transitory rise in blood pH begins at birth, peaks at about 20 hr, and falls slightly; (3) the pH increase coincides with a threefold increase in RBC fructose-1,6-diphosphate (FDP) concentration due, we believe, to pH activation of phosphofructokinase; (4) glycolytic intermediates after the glyceraldehyde-3-phosphate dehydrogenase (GAPD) step do not rise in the first 24 hr of life, possibly due to insufficient inorganic phosphate (Pi), a substrate of GAPD; (5) plasma Pi increases from about 7 mg/dl at birth to 11 mg/dl at 72 hr, activates the GAPD, and FDP levels decline; and (6) the in vitro activity of the DPG synthetic enzyme, DPG mutase, is increased 12-fold in neonatal compared to adult RBC. We conclude that the postnatal rise in DPG is explained at least in part by the sequential effects of these metabolic changes.


The association between spiritual and religious involvement and depressive symptoms in a Canadian population.
Data from a large epidemiologic survey were examined to determine the relationship of religious practice (worship service attendance), spiritual and religious self-perception, and importance (salience) to depressive symptoms. Data were obtained from 70,884 respondents older than 15 years from the Canadian National Population Health Survey (Wave II, 1996-1997). Logistic regression was used to examine the relationship of the religious/spiritual variables to depressive symptoms while controlling for demographic, social, and health variables. More frequent worship service attendees had significantly fewer depressive symptoms. In contrast, those who stated spiritual values or faith were important or perceived themselves to be spiritual/religious had higher levels of depressive symptoms, even after controlling for potential mediating and confounding factors. It is evident that spirituality/religion has an important effect on depressive symptoms, but this study underscores the complexity of this relationship. Longitudinal studies are needed to help elucidate mechanisms and the order and direction of effects.


Biofilm formation by clinical isolates and the implications in chronic infections.
Biofilm formation is a major virulence factor contributing to the chronicity of infections. To date few studies have evaluated biofilm formation in infecting isolates of patients including both Gram-positive and Gram-negative multidrug-resistant (MDR) species in the context of numerous types of infectious syndromes. Herein, we investigated the biofilm forming capacity in a large collection of single patient infecting isolates and compared the relationship between biofilm formation to various strain characteristics. The biofilm-forming capacity of 205 randomly sampled clinical isolates from patients, collected from various anatomical sites, admitted for treatment at Brooke Army Medical Center (BAMC) from 2004-2011, including methicillin-resistant/methicillin susceptible Staphylococcus aureus (MRSA/MSSA) (n=23), Acinetobacter baumannii (n=53), Pseudomonas aeruginosa (n=36), Klebsiella pneumoniae (n=54), and Escherichia coli (n=39), were evaluated for biofilm formation using the high-throughput microtiter plate assay and scanning electron microscopy (SEM). Relationships between biofilm formation to clonal type, site of isolate collection, and MDR phenotype were evaluated. Furthermore, in patients with relapsing infections, serial strains were assessed for their ability to form biofilms in vitro. Of the 205 clinical isolates tested, 126 strains (61.4%) were observed to form biofilms in vitro at levels greater than or equal to the Staphylococcus epidermidis, positive biofilm producing strain, with P. aeruginosa and S. aureus having the greatest number of biofilm producing strains. Biofilm formation was significantly associated with specific clonal types, the site of isolate collection, and strains positive for biofilm formation were more frequently observed to be MDR. In patients with relapsing infections, the majority of serial isolates recovered from these individuals were observed to be strong biofilm producers in vitro. This study is the first to evaluate biofilm formation in a large collection of infecting clinical isolates representing diverse types of infections. Our results demonstrate: (1) biofilm formation is a heterogeneous property amongst clinical strains which is associated with certain clonal types, (2) biofilm forming strains are more frequently isolated from non-fluid tissues, in particular bone and soft tissues, (3) MDR pathogens are more often biofilm formers, and (4) strains from patients with persistent infections are positive for biofilm formation.


Urban/rural differences in health service utilization by elderly persons in the United States.
This paper presents the results of a longitudinal analysis of differences between urban and rural elderly persons in the use of hospital, nursing home, and physician services. Multivariate logistic and Tobit utilization models were estimated with data from the National Center for Health Statistics' Longitudinal Study of Aging (a national survey of more than 5,000 elderly, 70 years of age and older) and health resource data from the Bureau of Health Professions' Area Resources File. The research investigated the independent effect of residential location on both the frequency of service use and the likelihood of using a service over the period 1984-1986. Under a trichotomous definition of urban/rural residency and controlling for differences in predisposing, enabling, and need characteristics, the analysis revealed that the utilization pattern of hospital, nursing home, and physician services was unrelated to either rural or urban residential location or the availability of health resources in those areas.


Urgent invasive coronary strategy in patients with sudden cardiac arrest.
To review the evidence on urgent coronary angiography and percutaneous coronary intervention after resuscitated cardiac arrest and during ongoing cardiocerebral resuscitation. In almost 450 patients with acute ST-elevation myocardial infarction after reestablishment of spontaneous circulation, success rate of primary percutaneous coronary intervention was 89%. Survival rates in conscious patients after reestablishment of spontaneous circulation were comparable to patients without preceding cardiac arrest while in comatose patients, survival was 57% and survival with acceptable neurological outcome 38%. Nonrandomized trials in 106 comatose survivors of cardiac arrest indicate that urgent invasive coronary strategy can be safely combined with mild induced hypothermia. Percutaneous coronary intervention is also feasible in patients undergoing cardiocerebral resuscitation. In 34 reported patients, the success rate of percutaneous coronary intervention was 88% and survival to hospital discharge 41%. Urgent coronary angiography and percutaneous coronary intervention should be attempted in conscious patients after reestablishment of spontaneous circulation similarly as in patients with acute coronary syndromes without preceding cardiac arrest. In comatose survivors, urgent coronary strategy is reasonable if acute ischemic cause is suspected and if there is realistic hope for neurological recovery that should be facilitated with mild induced hypothermia. Urgent coronary invasive strategy may be successful also during ongoing resuscitation in selected patients without advanced heart diseases and significant comorbidities.


Neurospora in temperate forests of western North America.
The fungal genus Neurospora has a distinguished history as a laboratory model in genetics and biochemistry. The most recent milestone in this history has been the sequencing of the genome of the best known species, N. crassa. The hope and promise of a complete genome sequence is a full understanding of the biology of the organism. Full understanding cannot be achieved, however, in the absence of fundamental knowledge of natural history. We report that species of Neurospora, heretofore thought to occur mainly in moist tropical and subtropical regions, are common primary colonizers of trees and shrubs killed by forest fires in western North America, in regions that are often cold and dry. Surveys in 36 forest-fire sites from New Mexico to Alaska yielded more than 500 cultures, 95% of which were the rarely collected N. discreta. Initial characterization of genotypes both within a site and on a single tree showed diversity consistent with sexual reproduction of N. discreta. These discoveries fill important gaps in knowledge of the distribution of members of the genus on both large and small spatial scales and provide the framework for future studies in new regions and microhabitats. The overall result is that population biology and genetics now can be combined, placing the genus Neurospora in a unique position to expand its role in experimental biology as a useful model organism for ecology, population genetics and evolution.


Analysis of blood flow in the long posterior ciliary artery of the cat.
Experiments were undertaken to use a new technique for direct on-line measurement of blood flow in the long posterior ciliary artery (LPCA) in cats and to evaluate possible physiological mechanisms controlling blood flow in the vascular beds perfused by this artery. Blood flow in the temporal LPCA was measured on a continuous basis using ultrasonic flowmetry in anesthetized cats. Effects of acute sectioning of the sympathetic nerve and changes in LPCA and cerebral blood flows in response to altered levels of inspired CO2 and O2 were tested in some animals. In others, the presence of vascular autoregulatory mechanisms in response to stepwise elevations of intraocular pressure was studied. Blood flow in the temporal LPCA averaged 0.58+/-0.03 ml/min in 45 cats anesthetized with pentobarbital. Basal LPCA blood flow was not altered by acute sectioning of the sympathetic nerve or by changes in low levels of inspired CO2 and O2, although 10% CO2 caused a modest increase. Stepwise elevations of intraocular pressure resulted in comparable stepwise decreases of LPCA blood flow, with perfusion pressure declining in a linear manner throughout the perfusion-pressure range. Ultrasonic flowmetry seems to be a useful tool for continuous on-line measurement of LPCA blood flow in the cat eye. Blood flow to vascular beds perfused by this artery does not seem to be under sympathetic neural control and is refractory to modest alterations of blood gas levels of CO2 and O2. Blood vessels perfused by the LPCA show no clear autoregulatory mechanisms.


Production and characterization of a monoclonal antibody to a human interferon-induced double-stranded RNA-binding Mr 68,000 protein kinase.
One of the interferon-induced proteins thought to be involved in the antiviral effects of interferon is a double-stranded RNA-dependent protein kinase. This paper reports the development of a monoclonal antibody, 10A5, that recognizes a protein that co-migrates with the double-stranded RNA-dependent protein kinase at an approximate molecular weight of 68,000. Levels of this protein and of the protein kinase activity increase 3-fold on interferon treatment of T98G cells. The specificity of the monoclonal antibody was determined by ELISA, immunoblotting, and immunoprecipitation procedures. Furthermore, immunoaffinity chromatography of an interferon-induced T98G cell extract previously phosphorylated in the presence of double-stranded RNA and radiolabeled ATP resulted in the specific elution of a phosphorylated Mr 68,000 protein from the monoclonal antibody 10A5-Sepharose column. Monoclonal antibody 10A5 recognizes both native and denatured protein kinase, independent of double-stranded RNA binding or phosphorylation, and should therefore serve as a useful tool in analyzing the role of the double-stranded RNA-dependent protein kinase in the mechanism of interferon action.


Cardiovascular manifestations of Erdheim-Chester disease.
Erdheim-Chester disease (ECD) is a rare inflammatory disorder of unknown etiology, characterised by diffuse organ infiltration of CD68-positive, CD1a-negative, S100-low/negative foamy histiocytes. It is a non-Langerhans cell histiocytosis which invariably involves bones (96% of cases). Extraskeletal involvement is observed in about 50% of cases. Cardiovascular involvement affects more than 20% of patients and associates with poor prognosis, conferring a reduced response to treatment. Frequent findings are pericardial effusion (24% of patients), "coated aorta", a perivascular circumferential thickening of the aorta, and pericardial thickening. Other typical features include right atrial mass with pseudo-tumoural appearance and histiocytes' infiltration of right atrial walls, atrioventricular sulcus and interatrial septum. After the recent introduction of cardiac cine MRI in the clinical assessment of patients affected by ECD, a growing body of case reports and retrospective data showed that cardiovascular involvement is present more frequently than previously thought and that it is relatively often asymptomatic. Hence, clinicians should systematically screen ECD patients for occult cardiovascular involvement by means of highly sensitive imaging tools. Despite these recent novelties, comprehensive literature reviews focusing on ECD cardiovascular involvement and its imaging assessment in the last decade are lacking.


Relation of cell viability and apoptosis with clinical remission following induction chemotherapy in ALL and AML.
Evaluation of in vitro spontaneous apoptosis of acute leukemic blast cells after incubating for different time period and its correlation with clinical outcome is well documented in the literature. However, there is insufficient information available on the flowcytometric determination of cell viability immediately after separating blast cells and its correlation with the clinical response. In this study, we attempted to evaluate the relationship between viability of freshly isolated leukemic cells and the clinical response. Cell viability was evaluated in freshly isolated leukemic cells from 84 patients with acute leukemia (AL) using 7-Amino-Actinomycin D and was correlated with the clinical response following induction chemotherapy. Patients with ALL who achieved complete remission (CR) had significantly lower mean live cell (70.9%) compared to those patients who did not achieve CR (93.3%) (p=0.02). Furthermore, ALL responders had also significantly higher mean early apoptotic cell (19.4%) as compared to non responders (5%) (p=0.04). No significant difference was found in the mean live / early apoptotic cell count of responders and non responders of AML patients. The probability of obtaining CR in ALL patients was 3.7 and 2.7 times higher in those who had mean live cell count less than 70% and apoptotic cell count more than 10%, respectively. A lower cell viability and higher apoptosis in freshly isolated leukemic cells at the time of diagnosis may indicate a favorable response in patients with ALL but may not provide any sufficient information in predicting the response in AML patients to induction chemotherapy.


SMA CARNI-VAL trial part I: double-blind, randomized, placebo-controlled trial of L-carnitine and valproic acid in spinal muscular atrophy.
Valproic acid (VPA) has demonstrated potential as a therapeutic candidate for spinal muscular atrophy (SMA) in vitro and in vivo. Two cohorts of subjects were enrolled in the SMA CARNIVAL TRIAL, a non-ambulatory group of "sitters" (cohort 1) and an ambulatory group of "walkers" (cohort 2). Here, we present results for cohort 1: a multicenter phase II randomized double-blind intention-to-treat protocol in non-ambulatory SMA subjects 2-8 years of age. Sixty-one subjects were randomized 1:1 to placebo or treatment for the first six months; all received active treatment the subsequent six months. The primary outcome was change in the modified Hammersmith Functional Motor Scale (MHFMS) score following six months of treatment. Secondary outcomes included safety and adverse event data, and change in MHFMS score for twelve versus six months of active treatment, body composition, quantitative SMN mRNA levels, maximum ulnar CMAP amplitudes, myometry and PFT measures. At 6 months, there was no difference in change from the baseline MHFMS score between treatment and placebo groups (difference = 0.643, 95% CI = -1.22-2.51). Adverse events occurred in >80% of subjects and were more common in the treatment group. Excessive weight gain was the most frequent drug-related adverse event, and increased fat mass was negatively related to change in MHFMS values (p = 0.0409). Post-hoc analysis found that children ages two to three years that received 12 months treatment, when adjusted for baseline weight, had significantly improved MHFMS scores (p = 0.03) compared to those who received placebo the first six months. A linear regression analysis limited to the influence of age demonstrates young age as a significant factor in improved MHFMS scores (p = 0.007). This study demonstrated no benefit from six months treatment with VPA and L-carnitine in a young non-ambulatory cohort of subjects with SMA. Weight gain, age and treatment duration were significant confounding variables that should be considered in the design of future trials. Clinicaltrials.gov NCT00227266.


Augmenting drug-carrier compatibility improves tumour nanotherapy efficacy.
A major goal of cancer nanotherapy is to use nanoparticles as carriers for targeted delivery of anti-tumour agents. The drug-carrier association after intravenous administration is essential for efficient drug delivery to the tumour. However, a large number of currently available nanocarriers are self-assembled nanoparticles whose drug-loading stability is critically affected by the in vivo environment. Here we used in vivo FRET imaging to systematically investigate how drug-carrier compatibility affects drug release in a tumour mouse model. We found the drug's hydrophobicity and miscibility with the nanoparticles are two independent key parameters that determine its accumulation in the tumour. Next, we applied these findings to improve chemotherapeutic delivery by augmenting the parent drug's compatibility; as a result, we achieved better antitumour efficacy. Our results help elucidate nanomedicines' in vivo fate and provide guidelines for efficient drug delivery.


Olfactory functioning in Gulf War-era veterans: relationships to war-zone duty, self-reported hazards exposures, and psychological distress.
To explore possible neurotoxic sequelae of Gulf War (GW) participation, olfactory identification performance, neurocognitive functioning, health perceptions, and emotional distress were assessed in 72 veterans deployed to the GW and 33 military personnel activated during the GW but not deployed to the war zone. Findings revealed that war-zone-exposed veterans reported more concerns about health, cognitive functioning, and depression than did their counterparts who did not see war-zone duty. There was no evidence that performances on olfactory or neurocognitive measures were related to war-zone duty or to self-reported exposure to GW toxicants. However, symptoms of emotional distress were positively correlated with self-report of health and cognitive complaints. Results do not provide support for the hypothesis that objectively-measured sensory (i.e., olfactory) or cognitive deficits are related to war-zone participation but do underscore the increasingly demonstrated association between self-reported health concerns and symptoms of emotional distress.


Adenoid Cystic Carcinoma Metastatic to the Pituitary: A Case Report and Discussion of Potential Diagnostic Value of Magnetic Resonance Elastography in Pituitary Tumors.
Adenoid cystic carcinoma (ACC) is an exocrine gland tumor accounting for approximately 10%-15% of all epithelial salivary neoplasms and occurs most often in the parotid and submandibular glands. Metastatic pituitary tumors are rare, and there is only 1 previously reported case of parotid ACC metastatic to the pituitary. Magnetic resonance elastography (MRE) is a dynamic magnetic resonance imaging (MRI)-based technique that measures the propagation of mechanically induced shear waves through a particular tissue to determine stiffness and offers a method to evaluate tissue consistency. We present the case of a 72-year-old woman with a remote history of parotid gland ACC and subsequent lung metastases presented after a fall that resulted in facial trauma. A non-contrast head computed tomography scan revealed a sellar/suprasellar mass, and follow-up MRI revealed a well-defined, enhancing 3.8-cm lesion. MRE showed the tumor to be firm. The tumor was resected through a transsphenoidal approach and was consistent with the MRE findings. Pathology returned as metastatic ACC. We report the second case of ACC metastatic to pituitary and the first firm pituitary tumor found by MRE and discuss the potential diagnostic value of MRE in pituitary lesions.


Physiological performance and work capacity of Sudanese cane cutters with Schistosoma mansoni infection.
Physiological tests of work performance and measurement of field productivity were made in 194 Sudanese cane cutters in order to study the effect of Schistosoma mansoni infection. The cane cutters were selected from two age ranges (16-24 and 25-45 years) and subdivided into three clinical groups: not infected, infected with, and infected without clinical signs of hepatosplenomegaly. Men infected with Schistosoma haemotobium, malaria (blood film), or with hemoglobin levels less than 10 g/100 ml were excluded. There was a statistically significant (P less than 0.002) higher mean hemoglobin concentration in those not infected but the mean difference was less than 1 g/100 ml. Submaximal responses to exercise on a stationary bicycle ergometer, oxygen intake, ventilation, tidal volume, cardiac frequency and estimated maximal aerobic power output calculated both in absolute terms and relative to lean body mass and leg volume were similar in the six groups of cane cutters. No significant differences were found in physique, body composition or in thermoregulatory function tests. The cane cutters were found to have little natural acclimatization to heat in terms of sweating capacity when compared with a group of fully acclimatized Sudanese soldiers. The mean productivity (mean daily weight of cane cut per man) was significantly correlated with the individual's estimated maximum aerobic capacity determined in the laboratory, but not with the degree of S. mansoni infection. The noninfected group was less "efficient" (mean productivity:oxygen intake) during cutting than the infected groups but a larger proportion of the noninfected were in their first season of cutting. There was a positive correlation between the number of seasons' cutting experience and the individual's age, degree of infection and mean productivity. Cane cutters studied in this investigation were a relatively fit, active population from whom the more seriously ill were excluded. These results do not, therefore necessarily reflect the effects of S. mansoni on physiological work capacity and productivity of more static populations in areas of high endemicity.


Regulation of CncC in insecticide-induced expression of cytochrome P450 CYP9A14 and CYP6AE11 in Helicoverpa armigera.
The expression of many detoxification genes can be regulated by CncC pathway and contributes to insecticide tolerance in insects. Our previous study has demonstrated that the transcripts of CncC and cytochrome P450s (CYP9A14, CYP6AE11) were significantly up-regulated after different insecticides treatment in Helicoverpa armigera. Further study indicated that H2O2, GSH, and MDA contents and antioxidant enzyme activities of H. armigera were enhanced after chlorantraniliprole, cyantraniliprole, indoxacarb, and spinosad exposure. Silencing CncC by RNA interference significantly down-regulated the expression levels of CYP9A14 and CYP6AE11, and increased the susceptibility of dsRNA-injected larvae to λ-cyhalothrin, chlorantraniliprole, and cyantraniliprole. On the contrary, applying CncC agonist curcumin on H. armigera induced the expression of CYP9A14 and CYP6AE11, and enhanced the tolerance of H. armigera to insecticides. Treatment of ROS scavenger N-acetylcysteine on H. armigera reduced the H2O2 content and antioxidant enzyme activities, suppressed the transcripts of CncC, CYP9A14, and CYP6AE11, and decreased the larval tolerance to insecticides. These results demonstrated that the induced-expression of CYP9A14 and CYP6AE11 related with insecticides tolerance in H. armigera was regulated by CncC, which may be activated by ROS generated by insecticides. This study will help to better understand the underlying regulation mechanisms of CncC pathway in H. armigera tolerance to insecticides.


Transient receptor potential melastatin-3 in the rat sensory ganglia of the trigeminal, glossopharyngeal and vagus nerves.
Transient receptor potential melastatin-3 (TRPM3) is a nonselective cation channel, has permeability of Ca2+, and probably participates in thermosensitive nociception. In this study, immunohistochemistry for TRPM3 was conducted in the rat trigeminal, glossopharyngeal and vagal sensory ganglia. TRPM3-immunoreactivity was expressed by half of sensory neurons in the trigeminal (TG), petrosal (PG) and jugular ganglia (JG), and by about 80% of sensory neurons in the nodose ganglion (NG). They mostly had small to medium-sized cell bodies. A trichrome immunofluorescence method showed co-existence of TRPM3 with TRP vanilloid 1 (TRPV1) and calcitonin gene-related peptide (CGRP). Approximately 70% of TRPM3-immunoreactive (-IR) neurons contained TRPV1-immunoreactivity in all the examined ganglia. More than 40% of TRPM3-IR neurons exhibited CGRP-immunoreactivity in the TG, PG and JG. Only a few sensory neurons co-expressed TRPM3- and CGRP-immunoreactivity in the NG. In addition, more than 40% of TRPM3-IR neurons bound to isolectin B4 in all the examined ganglia. By combination of retrograde tracing method and immunohistochemistry, half of TG neurons innervating the facial skin and incisive papilla expressed TRPM3-immunoreactivity whereas approximately 20% of those innervating the tooth pulp contained TRPM3-immunoreactivity. Co-expression of TRPM3-immunoreactivity with TRPV1- or CGRP-immunoreactivity was common among cutaneous and papillary TG neurons but not among pulpal TG neurons. More than 60% of PG and JG neurons innervating the external ear canal skin and circumvallate papilla contained TRPM3-immunoreactivity. Co-expression of TRPM3 with TRPV1 or CGRP was common among PG and JG neurons innervating the external ear canal skin. However, a smaller number of TRPM3-IR neurons co-expressing TRPV1- or CGRP-immunoreactivity innervate the circumvallate papilla in the PG. The present study suggests that expression of TRPM3 and its co-existence with TRPV1 and CGRP in sensory neurons depend on the variety of their peripheral targets in the trigeminal, glossopharyngeal and vagal nervous systems.


Development of Loop-Mediated Isothermal Amplification (LAMP) Assay for Rapid Detection of Cannabis sativa.
In many parts of the world, the possession and cultivation of Cannabis sativa L. are restricted by law. As chemical or morphological analyses cannot identify the plant in some cases, a simple yet accurate DNA-based method for identifying C. sativa is desired. We have developed a loop-mediated isothermal amplification (LAMP) assay for the rapid identification of C. sativa. By optimizing the conditions for the LAMP reaction that targets a highly conserved region of tetrahydrocannabinolic acid (THCA) synthase gene, C. sativa was identified within 50 min at 60-66°C. The detection limit was the same as or higher than that of conventional PCR. The LAMP assay detected all 21 specimens of C. sativa, showing high specificity. Using a simple protocol, the identification of C. sativa could be accomplished within 90 min from sample treatment to detection without use of special equipment. A rapid, sensitive, highly specific, and convenient method for detecting and identifying C. sativa has been developed and is applicable to forensic investigations and industrial quality control.


The effect of alternative staff time data collection methods on drug treatment service cost estimates.
Although a limited number of service cost estimates exist, no study has evaluated how differences in the method used to collect the staff time allocation across treatment services contribute to differences in service cost estimates. Three alternative data collection methods for estimating service-level costs in methadone treatment programs were evaluated: key informants, staff surveys, and staff diaries. We analyzed data from 25 methadone clinics across the United States. Results indicate that for the three primary services offered at methadone clinics-individual counseling, group counseling, and methadone dosing-no statistically significant differences exist in the mean estimates of costs per session across programs. Of the other five services analyzed, we found no statistically significant differences in two of the mean costs per session and a small but statistically significant difference in another service. We found large and statistically significant differences in mean costs for two services, initial patient assessment and initial medical services. Although there is no gold standard available to judge which method is the best to use, we concluded that the key informant method yields more reliable cost estimates compared with the staff methods and is less burdensome to both the treatment programs and to researchers. Our findings suggest that the key informant method is the preferred method for costing substance abuse treatment services.


The histone variant H3.3 G34W substitution in giant cell tumor of the bone link chromatin and RNA processing.
While transcription as regulated by histones and their post-translational modifications has been well described, the function of histone variants in this process remains poorly characterized. Potentially important insight into this process pertain to the frequently occurring mutations of H3.3, leading to G34 substitutions in childhood glioblastoma and giant cell tumor of the bone (GCTB). In this study, we have established primary cell lines from GCTB patients and used them to uncover the influence of H3.3 G34W substitutions on cellular growth behavior, gene expression, and chromatin compaction. Primary cell lines with H3.3 G34W showed increased colony formation, infiltration and proliferation, known hallmarks of tumor development. Isogenic cell lines with H3.3 G34W recapitulated the increased proliferation observed in primary cells. Transcriptomic analysis of primary cells and tumor biopsies revealed slightly more downregulated gene expression, perhaps by increased chromatin compaction. We identified components related to splicing, most prominently hnRNPs, by immunoprecipitation and mass spectrometry that specifically interact with H3.3 G34W in the isogenic cell lines. RNA-sequencing analysis and hybridization-based validations further enforced splicing aberrations. Our data uncover a role for H3.3 in RNA processing and chromatin modulation that is blocked by the G34W substitution, potentially driving the tumorigenic process in GCTB.


Redirecting the specificity of tripartite motif containing-21 scaffolds using a novel discovery and design approach.
Hijacking the ubiquitin proteasome system to elicit targeted protein degradation (TPD) has emerged as a promising therapeutic strategy to target and destroy intracellular proteins at the post-translational level. Small molecule-based TPD approaches, such as proteolysis-targeting chimeras (PROTACs) and molecular glues, have shown potential, with several agents currently in clinical trials. Biological PROTACs (bioPROTACs), which are engineered fusion proteins comprised of a target-binding domain and an E3 ubiquitin ligase, have emerged as a complementary approach for TPD. Here, we describe a new method for the evolution and design of bioPROTACs. Specifically, engineered binding scaffolds based on the third fibronectin type III domain of human tenascin-C (Tn3) were installed into the E3 ligase tripartite motif containing-21 (TRIM21) to redirect its degradation specificity. This was achieved via selection of naïve yeast-displayed Tn3 libraries against two different oncogenic proteins associated with B-cell lymphomas, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) and embryonic ectoderm development protein (EED), and replacing the native substrate-binding domain of TRIM21 with our evolved Tn3 domains. The resulting TRIM21-Tn3 fusion proteins retained the binding properties of the Tn3 as well as the E3 ligase activity of TRIM21. Moreover, we demonstrated that TRIM21-Tn3 fusion proteins efficiently degraded their respective target proteins through the ubiquitin proteasome system in cellular models. We explored the effects of binding domain avidity and E3 ligase utilization to gain insight into the requirements for effective bioPROTAC design. Overall, this study presents a versatile engineering approach that could be used to design and engineer TRIM21-based bioPROTACs against therapeutic targets.


Hypothermic Oxygenated Machine Perfusion of Extended Criteria Kidney Allografts from Brain Dead Donors: Protocol for a Prospective Pilot Study.
Kidney transplantation is the only curative treatment option for end-stage renal disease. The unavailability of adequate organs for transplantation has resulted in a substantial organ shortage. As such, kidney donor allografts that would have previously been deemed unsuitable for transplantation have become an essential organ pool of extended criteria donor allografts that are now routinely being transplanted on a global scale. However, these extended criteria donor allografts are associated with significant graft-related complications. As a result, hypothermic oxygenated machine perfusion (HOPE) has emerged as a powerful, novel technique in organ preservation, and it has recently been tested in preclinical trials in kidney transplantation. In addition, HOPE has already provided promising results in a few clinical series of liver transplantations where the liver was donated after cardiac death. The present trial is an investigator-initiated prospective pilot study on the effects of HOPE on extended criteria donor allografts donated after brain death and used in kidney transplantation. A total of 15 kidney allografts with defined inclusion/exclusion criteria will be submitted to two hours of HOPE via the renal artery before implantation, and are going to be compared to a case-matched group of 30 patients (1:2 matching) who had kidneys transplanted after conventional cold storage. Primary (posttransplant dialysis within 7 days) and secondary (postoperative complications, early graft function, duration of hospital and intensive care unit stay, and six-month graft survival) endpoints will be analyzed within a six-month follow-up period. The extent of ischemia-reperfusion injury will be assessed using kidney tissue, perfusate, and serum samples taken during the perioperative phase of kidney transplantation. The results of this trial are expected in the first quarter of 2020 and will be presented at national and international scientific meetings and published in international peer-reviewed medical journals. The trial was funded in the third quarter of 2017 and patient enrollment is currently ongoing. This prospective study is designed to explore the effects of HOPE on extended criteria donor kidney allografts donated after brain death. The present report represents the preresults phase. Clinicaltrials.gov NCT03378817; https://clinicaltrials.gov/ct2/show/NCT03378817.


Evidence accumulation detected in BOLD signal using slow perceptual decision making.
We assessed whether evidence accumulation could be observed in the BOLD signal during perceptual decision making. This presents a challenge since the hemodynamic response is slow, while perceptual decisions are typically fast. Guided by theoretical predictions of the drift diffusion model, we slowed down decisions by penalizing participants for incorrect responses. Second, we distinguished BOLD activity related to stimulus detection (modeled using a boxcar) from activity related to integration (modeled using a ramp) by minimizing the collinearity of GLM regressors. This was achieved by dissecting a boxcar into its two most orthogonal components: an "up-ramp" and a "down-ramp." Third, we used a control condition in which stimuli and responses were similar to the experimental condition, but that did not engage evidence accumulation of the stimuli. The results revealed an absence of areas in parietal cortex that have been proposed to drive perceptual decision making but have recently come into question; and newly identified regions that are candidates for involvement in evidence accumulation. Previous fMRI studies have either used fast perceptual decision making, which precludes the measurement of evidence accumulation, or slowed down responses by gradually revealing stimuli. The latter approach confounds perceptual detection with evidence accumulation because accumulation is constrained by perceptual input. We slowed down the decision making process itself while leaving perceptual information intact. This provided a more sensitive and selective observation of brain regions associated with the evidence accumulation processes underlying perceptual decision making than previous methods.


Malignant atrophic papulosis. A report of two cases with altered fibrinolysis and platelet function.
Malignant atrophic papulosis is a systemic vaso-occlusive disorder characterized by typical skin lesions. We report two new cases with impairment of blood fibrinolytic activity and alterations in platelet function. The first case showed an increase in plasminogen activator inhibitor-1 (PAI-1) activity, and the second case had a decrease in platelet aggregation induced by adenosine diphosphate and adrenaline but normal with collagen. The impairment of blood fibrinolytic activity and platelet aggregation may have pathogenic and therapeutic implications in malignant atrophic papulosis.


Diffusivelike Motions in a Solvent-Free Protein-Polymer Hybrid.
The interaction between proteins and hydration water stabilizes protein structure and promotes functional dynamics, with water translational motions enabling protein flexibility. Engineered solvent-free protein-polymer hybrids have been shown to preserve protein structure, function, and dynamics. Here, we used neutron scattering, protein and polymer perdeuteration, and molecular dynamics simulations to explore how a polymer dynamically replaces water. Even though relaxation rates and vibrational properties are strongly modified in polymer coated compared to hydrated proteins, liquidlike polymer dynamics appear to plasticize the conjugated protein in a qualitatively similar way as do hydration-water translational motions.


Effectiveness of an overall progressive resistance strength program for improving the functional capacity of patients with rheumatoid arthritis: a randomized controlled trial.
To evaluate the effectiveness of overall progressive resistance training in patients with rheumatoid arthritis. Randomized controlled clinical trial with blinded assessor and intention-to-treat analysis. Outpatient clinics. Sixty patients with rheumatoid arthritis according to the American College of Rheumatology criteria, aged between 18 and 65 years old, under stable medication and not performing regular physical activity were randomized into two groups: intervention group (IG) and control group (CG). IG performed the progressive resistance strength training, twice a week, during 12 weeks. The training consists of exercising various muscle groups using a load of 50% and 70% of one repetition maximum. The load was reassessed and adjusted after six weeks of baseline. Both groups remained in conventional drug treatment during the study. Patients were evaluated at baseline and after 6, 12, and 24 weeks, using HAQ and SF-36 questionnaires and strength. Thirty-three patients in the CG and 27 in the IG were evaluated. The groups were homogeneous at baseline. Statistical and clinical improvement were found with better results for the IG in the HAQ questionnaire ( P=0.030), functional capacity (0=0.022) and pain ( P=0.027) domains of SF-36; and muscle strength for flexors of right and left knee ( P=0.005 and p=0.14), abductors of shoulder ( P=0.041) and extensors of right and left wrists ( P=0.003 and P= 0.005). This progressive resistance strength training improves physical function as well as grip and muscular strength of knee flexors, shoulder abductors and wrist extensors in patients with RA, without adverse effects.


Reactive oxygen production by cultured rat glomerular mesangial cells during phagocytosis is associated with stimulation of lipoxygenase activity.
To investigate the phagocytic capability of glomerular mesangial cells and the biochemical events associated with phagocytosis, rat cultured mesangial cells were incubated in the presence of opsonized zymosan (STZ) and production of reactive-oxygen species and lipoxygenase products were determined. Mesangial cells were identified on the basis of morphologic (presence of microfilaments and pattern of staining by an anti-myosin antiserum) and physiologic (contractile activity in response to angiotensin II) characteristics. No contamination by esterase-positive cells was observed. Electron microscopy revealed that the phagocytic process started after 5 min of incubation, and affected approximately 50% of the cells. Superoxide anion (.O2-) and hydrogen peroxide (H2O2) generation by mesangial cells exposed to STZ increased with time and STZ concentration. Cells incubated with zymosan particles treated with heated serum produced undetectable amounts of .O2- and 6 times less H2O2 than cells exposed to STZ. Pretreatment by cytochalasin B produced a marked decrease in STZ-stimulated production of reactive oxygen species. [3H]Arachidonic acid was incorporated into mesangial cell phospholipids and its release and conversion into monohydroxyeicosatetraenoic acids (HETE) was measured by radiometric high performance liquid chromatography (HPLC). Incubation with STZ markedly stimulated the release of arachidonic acid from its phospholipid stores and its transformation into 11-, 12-, and 15-HETE. Lipoxygenase inhibitors inhibited STZ-stimulated H2O2 production, whereas they did not modify the phagocytic process as shown by the absence of any effect on the uptake of 125I-STZ by the mesangial cells. This study demonstrates that a high percentage of rat cultured mesangial cells phagocytose opsonized particles. The phagocytic process results in an oxidative burst that appears to be dependent on stimulation of the lipoxygenase pathway.


Gated blood pool scintigraphy as a tool for non-invasive measurements of left ventricular function.
Gated Blood Pool Scintigraphy (GBPS), i.e. the noninvasive evaluation of ventricular performance following the administration of radionuclides as intravascular tracers has had a major impact on many aspects of cardiology and has proven its clinical value and reliability in the past years. Today it is an accepted method in clinical practice, permitting the assessment of both global and regional cardiac function. The most important parameters derived from GBPS volume curves for the determination of left ventricular global function are ejection fraction (EF) at rest and under exercise and peak filling rate of the left ventricle at rest. In addition, GBPS permits the assessment of regional left ventricular function by determining regional EF and phase shifts. Echocardiography is no true alternative to GBPS due to frequent problems in quantitative evaluation and unpredictable errors in patients with non-uniform heart geometry or dyskinetic left ventricles. Thus, GBPS is not only useful in a wide variety of clinical settings, but has become an accepted tool in the methodological approach for non-invasive evaluation of new drugs and sequential drug therapy monitoring. This application of GBPS can be particularly recommended for the investigation of two different problems: a) exclusion of adverse drug effects on left ventricular performance in the process of drug safety evaluation, and b) demonstration of hemodynamic effects of new drugs particularly after long-term medication. GBPS provides valuable information as to the type, onset and duration of hemodynamic changes, permitting the determination of regional changes in myocardial function as well as its global evaluation.(ABSTRACT TRUNCATED AT 250 WORDS)


[Comparative effectiveness of rifampicin for parenteral administration and internal dose in the treatment of experimental plague in albino mice].
The therapeutic effects of parenteral and oral rifampicins were studied comparatively in a model of experimental plague of albino mice infected subcutaneously and by aerosol. The study showed that in a dose of 25 mg/kg rifampicin was highly efficient in the treatment of the albino mice with experimental glandular plague when the drug was administered either parenterally or orally for 7 days (100-percent survival). The parenteral rifampicin was advantageous when used in lower doses (6.25-12.5 mg/kg) or for a shorter period (3-5 days): 70-100-percent survival against not more than 30 per cent with the oral administration of the drug. It was especially evident when the animals were infected by aerosol. The results made it possible to recommend rifampicin injections in the treatment of the most severe forms of pneumonic plague.


Standardization of laparoscopic left hemicolectomy: a single-center experience of 484 cases.
Aim: Laparoscopic surgery has become recognized as an established technique for colon diseases and many different surgical techniques have been described. The aim of our study is to show the results of a single institution where a standardized operative and perioperative procedure for laparoscopic left hemicolectomy (LLH) has been used. Methods: Between January 2005 and April 2011, 484 patients underwent LLH for colon diseases. Data collected included age, indication for surgery, ASA class, body mass index, operating time, intra and post-operative complications, conversion rate, length of hospital stay, tumor stage, number of lymph nodes harvested, mortality, and a 30-day readmission rate. Results: We found 299 cancer, 29 large dysplastic polyps and 156 complicated diverticular diseases. Average operation time was 120 minutes. The average hospital stay was 5.7 days. In the cancer group, the average number of lymph nodes harvested was 12.7. The intraoperative and early postoperative complications were 3.3% and 10.7 % respectively. The conversion rate was 3.7%. The 30-day readmission rate was 3%. The 30-day mortality rate was 0.4%. Conclusion: The standardization of the LLH technique might reduce the technical difficulties and complications. Its potential benefits include the standardization of surgical instrument sets, the definition of benchmarks for conversion before making any inappropriate investment in time and equipment, low rates of complications and readmission rate.


Electronic Excitations in Complex Molecular Environments: Many-Body Green's Functions Theory in VOTCA-XTP.
Many-body Green's functions theory within the GW approximation and the Bethe-Salpeter Equation (BSE) is implemented in the open-source VOTCA-XTP software, aiming at the calculation of electronically excited states in complex molecular environments. Based on Gaussian-type atomic orbitals and making use of resolution of identity techniques, the code is designed specifically for nonperiodic systems. Application to a small molecule reference set successfully validates the methodology and its implementation for a variety of excitation types covering an energy range from 2 to 8 eV in single molecules. Further, embedding each GW-BSE calculation into an atomistically resolved surrounding, typically obtained from Molecular Dynamics, accounts for effects originating from local fields and polarization. Using aqueous DNA as a prototypical system, different levels of electrostatic coupling between the regions in this GW-BSE/MM setup are demonstrated. Particular attention is paid to charge-transfer (CT) excitations in adenine base pairs. It is found that their energy is extremely sensitive to the specific environment and to polarization effects. The calculated redshift of the CT excitation energy compared to a nucelobase dimer treated in vacuum is of the order of 1 eV, which matches expectations from experimental data. Predicted lowest CT energies are below that of a single nucleobase excitation, indicating the possibility of an initial (fast) decay of such an UV excited state into a binucleobase CT exciton. The results show that VOTCA-XTP's GW-BSE/MM is a powerful tool to study a wide range of types of electronic excitations in complex molecular environments.


Visual Saliency Detection Based on Multiscale Deep CNN Features.
Visual saliency is a fundamental problem in both cognitive and computational sciences, including computer vision. In this paper, we discover that a high-quality visual saliency model can be learned from multiscale features extracted using deep convolutional neural networks (CNNs), which have had many successes in visual recognition tasks. For learning such saliency models, we introduce a neural network architecture, which has fully connected layers on top of CNNs responsible for feature extraction at three different scales. The penultimate layer of our neural network has been confirmed to be a discriminative high-level feature vector for saliency detection, which we call deep contrast feature. To generate a more robust feature, we integrate handcrafted low-level features with our deep contrast feature. To promote further research and evaluation of visual saliency models, we also construct a new large database of 4447 challenging images and their pixelwise saliency annotations. Experimental results demonstrate that our proposed method is capable of achieving the state-of-the-art performance on all public benchmarks, improving the F-measure by 6.12% and 10%, respectively, on the DUT-OMRON data set and our new data set (HKU-IS), and lowering the mean absolute error by 9% and 35.3%, respectively, on these two data sets.


Extensor mechanism allograft in total knee arthroplasty.
To analyze the experience with allograft transplantation of the extensor mechanism in total knee arthroplasty and compare results with the international experience. We retrospectively evaluated three cases of extensor mechanism allograft after total knee arthroplasty performed in our hospital with the aid of one of the few tissue banks in Brazil and attempt to establish whether our experiences were similar to others reported in the world literature regarding patient indication, techniques, and outcomes. Two cases went well with the adopted procedure, and one case showed bad results and progressed to amputation. As shown in the literature, the adequate tension of the graft, appropriate tibial fixation and especially the adequate patient selection are the better predictors of good outcomes. Previous chronic infection can be an unfavorable predictor. This surgical procedure has precise indication, albeit uncommon, either because of the rarity of the problem or because of the low availability of allografts, due to the scarcity of tissue banks in Brazil. Level of Evidence IV, Case Series.


Distribution of the src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells.
The termination of activation signals is a critical step in the control of the immune response; perturbation of inhibitory feedback pathways results in profound immune defects culminating in autoimmunity and overwhelming inflammation. FcgammaRIIB receptor is a well described inhibitory receptor. The ligation of B-cell receptor (BCR) and FcgammaRIIB leads to the inhibition of B-cell activation. Numerous studies have demonstrated that the SH2-domain-containing inositol 5-phosphatase SHIP (referred hereto as SHIP-1) is essential in this process. The cDNA encoding a second SH2-domain-containing inositol 5-phosphatase, SHIP-2, has been cloned [Pesesse, Deleu, De Smedt, Drayer and Erneux (1997) Biochem. Biophys. Res. Commun. 239, 697-700]. Here we report the distribution of SHIP-2 in mouse tissues: a Western blot analysis of mouse tissues reveals that SHIP-2 is expressed in both haemopoietic and non-haemopoietic cells. In addition to T-cell and B-cell lines, spleen, thymus and lung are shown to coexpress SHIP-1 and SHIP-2. Moreover, SHIP-2 is detected in fibroblasts, heart and different brain areas. SHIP-2 shows a maximal tyrosine phosphorylation and association to Shc after ligation of BCR to FcgammaRIIB but not after stimulation of BCR alone. Our results therefore suggest a possible role for SHIP-2 in the negative regulation of immunocompetent cells.


Superior potency of infused IGF-I analogues which bind poorly to IGF-binding proteins is maintained when administered by injection.
The relative potency of IGF-I and the analogue LR3IGF-I to either promote growth or reverse catabolism in rats when administered by injection rather than by continuous infusion has been examined. LR3IGF-I has very low affinity for the IGF-binding proteins in the rat and hence is cleared from the circulation more quickly than is IGF-I. Experiments were performed in normal growing rats (150 g body weight) and in rats made catabolic by dexamethasone infusion (20 micrograms/day). IGFs or vehicle were delivered subcutaneously for 7 days either by continuous infusion via osmotic pumps or by injection once or twice daily at 320 and 400 micrograms/day in normal and catabolic rats respectively. As expected, continuous infusion of IGFs showed greater efficacy than either of the injection modes especially in its anti-catabolic actions. When infused continuously LR3IGF-I was generally 1.5- to 2-fold more potent than IGF-I for changes in body weight gain, visceral organ weights and feed use efficiency. Notably, LR3IGF-I remained more potent than IGF-I in several of these effects even when the peptides were given by once-daily injection. In addition, N tau-methylhistidine excretion by dexamethasone-treated rats was reduced to a threefold greater extent by injected LR3IGF-I than by injected IGF-I. Notwithstanding these effects, LR3IGF-I was barely equipotent with IGF-I for reversal of carcass muscle loss in dexamethasone-treated rats. Despite its more rapid clearance from the circulation, injected LR3IGF-I retains superior potency to injected IGF-I for several actions, albeit the potency is much reduced compared with continuous infusion. Thus our data indicate that use of IGF analogues which have low affinity for binding proteins may have advantages in potency and/or tissue specificity where IGFs are necessarily administered by injection.


Development of Korean standard brain templates.
We developed age, gender and ethnic specific brain templates based on MR and Positron-Emission Tomography (PET) images of Korean normal volunteers. Seventy-eight normal right-handed volunteers (M/F=49/29) underwent 3D T1-weighted SPGR MR and F-18-FDG PET scans. For the generation of standard templates, an optimal target brain that has the average global hemispheric shape was selected for each gender. MR images were then spatially normalized by linear transformation to the target brains, and normalization parameters were reapplied to PET images. Subjects were subdivided into 2 groups for each gender: the young/midlife (<55 yr) and the elderly groups. Young and elderly MRI/PET templates were composed by averaging the spatially normalized images. Korean templates showed different shapes and sizes (mean length, width, and height of the brains were 16.5, 14.3 and 12.1 cm for man, and 15.6, 13.5 and 11.4 cm for woman) from the template based on Caucasian (18.3, 14.2, and 13.3 cm). MRI and PET templates developed in this study will provide the framework for more accurate stereotactic standardization and anatomical localization.


Value of Online Group Reflection After International Service-Learning Experiences: I Never Thought of That.
Reflection is a widely accepted learning tool and a component of competent professional practice. An exploratory descriptive study was conducted to compare the breadth and level of reflection between students engaged in individual reflection papers and students engaged in an online group reflection discussion after an international cultural immersion service-learning program. Results indicated that students participating in the online group discussion had a higher level of reflective thinking and discussed more topics in their written reflections.


Worse outcomes in patients undergoing urgent surgery for left-sided diverticulitis admitted on weekends vs weekdays: a population-based study of 31 832 patients.
Among patients undergoing urgent surgery for left-sided diverticulitis, those admitted on weekends vs weekdays have higher rates of Hartmann procedure and adverse outcomes. Analysis of data from the Nationwide Inpatient Sample between January 2002 and December 2008. Unadjusted and risk-adjusted generalized linear regression models were used. Academic research. Data on patients undergoing urgent surgery for acute diverticulitis. Rates of Hartmann procedure vs primary anastomosis, complications, length of hospital stay, and total hospital charges. In total, 31 832 patients were included; 7066 (22.2%) were admitted on weekends, and 24 766 (77.8%) were admitted on weekdays. The mean (SD) age of patients was 60.8 (15.3) years, and 16 830 (52.9%) were female. A Hartmann procedure was performed in 4580 patients (64.8%) admitted on weekends compared with 13 351 patients (53.9%) admitted on weekdays (risk-adjusted odds ratio [OR], 1.57; P < .001). In risk-adjusted analyses, patients admitted on weekends had significantly higher risk for any postoperative complication (OR, 1.10; P = .005) and nonroutine hospital discharge (OR, 1.33; P < .001) compared with patients admitted on weekdays, as well as a median length of hospital stay that was 0.5 days longer and median total hospital charges that were $3734 higher (P < .001 for both). Patients undergoing urgent surgery for left-sided diverticulitis who are admitted on a weekend have a higher risk for undergoing a Hartmann procedure and worse short-term outcomes compared with patients who are admitted on a weekday. Further research is warranted to investigate possible underlying mechanisms and to develop strategies for reducing this substantial weekend effect.


Prevention of diarrhoea in young children: abundant experience in developing countries.
(1) The prevention of diarrhoea in young children has been the subject of many intervention studies in developing countries, and their combined results identify the most effective measures. (2) While it lasts, maternal breast-feeding reduces the overall mortality and mortality linked to diarrhoea. (3) In vitamin A-deficient children, supplementation reduces overall mortality and deaths specifically due to diarrhoea. (4) Maternal education on weaning can improve children's nutritional status and may thereby reduce mortality related to diarrhoea. (5) The promotion of personal and domestic hygiene reduces morbidity due to diarrhoea. (6) Facilitating access to drinking water and sanitation is a very effective way of reducing overall childhood mortality.


Women have higher protein content of beta-oxidation enzymes in skeletal muscle than men.
It is well recognized that compared with men, women have better ultra-endurance capacity, oxidize more fat during endurance exercise, and are more resistant to fat oxidation defects i.e. diet-induced insulin resistance. Several groups have shown that the mRNA and protein transcribed and translated from genes related to transport of fatty acids into the muscle are greater in women than men; however, the mechanism(s) for the observed sex differences in fat oxidation remains to be determined. Muscle biopsies from the vastus lateralis were obtained from moderately active men (N=12) and women (N=11) at rest to examine mRNA and protein content of genes involved in lipid oxidation. Our results show that women have significantly higher protein content for tri-functional protein alpha (TFPalpha), very long chain acyl-CoA dehydrogenase (VLCAD), and medium chain acyl-CoA dehydrogenase (MCAD) (P<0.05). There was no significant sex difference in the expression of short-chain hydroxyacyl-CoA dehydrogenase (SCHAD), or peroxisome proliferator activated receptor alpha (PPARalpha), or PPARgamma, genes potentially involved in the transcriptional regulation of lipid metabolism. In conclusion, women have more protein content of the major enzymes involved in long and medium chain fatty acid oxidation which could account for the observed differences in fat oxidation during exercise.


Gene cluster conservation provides insight into cercosporin biosynthesis and extends production to the genus Colletotrichum.
Species in the genus Cercospora cause economically devastating diseases in sugar beet, maize, rice, soy bean, and other major food crops. Here, we sequenced the genome of the sugar beet pathogen Cercospora beticola and found it encodes 63 putative secondary metabolite gene clusters, including the cercosporin toxin biosynthesis (CTB) cluster. We show that the CTB gene cluster has experienced multiple duplications and horizontal transfers across a spectrum of plant pathogenic fungi, including the wide-host range Colletotrichum genus as well as the rice pathogen Magnaporthe oryzae Although cercosporin biosynthesis has been thought to rely on an eight-gene CTB cluster, our phylogenomic analysis revealed gene collinearity adjacent to the established cluster in all CTB cluster-harboring species. We demonstrate that the CTB cluster is larger than previously recognized and includes cercosporin facilitator protein, previously shown to be involved with cercosporin autoresistance, and four additional genes required for cercosporin biosynthesis, including the final pathway enzymes that install the unusual cercosporin methylenedioxy bridge. Lastly, we demonstrate production of cercosporin by Colletotrichum fioriniae, the first known cercosporin producer within this agriculturally important genus. Thus, our results provide insight into the intricate evolution and biology of a toxin critical to agriculture and broaden the production of cercosporin to another fungal genus containing many plant pathogens of important crops worldwide.


High-density vs low-density lipoprotein cholesterol as the risk factor for coronary artery disease and stroke in old age.
A high total serum cholesterol level does not carry a risk of cardiovascular mortality among people 85 years and older and is related to decreased all-cause mortality. At this old age, there are few data on fractionated lipoprotein levels in the determination of cardiovascular disease risk. The aim of this study was to evaluate the relationships between low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels and mortality from specific causes among people in the oldest age categories. Between September 1, 1997, and September 1, 1999, a total of 705 inhabitants in the community of Leiden, the Netherlands, reached the age of 85 years. Among these old people, we initiated a prospective follow-up study to investigate determinants of successful aging. A total of 599 subjects participated (response rate, 87%) and all were followed up to September 2001. Serum levels of total, LDL, and HDL cholesterol were assessed at baseline along with detailed information on comorbid conditions. The main outcome measure was all-cause and specific mortality risk. During 4 years of follow-up, 152 subjects died. The leading cause of death was cardiovascular disease, with similar mortality risks in all tertiles of LDL cholesterol level. In contrast, low HDL cholesterol level was associated with a 2.0-fold higher risk of fatal cardiovascular disease (95% confidence interval [CI], 1.2-3.2). The mortality risk of coronary artery disease was 2.0 (95% CI, 1.0-3.9) and for stroke it was 2.6 (95% CI, 1.0-6.6). Both low LDL cholesterol and low HDL cholesterol concentrations were associated with an increased mortality risk of infection: 2.7 (95% CI, 1.2-6.2) and 2.4 (95% CI, 1.1-5.6), respectively. The risks were unaffected by comorbidity. In contrast to high LDL cholesterol level, low HDL cholesterol level is a risk factor for mortality from coronary artery disease and stroke in old age.


Targeting FBW7 as a Strategy to Overcome Resistance to Targeted Therapy in Non-Small Cell Lung Cancer.
Inhibition of EGFR and anaplastic lymphoma kinase (ALK) signaling is highly effective in a subgroup of non-small cell lung cancer (NSCLC) patients with distinct clinicopathologic features. However, resistance to EGFR and ALK inhibitors inevitably occurs, and the molecular mechanism underlying resistance is not fully understood. In this study, we report a PI3K/Akt- and MEK/ERK-independent resistance mechanism by which loss of the E3 ubiquitin ligase F-box and WD repeat domain containing 7 (FBW7α) leads to targeted therapy resistance via stabilization of antiapoptotic protein MCL-1. Using a panel of in vitro and in vivo studies, we showed that the regulatory machinery responsible for MCL-1 protein degradation was a step-wise event involving phosphorylation and nucleus translocation. ERK cooperated with GSKβ to phosphorylate MCL-1 Ser159 residue, which enabled MCL-1 to translocate into the nucleus and bind FBW7. Defects in this sequence impaired MCL-1 degradation and cell apoptosis, recapitulating phenotypes observed in FBW7 deficiency. Downregulation of FBW7 was found in EGFR inhibitor-resistant human NSCLC specimens and correlated with increased MCL-1 protein expression. Reactivation of FBW7 sensitized resistant cells to targeted therapy and facilitated MCL-1 degradation. Overall, our study provides proof-of-principle insight into a PI3K/Akt- and MEK/ERK-independent resistant model and suggests that targeting FBW7 can overcome resistance to targeted therapy. Cancer Res; 77(13); 3527-39. ©2017 AACR.


[Pronostic value of the immunohistochemical expression of cyclin D1 (DCS6) in epidermoid larynx carcinoma].
In this paper we carried out an immunohistochemical study of cyclin D1 (DCS6 ) expression in a series of 195 patients with laryngeal carcinoma that were diagnosticated, treated and followed at the Department of Otolaryngology at "Virgen de la Salud" Hospital (Toledo, Spain) for a time of 5 years. In the cases with lymph node metastasis we also studied cyclin D1 expression at this level. Furthermore we have analysed the value of cyclin D1 expression as a prognostic factor (tumor recurrence, deads due to cancer and survival) and we evaluate the relationship between cyclin D1 expression and other clinic and pathologic parameters.


Ploidy analysis and S-phase fraction determination by flow cytometry in anembryonic pregnancy and spontaneous abortions.
The nuclear DNA content of 20 anembryonic pregnancies was studied by flow cytometry from paraffin embedded tissue blocks. An abnormal amount of DNA content was found in 8 of the cases. This was a significantly higher percentage than encountered in spontaneous abortions studied by the same population (40 and 9%, respectively, p < 0.05). The S-phase fraction in anembryonic pregnancies was lower than in spontaneous abortions (22.4 +/- 12.7 and 35.4 +/- 6.8, respectively, p < 0.01). The results indicated that abnormal embryogenesis with grave chromosomal aberrations may play a major role in the etiology of anembryonic pregnancy.


Off-design considerations of the 50cc Penn State Ventricular Assist Device.
Particle image velocimetry is used to study the flow field associated with off-design conditions of the 50cc Penn State Ventricular Assist Device. Phase average data, for 300 consecutive beats, was acquired for 60, 75, and 90 beats per minute (bpm) at 35/65 systolic duration and at 75 bpm for 50/50 systolic duration. Diastolic flow is dominated by the inflow jet and shows more penetration and better wall washing at higher beat rates and shorter diastolic time. A flow separation near the minor orifice of the aortic valve, however, is larger under these conditions. Turbulent energy, which peaks during diastole, is found to be strongest at the edges of the jet and near the valves and scales well with the maximum inlet jet velocity. A region of potential separation on the right lateral wall is identified and will be relieved by geometric modifications of the evolving design.


Temperature dependence of the aggregation kinetics of Sup35 and Ure2p yeast prions.
Fungal prions are protein-based genetic elements. Sup35 and Ure2p constitute the best-characterized prion proteins in the yeast Saccharomyces cerevisiae. No high-resolution molecular models of the amyloid conformations adopted by the prion domains of these proteins are available yet. A quantitative description of the kinetics and thermodynamics of their self-assembly processes might provide clues on the nature of the structural changes originating their heritable and transmissible phenotypes. Here we study the temperature dependence of Sup35 and Ure2p amyloid fibril nucleation and elongation reactions at physiological pH. Both processes follow the Arrhenius law, allowing calculation of their associated thermodynamic activation parameters. Although the Gibbs energies (ΔG*) for the nucleation and elongation of both prions are similar, the enthalpic and entropic contributions to these two processes are dramatically different. In addition, the structural properties of the two types of prion fibrils exhibit different dependence on the polymerization temperature. Overall, we show here that the amyloidogenic pathways of Sup35 and Ure2p prions diverge significantly.


Peroxisome proliferator-activated receptor-γ regulates inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorates peripheral manifestations of heart failure.
Activation of peroxisome proliferator-activated receptor (PPAR)-γ, a nuclear transcription factor, has been shown to inhibit the production of proinflammatory cytokines and, in peripheral tissues, to downregulate the renin-angiotensin system. PPAR-γ is expressed in key brain areas involved in cardiovascular and autonomic regulation. We hypothesized that activation of central PPAR-γ would reduce sympathetic excitation and ameliorate peripheral manifestations of heart failure (HF) by inhibiting central inflammation and brain renin-angiotensin system activity. Two weeks after coronary artery ligation, HF rats received an intracerebroventricular infusion of the PPAR-γ agonist pioglitazone or vehicle for another 2 weeks. PPAR-γ expression in the paraventricular nucleus of hypothalamus, an important cardiovascular region, was unchanged in HF compared with sham-operated rats. However, PPAR-γ DNA binding activity was reduced, nuclear factor-κB activity was increased, and expression of proinflammatory cytokines and angiotensin II type-1 receptor was augmented in the HF rats. Mean blood pressure response to ganglionic blockade was greater; plasma norepinephrine levels, lung/body weight, right ventricle/body weight, and left ventricular end-diastolic pressure were increased; and maximal left ventricular dP/dt was decreased. All of these findings were ameliorated in HF rats treated with intracerebroventricular pioglitazone, which increased PPAR-γ expression and DNA binding activity in the paraventricular nucleus of hypothalamus. The results demonstrate that cardiovascular and autonomic mechanisms leading to heart failure after myocardial infarction can be modulated by activation of PPAR-γ in the brain. Central PPAR-γ may be a novel target for treatment of sympathetic excitation in myocardial infarction-induced HF.


Isoflavones of the soybean components and the effect of germination time in the cotyledons and embryonic axis.
The aim of this study was to evaluate the content of different forms of isoflavones of BRS 284 soybean components and the effect of germination time in the cotyledons, radicle, and hypocotyl. Seeds were germinated until 168 h at 35 °C and collected each 24 h. The isoflavone content was determined by ultraperformance liquid chromatography, and the data were subjected to regression analysis. In cotyledons, germination time had a quadratic effect on daidzin and genistin contents and a linear effect on malonyldaidzin and malonylgenistin contents. In radicles, germination time had a quadratic effect on daidzin, glycitin, malonylgenistin, and malonylglycitin contents in addition to a linear effect on malonyldaidzin content. In hypocotyls, germination time showed a cubic effect on daidzin and genistin contents, a quadratic effect on malonyldaidzin, malonylgenistin, and malonylglycitin contents, and a linear effect on genistein content; glycitin, daidzein and glycitein were detected in a few germination times.


Reporting Data on Auditory Brainstem Responses (ABR) in Rats: Recommendations Based on Review of Experimental Protocols and Literature.
Research in hearing science is accelerating, and a wealth of data concerning auditory brainstem responses (ABR) in various animal models is published in peer-reviewed journals every year. Recently, we reviewed studies using ABR measurements in tinnitus rat models. We found significant discrepancies in the outcomes of these studies, some due to different research approaches and others due to different methodologies. Thus, the present work aimed to collect comprehensive information on all factors influencing ABR recordings in rats and compile recommendations on ABR data reporting. A questionnaire with queries about animal husbandry, transfer, handling, and the exact test conditions before, during, and after ABR recordings was sent to 125 researchers who published the relevant studies between 2015 and 2021. Eighteen researchers provided detailed answers on factors related to ABR measurements. Based on the analysis of the returned questionnaires, we identified three domains reflecting animal-, equipment-, and experiment-dependent factors that might influence the ABR outcome, thus requiring reporting in published research. The analysis of survey results led to the compilation of recommendations for reporting ABR outcomes supported by a literature review. Following these recommendations should facilitate comparative and meta-analyses of ABR results provided by various research groups.


Intention to provide tobacco cessation counseling among Indonesian dental students and association with the theory of planned behavior.
Use of tobacco is a serious public health problem in Indonesia that requires a multidisciplinary approach by healthcare providers to address it. The study assessed the intentions of undergraduate students in dental schools to provide tobacco cessation counseling (TCC) and their association with the constructs of the theory of planned behavior (TPB). A cross sectional study was conducted in October 2019 using an electronic survey for dental students in Indonesian dental schools (n = 30). The survey assessed schools and students' characteristics and eleven statements assessed their perspectives toward TCC based on the TPB using a 5-point Likert scale. Principal component analysis (PCA) was used to identify components within the items of perspective. Multilevel linear regression analysis was used to assess the association between intention to provide TCC and the constructs of the TPB as identified in the perspectives' items using TPB controlling for confounders. About 1288 students participated from 30 dental schools, 83.3% females with mean age = 21.5 years with average intention to provide TCC = 4.3 out of 5. They had above average positive attitude about provision of TCC being the dentist's role (mean = 3.8 out of 5). PCA identified two components: confidence in their own abilities and perception of favorable environment with average scores = 3.2 and 2.7 out of 5. Intention to provide TCC was significantly associated with more positive attitude recognizing TCC as a dentist's role (B = 0.10, P < 0.0001), greater confidence in skills to provide TCC (B = 0.17, P < 0.0001) and less perception of favorable environment supportive off providing TCC (B = - 0.20, P < 0.0001). Indonesian dental students' intention to provide TCC can be explained by the constructs of the TPB. Development of dental curricula promoting professional responsibility toward TCC should be given attention. Improving students' attitude and confidence potentially may support their patients' efforts to quit smoking.