[Indicators and standards proposal for the evaluation of the quality of hospital care: the case for bronchial asthma]
The objectives of this article are to propose indicators for evaluation of the quality of hospital management of bronchial asthma patients, based on explicit criteria from literature reviews. The central problem identified in the literature review is the erroneous evaluation of severity of asthma crises, either by patients and their relatives, or by health professionals at all levels of care, causing serious consequences not only for the patient, but for society as a whole. Mortality figures indicate that from 1980 to 1990, an average of 2000 deaths per year from asthma occurred in Brazil, of which 70% occurred in hospital. Asthma was the fourth cause of hospitalization (hospital admissions), in the state of Rio de Janeiro in 1993. Only 12% of the admissions that resulted in death made use of the ICU. The above information highlights the need for a thorough evaluation of hospital care of bronchial asthma in Brazil, including a review of all admissions resulting in death and reviews of a sample of all bronchial asthma admissions. Proposed criteria are for this evaluation include: severity of the crise, treatment prescribed, information given to the patient and their relatives, and follow-up appointments made after discharge from hospital.


Oxidative stress suppression in C. elegans by peptides from dogfish skin via regulation of transcription factors DAF-16 and HSF-1.
Functional peptides were obtained via enzymatic hydrolysis of smooth dogfish (Mustelus canis) skin. The enzyme-assisted process was optimized to achieve high yield of smooth dogfish skin peptides (SDSP). Fractions of SDSP (MW < 2 kDa, 2-5 kDa, 5-10 kDa and >10 kDa) showed in vitro antioxidant activities. The peptides <2 kDa (SDSP<2 kDa) significantly improved motility, reduced ROS and H2O2 levels of Caenorhabditis elegans, and increased its resistance to oxidative stress compared to the other peptide fractions. In vivo function of SDSP<2 kDa could be explained by their capacity to increase the expression of stress-response genes. The enhanced resistance to oxidative stress mediated by SDSP<2 kDa was dependent on DAF-16 and HSF-1. The amino acid residues and sequences of SDSP<2 kDa were characterized and revealed a higher content of hydrophobic versus polar amino acid contents. This study (especially the in vivo investigation) explored new potent antioxidant peptides derived from dogfish skin.


Cognitive-Adaptive Trait Theory: A Shift in Perspective on Personality.
Traditional, biologically based trait theories have deservedly gained broad acceptance, but some long-standing core issues of personality research remain unresolved. Recent research questions whether (a) there can be a single universal structural model of personality superfactors, (b) current theory adequately specifies the processes that mediate behavioral and emotional expressions of traits, and (c) brain-based accounts of traits adequately explain their role in real-world functioning and adaptation. This article reviews the perspective on these issues provided by cognitive-adaptive trait theory. This theory rejects the view that personality dimensions directly reflect brain systems. Instead, traits correspond to variation in strategies for managing key adaptive challenges. Thus, each trait is expressed in environments that pose those challenges, and each trait corresponds to skills and self-knowledge that facilitate adaptation to those environments. The cognitive-adaptive theory affords novel perspectives on trait psychometrics, theoretical accounts of mediating processes, and real-world adaptation.


Requirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcription.
The mechanism by which bone morphogenetic protein-2 (BMP-2) induces osteoblast differentiation is not precisely known. We investigated the involvement of the phosphatidylinositol (PI) 3-kinase/Akt signal transduction pathway in modulation of this process. BMP-2 stimulated PI 3-kinase activity in osteogenic cells. Inhibition of PI 3-kinase activity with the specific inhibitor Ly-294002 prevented BMP-2-induced alkaline phosphatase, an early marker of osteoblast differentiation. Expression of dominant-negative PI 3-kinase also abolished osteoblastic induction of alkaline phosphatase in response to BMP-2, confirming the involvement of this lipid kinase in this process. BMP-2 stimulated Akt serine/threonine kinase activity in a PI 3-kinase-dependent manner in osteoblast precursor cells. Inhibition of Akt activity by a dominant-negative mutant of Akt blocked BMP-2-induced osteoblastic alkaline phosphatase activity. BMP-2 stimulates its own expression during osteoblast differentiation. Expression of dominant-negative PI 3-kinase or dominant-negative Akt inhibited BMP-2-induced BMP-2 transcription. Because all the known biological activities of BMP-2 are mediated by transcription via BMP-specific Smad proteins, we investigated the involvement of PI 3-kinase in Smad-dependent BMP-2 transcription. Smad5 stimulated BMP-2 transcription independent of addition of the ligand. Dominant-negative PI 3-kinase or dominant-negative Akt inhibited Smad5-dependent transcription of BMP-2. Furthermore dominant-negative Akt inhibited translocation of BMP-specific Smads into nucleus. Together these data provide the first evidence that activation of BMP receptor serine/threonine kinase stimulates the PI 3 kinase/Akt pathway and define a role for this signal transduction pathway in BMP-specific Smad function during osteoblast differentiation.


Unilateral tonsillar enlargement and tonsillar lymphoma in children.
The clinical presentation and surgical and pathological findings of 46 children with unilateral tonsillar enlargement (UTE; age range 2 to 13 years, mean age 6.5) who underwent tonsillectomy for biopsy purposes between 1975 and 1995 were compared with those of 7 children who received treatment for tonsillar lymphoma (TL; age range 2 to 9 years, mean age 4.8) during the same period. There was no history of rapid tonsillar enlargement in children in the UTE group, and only 20 (43%) were symptomatic. Symptoms included recurrent sore throats in 10 patients (22%), snoring in 5 (11%), nasal obstruction in 4 (9%), and dysphagia in 1 (2%). No children had systemic symptoms or significant cervical lymphadenopathy. In contrast, tonsillar enlargement was observed to occur within a 6-week period in all children with TL, and 6 (86%) children had symptoms at presentation that included dysphagia in 5 (71%), snoring in 3 (43%), night sweats in 2 (29%), and fever and rigors in 2 (29%). Cervical lymphadenopathy greater than 3 cm was present in 6 (86%) children, while 1 child (14%) had hepatosplenomegaly. There was no histopathologic evidence of neoplasia in the UTE group, and a true discrepancy in size between the two tonsils was confirmed in only 21 of 44 (48%) cases. All 7 patients in the TL group had non-Hodgkin's lymphoma. All received chemotherapy, with 5 of the 7 cured and 2 dying of disease. The data suggest that tonsillectomy should be performed for biopsy purposes in UTE where there is a history of progressive enlargement, significant upper aerodigestive tract symptoms, systemic symptoms, suspicious appearance of the tonsil, cervical lymphadenopathy, or hepatosplenomegaly. The diagnosis of TL should also be considered when UTE is present in an immunocompromised child or one with a previous malignancy, when acute tonsillitis is asymmetric and unresponsive to medical treatment, or when rapid bilateral tonsil enlargement occurs. Observation is appropriate management for other cases of UTE.


Sensitized RNAi screen of human kinases and phosphatases identifies new regulators of apoptosis and chemoresistance.
Evasion from apoptosis is a hallmark of cancer, and recent success using targeted therapeutics underscores the importance of identifying anti-apoptotic survival pathways. Here we utilize RNA interference (RNAi) to systematically screen the kinase and phosphatase component of the human genome. In addition to known kinases, we identified several new survival kinases. Interestingly, numerous phosphatases and associated regulatory subunits contribute to cell survival, revealing a previously unrecognized general role for phosphatases as negative regulators of apoptosis. We also identified a subset of phosphatases with tumour-suppressor-like activity. Finally, RNAi targeting of specific protein kinases sensitizes resistant cells to chemotherapeutic agents. The development of inhibitors that target these kinases or phosphatases may lead to new anti-cancer strategies.


Adsorbate-induced pinning of a charge-density wave in a quasi-1D metallic chains: Na on the In/Si(111)-(4x1) surface.
We find that foreign adsorbates acting as local impurities can induce a metal-insulator transition by pinning a charge-density wave (CDW) on the quasi-1D metallic In/Si(111)-(4x1) chain system. Our scanning tunneling microscopy image clearly reveals the presence of a new local 4x2 structure nucleated by Na adatoms at room temperature, which turns out to be insulating with a doubled periodicity along the chains. We directly determine a CDW gap energy Delta = 105+/-8 meV by identifying a characteristic loss peak in our high-resolution electron-energy-loss spectra. We thus report the first observation of a local impurity-derived Peierls-like reconstruction of a quasi-1D system.


Silver nanoparticles coupled to anti‑EGFR antibodies sensitize nasopharyngeal carcinoma cells to irradiation.
Radiotherapy is the major form of treatment for head and neck carcinoma, a malignant tumour of epithelial origin. The identification of agents, which can be co‑administered in order to sensitize these tumours to radiotherapy, has become a major focus of investigations. In the present study, a novel 20 nm nanocomposite, Ag/C225, was constructed, which consisted of silver nanoparticles (AgNPs) conjugated to an epidermal growth factor receptor‑specific antibody (C225). Physical characterization demonstrated that the Ag/C225 nanoparticles were spherical and dispersed well in water. Enzyme‑linked immunosorbent assays showed that the activity of C225 was preserved in the Ag/C225 nanoparticles. The results of 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide analysis revealed that AgNPs and Ag/C225 inhibited the proliferation of nasopharyngeal carcinoma epithelial (CNE) cells in a dose‑ and time‑dependent manner. Flow cytometry revealed that AgNPs and Ag/C225 induced the apoptosis of CNEs, and abrogated G2 arrest; the latter effect was more marked with Ag/C225 than with AgNPs. Clonogenic assays indicated that AgNPs and Ag/C225 increased the sensitivity of CNEs to irradiation. The sensitizer enhancement ratios were 1.610±0.012 and 1.405±0.033 Gy for AgNPs and Ag/C225, respectively. Western blot analysis revealed that combining X‑ray irradiation with either AgNPs or Ag/C225 reduced the expression levels of DNA damage/repair proteins Ku‑70, Ku‑80 and Rad51; Ag/C225 was also more effective than AgNPs in this context. These results indicated that AgNPs and Ag/C225 effectively enhanced CNE cell radiosensitivity in vitro. Therefore, these potent agents may be considered for use as radiosensitizers during the treatment of human nasopharyngeal carcinoma.


Extended endoscopic endonasal approach to the clival region.
The objective of this study was to recognize the endoscopic anatomy of the clival region of the skull base and its neurovascular relations, which will make us able to perform safer and minimal invasive endoscopic approaches to this region with lower rate of complications. Six fresh cadavers were studied (n = 5). We approached the clivus by performing binostril extended endoscopic endonasal approach. After locating the sphenoid sinus as a key point, the vomer was totally removed to expose the clival region located inferiorly to the sphenoid sinus. Mucosal incision is done vertically from the sphenoidal portion the clivus caudally to the inferior portion of nasal cavity just medially to vidian nerve. The mucosal flap is then dissected and retracted. The clivus was resected until the foramen magnum inferiorly. The lateral limit of the resection is the paraclival portion of the internal carotid artery (ICA).The dura and the meningohypophyseal artery is exposed. A vertical dural incision was done and retracted laterally to expose the intradural structures. The prepontine cistern and basilar artery were visualized. The clivus was best localized by orienting the endoscope +15 degrees rostrally. After resecting the inferior wall of the sphenoid sinus and vomer and the overlying mucosa is retracted laterally until the vidian nerve, we obtained sufficient exposure of the clivus. The safe lateral limit of the surgical corridor was the vidian nerve. The clivus is resected until the foramen magnum inferiorly. The safe lateral limit of the resection in this step was the proximal cavernous and the distal petrosal portions of the ICA. This resection provided us with a wide exposure of the clival dura. The basilar plexus, the abducens nerve (sixth cranial nerve) passing through the basilar plexus, and the paraclival portion of the ICA can be injured when careful dissection is not performed. After dural incision, the prepontine cistern and the basilar artery were able to be exposed widely. Binostril extended endoscopic endonasal approach is an appropriate approach to the clival region of the skull base. With good knowledge of the endoscopic anatomic features of this region and its neurovascular relations, surgical procedures can be performed safely with more minimal invasiveness.


SPARC mRNA expression as a prognostic marker for pancreatic adenocarcinoma patients.
Secreted protein acidic and rich in cysteine (SPARC) is a protein which governs diverse cellular functions and matrix remodeling systems. It was reported that SPARC expression of peritumoral fibroblasts was correlated with poor prognosis in resectable pancreatic cancer patients in immunohistochemical analysis. However, the significance of SPARC mRNA expression in pancreatic adenocarcinoma remains unclear. SPARC mRNA expression was evaluated in 104 formalin-fixed paraffin-embedded tissue samples of pancreatic adenocarcinoma patients with macro-dissection technique. High SPARC mRNA expression was associated with a poorer prognosis than low SPARC. In univariate Cox's proportion hazard model, depth of tumor invasion, lymph node metastasis, histopathological tumor grade, lymphatic invasion, vascular invasion, surgical margin, no chemotherapy and high SPARC expression were significant prognostic factors. In multivariate analysis, histopathological tumor grade, surgical margin, no chemotherapy and high SPARC expression were independent significant prognostic factors. SPARC mRNA expression is a prognostic marker for pancreatic adenocarcinoma patients.


The cost of resident education.
Patients cared for by surgeons with resident coverage have an increase in cost versus those patients cared for by surgeons without resident coverage, despite no significant difference in complications. We evaluated the reasons for the disparate cost. In a single institutional analysis, patients received their care from a group of eight surgeons, four with and four without resident coverage. We analyzed ancillary costs, including pharmacy, radiology, laboratory, and central supply costs, and length of stay, total cost, and hospital margin for these patients. In a separate analysis, we compared data that contributes to cost from the National Surgical Quality Improvement Program (NSQIP) database, including age in years, ASA class I-IV, total operating room time in minutes (min), length of hospital stay in days (d), number of patients with a return to OR in 30 d, and complications. There were no significant differences in ancillary costs in patients cared for by residents. The length of stay was longer in patients cared for by residents (3.3 versus 4.6 d, no resident versus resident, respectively, P = 0.0001). When adjusted for the length of stay, the difference between total costs was $1949/d versus $2103/d (P = NS) for the no resident versus resident groups, respectively. There were 32,685 patients evaluated in the NSQIP database. In all comparisons, operating room time was significantly longer in patients with procedures involving residents. The increase in cost in patients cared for by surgeons with residents is not from significant differences in ancillary costs, and may be from length of stay. Surgical procedures are significantly longer with resident involvement.


Competing risk nomogram to predict cancer-specific survival in esophageal cancer during the intensity-modulated radiation therapy era: A single institute analysis.
The present study aimed to investigate the probability of cancer-associated mortality of patients with esophageal cancer undergoing intensity-modulated radiation therapy (IMRT), and to establish a competing risk nomogram to predict the esophageal cancer-specific survival (EC-SS) of these patients. A total of 213 patients with EC who underwent IMRT between January 2014 and May 2017 were selected to establish nomograms according to Fine and Gray's competing risk analysis. Predictive accuracy and discriminative ability of the model were determined using the concordance index (C-index), calibration curves and the area under receiver operating characteristic curves. Decision tree analysis was also constructed for patient grouping. With a median follow-up of 19 months (range, 3-50), the 2-year EC-specific mortality (EC-SM) and the non-esophageal cancer specific mortality (NEC-SM) of the cohort were 35.4 and 3.51%, respectively. Furthermore, an elevated 2-year EC-SM was observed in patients with tumor length ≥4.5 cm compared with patients with tumor length <4.5 cm (45.8% vs. 21.4%; P<0.001), patients with non-squamous cell carcinoma compared with patients with squamous cell carcinoma (49.9 vs. 33.7%; P=0.025) and patients with N3 stage (43.2%; P=0.005). The 2-year NEC-SM of patients with tumor length ≥4.5 cm was 6% vs. 0% in patients with tumor length <4.5 cm (P=0.016). Three independent risk factors for survival, including tumor length, histological type and N stage, were integrated to build competing nomograms for the EC-SS model (C-index=0.72; 95% confidence interval, 0.66-0.77). In addition, the nomograms displayed better discrimination power than the 7th edition of the Tumor-Node-Metastasis staging system for predicting EC-SS (area under the curve=0.707 vs. 0.634). Furthermore, the results from the classification tree analysis demonstrated that N stage was the initial node and that primary tumor length was a determinant for EC-SM in these patients. In conclusion, NEC-SM represented a competing event for patients with EC with a tumor length ≥4.5 cm. The competing risk nomograms may therefore be considered as convenient individualized predictive tools for cancer-specific survival in patients with EC undergoing IMRT treatment.


National Institutes of Health Funding for Tobacco Control: 2006 and 2016.
The study objective was to describe and compare changes in newly funded National Institutes of Health (NIH) tobacco-related awards between fiscal year (FY) 2006 and FY2016. Secondary analysis of NIH data. National Institutes of Health Research Portfolio Online Reporting Tool database was used. National Institutes of Health tobacco-related awards newly funded during FY2006 and FY2016. Search terms included tobacco, smoking, nicotine, secondhand smoke, and e-cigarettes. Grants and funding amounts were retrieved. We calculated frequency distributions to determine the number and percentage of total NIH grants funded overall and by specific institute, and inflation-adjusted total and median funding amounts. We computed percentage differences in number of new grants, funding amounts, and percentage of funding allocated overall, and by institute. There was a 187% increase in the percentage of total NIH funding allocated to new tobacco-related awards from 0.09% in FY2006 to 0.25% in FY2016. Total number of awards increased by 67% in FY2016 (n = 144; $56 015 931) compared to FY2006 (n = 86; $22 076 987), and there was a 154% increase in inflation-adjusted total funding for tobacco control. The top funding institutes were National Institute on Drug Abuse and National Cancer Institute; National Institute on Alcohol Abuse and Alcoholism was third in FY2006; and National, Heart, Lung and Blood Institute in FY2016. Research grants were the most frequently funded. Smoking cessation was a common topic area and increased by 64%. NIH funding is critical for advancing the science of nicotine and tobacco research.


Good or bad vibrations? Impacts of anthropogenic vibration on the marine epibenthos.
Anthropogenic activities directly contacting the seabed, such as drilling and pile-driving, produce a significant vibration likely to impact benthic invertebrates. As with terrestrial organisms, vibration may be used by marine species for the detection of biotic and abiotic cues, yet the significance of this and the sensitivities to vibration are previously undocumented for many marine species. Exposure to additional vibration may elicit behavioral or physiological change, or even physical damage at high amplitudes or particular frequencies, although this is poorly studied in underwater noise research. Here we review studies regarding the sensitivities and responses of marine invertebrates to substrate-borne vibration. This includes information related to vibrations produced by those construction activities directly impacting the seabed, such as pile-driving. This shows the extent to which species are able to detect vibration and respond to anthropogenically-produced vibrations, although the short and long-term implications of this are not known. As such it is especially important that the sensitivities of these species are further understood, given that noise and energy-generating human impacts on the marine environment are only likely to increase and that there are now legal instruments requiring such effects to be monitored and controlled.


Lateral positioning at the dorsal midline: Slit and Roundabout receptors guide Drosophila heart cell migration.
Heart morphogenesis requires the coordinated regulation of cell movements and cell-cell interactions between distinct populations of cardiac precursor cells. Little is known about the mechanisms that organize cardiac cells into this complex structure. In this study, we analyzed the role of Slit, an extracellular matrix protein and its transmembrane receptors Roundabout (Robo) and Roundabout2 (Robo2) during morphogenesis of the Drosophila heart tube, a process analogous to early heart formation in vertebrates. During heart assembly, two types of progenitor cells align into rows and coordinately migrate to the dorsal midline of the embryo, where they merge to assemble a linear heart tube. Here we show that cardiac-specific expression of Slit is required to maintain adhesion between cells within each row during dorsal migration. Moreover, differential Robo expression determines the relative distance each row is positioned from the dorsal midline. The innermost CBs express only Robo, whereas the flanking pericardial cells express both receptors. Removal of robo2 causes pericardial cells to shift toward the midline, whereas ectopic robo2 in CBs drives them laterally, resulting in an unfused heart tube. We propose a model in which Slit has a dual role during assembly of the linear heart tube, functioning to regulate both cell positioning and adhesive interactions between migrating cardiac precursor cells.


Combined immunocapture and laser desorption/ionization mass spectrometry on porous silicon.
There is considerable interest in the highly parallelized mass spectrometry analysis of complex sample mixtures without any time-consuming prepurification. Porous silicon-based laser desorption/ionization mass spectrometry (pSi LDI-MS) is enabling technology for such analysis. Previous studies have focused on pSi surface functionalization to enhance sensitivity of detection and engineer surfaces for sample capture and enrichment in LDI-MS analysis. In this report, we build on this work by showing that surface functionalization of thin pSi films can be extended to the covalent immobilization of antibodies, producing a porous immunoaffinity surface. We demonstrate highly selective mass spectrometric detection of illicit drugs (benzodiazepines) on pSi films displaying antibenzodiazepine antibodies covalently immobilized via isocyanate chemistry. The effects of antibody immobilization conditions, antibody concentration, and surface blocking on LDI-MS performance and selectivity were studied. X-ray photoelectron spectroscopy (XPS) was instrumental in characterizing surface chemistry and optimizing LDI-MS performance. Overall, our approach is suitable for rapid and sensitive confirmatory analysis in forensic toxicology requiring only minimal sample volume and may be applied to other areas requiring small molecular analysis such as metabolomics and pharmacology.


Surgical treatment of distal anterior cerebral artery aneurysms aided by electromagnetic navigation CT angiography.
The surgical treatment of distal anterior cerebral artery (DACA) aneurysms still presents a challenge for neurosurgeons because of their small size and their location in the depth of the narrow frontal interhemispheric fissure. This study aimed to investigate feasibility, safety, accuracy, and usefulness of electromagnetic (EM) navigation to aid clipping of DACA aneurysms. Eight patients (age between 2 and 68 years, mean age 49.8 years) with a DACA aneurysm underwent EM-guided neuronavigated microsurgery for clipping of the aneurysm. All patients underwent craniocervical 3D-CT angiography preoperatively. After planning the optimal approach and surgical trajectory avoiding opening of the frontal sinus, the head was fixed. Intraoperative screenshots were correlated with the microscopical view of the DACA aneurysms before clipping. EM-guided neuronavigation using CT angiography for DACA aneurysms enabled fast and accurate referencing of the patient and planning of a tailored craniotomy without opening of the frontal sinus. Intraoperative accuracy was highly reliable except in one instance due to dislocation of the dynamic reference frame (DRF). There was a good correlation between the 3D-CT angiography-based navigation data sets and the intraoperative vascular anatomy. In all patients, bridging veins were spared. The aid of EM neuronavigation was considered useful in all instances. EM-guided neuronavigation using CT angiography for surgery of DACA aneurysms is a useful tool optimizing the surgical approach directly to the aneurysm minimizing additional damage to the surrounding tissue during preparation of the aneurysm and the parent vessel.


Colorectal cancer cell adhesion attenuates Ad-E2F-1 mediated apoptosis.
The complex interplay of cell adhesion molecules, intracellular signaling, and tumor growth behavior have important implications for the failure of most conventional cancer therapies. Cell adhesion to the basement membrane has been shown to promote tumor cell survival. We hypothesize that the presence of matrix substrate contributes to chemoresistance through signaling via cell adhesion molecule. RKO colorectal cancer cells express integrin beta1 to adhere to substrate. We measured apoptosis of the cells after infection with adenovirus vector containing the transgene E2F-1 (Ad-E2F-1), a potent tumor suppressor gene, and Ad-LacZ (as control), both under the control of the cytomegalovirus promoter. Cells were plated on Matrigel, an extracellular substrate similar to basement membrane and compared to tissue culture plastic. Apoptosis was assessed by flow cytometry-based TUNEL assay and cell proliferation was assessed by WST-1 assay. E2F-1 expression was confirmed by Western blot analysis. A function-blocking anti-beta1 integrin antibody was used to assess the contribution of beta1 on cell survival. At 120 h postinfection of RKO cells with 50 multiplicity of infection, cells plated on plastic underwent marked apoptosis in response to Ad-E2F-1 compared with Ad-LacZ control-treated cells (53% vs 1% apoptosis, respectively). However, when cells were plated on Matrigel, the same dose of E2F-1 was ineffective at inducing apoptosis (3% vs 1% apoptosis, comparing Ad-E2F-1 with Ad-LacZ control). The cell proliferation assay showed >3-fold cell survival in E2F-1-infected cells on Matrigel vs plastic (P < 0.004). By Western blot analysis, attenuation of apoptosis may be a result of reduction in transduction efficiency on Matrigel and function-blocking anti-beta1 integrin antibody does not abolish the decrease in apoptosis afforded by Matrigel. These data suggest that escape from adenoviral E2F-1-mediated apoptosis, at least in part, is related to reduction of intracellular E2F-1 expression. Interactions involving cellular adhesion via beta1 integrin to matrix proteins does not seem to contribute toward gene therapy resistance. Further studies will investigate other specific receptor-ligand interactions after gene and/or chemotherapy.


A comparison of nucleolar organizer region staining and Ki-67 immunostaining in non-Hodgkin's lymphoma.
Eighty cases of non-Hodgkin's lymphomas were examined independently using the monoclonal antibody Ki-67 and an argyrophilic method for the demonstration of nucleolar organizer regions. The evidence that Ki-67 immunoreactivity may be used as a marker of cell proliferation is described and the nature of nucleolar organizer regions reviewed. The proportion of tumour cells with nuclear Ki-67 immunoreactivity and the mean number of nuclear organizer regions are shown to be linearly related (r = 0.86, P less than 0.001) although some scatter was observed. These data suggest that the mean number of nucleolar organizer regions may reflect the cellular kinetics of a tumour. This study also provides further evidence supporting the thesis that the mean nucleolar organizer region score is related to the histological grade of non-Hodgkin's lymphoma. Ki-67 immunostaining and nucleolar organizer region staining would seem to provide comparable data, at least in non-Hodgkin's lymphoma, but the latter method has the advantage of being applicable to conventionally fixed and processed paraffin sections.


EmojiGrid: A 2D Pictorial Scale for the Assessment of Food Elicited Emotions.
Research on food experience is typically challenged by the way questions are worded. We therefore developed the EmojiGrid: a graphical (language-independent) intuitive self-report tool to measure food-related valence and arousal. In a first experiment participants rated the valence and the arousing quality of 60 food images, using either the EmojiGrid or two independent visual analog scales (VAS). The valence ratings obtained with both tools strongly agree. However, the arousal ratings only agree for pleasant food items, but not for unpleasant ones. Furthermore, the results obtained with the EmojiGrid show the typical universal U-shaped relation between the mean valence and arousal that is commonly observed for a wide range of (visual, auditory, tactile, olfactory) affective stimuli, while the VAS tool yields a positive linear association between valence and arousal. We hypothesized that this disagreement reflects a lack of proper understanding of the arousal concept in the VAS condition. In a second experiment we attempted to clarify the arousal concept by asking participants to rate the valence and intensity of the taste associated with the perceived food items. After this adjustment the VAS and EmojiGrid yielded similar valence and arousal ratings (both showing the universal U-shaped relation between the valence and arousal). A comparison with the results from the first experiment showed that VAS arousal ratings strongly depended on the actual wording used, while EmojiGrid ratings were not affected by the framing of the associated question. This suggests that the EmojiGrid is largely self-explaining and intuitive. To test this hypothesis, we performed a third experiment in which participants rated food images using the EmojiGrid without an associated question, and we compared the results to those of the first two experiments. The EmojiGrid ratings obtained in all three experiments closely agree. We conclude that the EmojiGrid appears to be a valid and intuitive affective self-report tool that does not rely on written instructions and that can efficiently be used to measure food-related emotions.


Clinical phenotypes of COPD and their impact on quality of life: A cross-sectional study.
A Chronic Obstructive Pulmonary Disease (COPD) phenotype is a single or group of disease characteristics that describe differences between individuals based on clinically important factors such as symptoms, exacerbations, morbidity, and treatment responses. Many studies estimated the prevalence of various phenotypes, but very few studies looked into their quality of life. We aimed to estimate the prevalence of different COPD phenotypes and their disease-specific Health-Related Quality of Life (HRQoL). The prospective study, with a sample size of 136, was conducted between May 2021 and December 2022 in a tertiary teaching institute. Based on their clinical features, COPD patients were classified into 4 different clinical phenotypes, and their disease-specific quality of life was assessed using St. George Respiratory Questionnaire-COPD(SGRQ-c) and COPD Assessment Test (CAT) questionnaires. Among 136 COPD patients, the frequency of Non-Exacerbator (NE), Exacerbator Emphysema (EEM), Exacerbator Chronic Bronchitis (ECB), and Asthma COPD overlap (ACO) phenotypes was 79(58.1 %), 16(11.8 %), 31(22.8 %), and 10(7.4 %) respectively. Based on the SGRQ-c score, the ECB and EEM phenotypes had a significantly poorer Quality of life (QoL) when compared with NE(P<0.0001), ACO(P=0.011), phenotypes. Similarly, ECB and EEM phenotypes had significantly poorer QoL when compared to NE(P<0.0001), and ACO(P=0.015), based on the CAT score. ECB and EEM patients also had the worst scores in all individual CAT items and SGRQ-c components. NE was the most common followed by ECB phenotype. ECB and EEM phenotypes recorded the poorest quality of life without any significant differences among them. Further research is needed in the future to determine whether phenotype-specific therapies can produce better clinical outcomes.


Probing the accumulation history of the voluminous Toba magma.
The age and compositional zonation in crystals from the Youngest Toba Tuff record the prelude to Earth's largest Quaternary eruption. We used allanite crystals to date and decipher this zoning and found that the crystals retain a record of at least 150,000 years of magma storage and evolution. The dominant subvolcanic magma was relatively homogeneous and thermally stagnant for approximately 110,000 years. In the 35,000 years before eruption, the diversity of melts increased substantially as the system grew in size before erupting 75,000 years ago.


Factors associated with response to treatment of pulmonary exacerbations in cystic fibrosis patients.
Pulmonary exacerbations are associated with significant lung function decline from baseline in cystic fibrosis (CF) and it is not well understood why some patients do not respond to antibiotic therapy. The objective of this study was to identify factors associated with lung function response to antibiotic treatment of pulmonary exacerbations. As a secondary analysis of a randomized, controlled trial of intravenous antibiotic treatment for pulmonary exacerbations in CF patients, we investigated whether baseline factors and changes in sputum bacterial density, serum or sputum inflammatory markers were associated with recovery of lung function and risk of subsequent exacerbation. In 36 of the 70 exacerbations (51%), patients' lung function returned to >100% of their baseline at day 14 of antibiotic treatment; 34 exacerbations were classified as non-responders. Baseline characteristics were not significantly different between responders and non-responders. Less of a drop in FEV1 from baseline to exacerbation (OR 1.09, 95% CI 1.0, 1.18, p=0.04) as well as a greater decrease in sputum neutrophil elastase (OR 2.94, 95% CI 1.07, 8.06, p=0.04) were associated with response to antibiotic treatment at day 14. In addition, higher CRP (HR 1.35 (95% CI: 1.01, 1.78), p=0.04) and sputum neutrophil elastase (HR 1.71 (95% CI: 1.02, 2.88), p=0.04) at day 14 of antibiotic therapy were associated with an increased risk of subsequent exacerbation. Inadequate reduction of inflammation during an exacerbation is associated with failure to recover lung function and increased risk of subsequent re-exacerbation in CF patients.


Newborns health in the Danube Region: Environment, biomonitoring, interventions and economic benefits in a large prospective birth cohort study.
The EU strategy for the Danube Region addresses numerous challenges including environment, health and socioeconomic disparities. Many old environmental burdens and heavily polluted areas in Europe are located in the Danube Region, consisting of 14 countries, with over 100 million people. Estimating the burden of environmental exposures on early-life health is a growing research area in Europe which has major public health implications, but the data from the Danube Region are largely missing. This review presents an inventory of current environmental challenges, related early-life health risks, and knowledge gaps in the Danube Region, based on publicly available databases, registers, and literature, as a rationale and incentive for a new integrated project. The review also proposes the concept for the project aiming to characterize in utero exposures to multiple environmental factors and estimate their effect on early-life health, evaluate economic impact, as well as identify interventions with a potential to harness social norms to reduce emissions, exposures and health risks in the Danube Region. Experts in environmental epidemiology, human biomonitoring and social science in collaboration with clinicians propose to establish a new large multi-center birth cohort of mother-child pairs from Danube countries, measure biomarkers of exposure and health in biological samples at birth, collect centrally measured climate, air and water pollution data, conduct pre- and postnatal surveys on lifestyle, indoor exposures, noise, occupation, socio-economic status, risk-averting behavior, and preferences; and undertake clinical examinations of children at and after birth. Birth cohort will include at least 2000 newborns per site, and a subset of at least 200 mother-child pairs per site for biomonitoring. Novel biomarkers of exposure, susceptibility, and effect will be applied, to gain better mechanistic insight. Effects of multiple environmental exposures on fetal and child growth, respiratory, allergic, immunologic, and neurodevelopmental health outcomes will be estimated. Parent's willingness to pay for reducing health risks in children will be elicited by survey, while values of cost-of-illness will be gathered from literature and national statistics. Effects of risk reducing interventions will be examined. The proposed project would provide novel estimates of the burden of early childhood diseases attributable to environmental exposures and assess health impacts of different intervention scenarios in the Danube Region, in an integrated approach combining human biomonitoring, epidemiological and social science research.


An important role for pentose cycle in the synthesis of citrulline and proline from glutamine in porcine enterocytes.
This study was designed to determine a role of pentose cycle in the provision of NADPH for the synthesis of citrulline and proline from glutamine in porcine enterocytes. Enterocytes from 4-day-old pigs were incubated at 37 degrees C for 0 to 30 min in Krebs-Henseleit bicarbonate buffer (pH 7.4) containing 2 mM glutamine and 5 mM glucose in the presence of 0, 0.1, or 0.25 mM dehydroepiandrosterone (DHEA), a potent inhibitor of glucose-6-phosphate dehydrogenase which is the key regulatory enzyme of pentose cycle. The activity of this cycle was estimated with the use of [1-14C]glucose and [6-14C]glucose. In some experiments, the medium included 2 mM ornithine and 2 mM NH4Cl (no glutamine). About 14% of glucose taken up by enterocytes was metabolized via pentose cycle. The flux from glucose into this cycle was decreased by 70 and 86%, respectively, in the presence of 0.1 and 0.25 mM DHEA compared with its absence. DHEA inhibited the synthesis of ornithine, citrulline, arginine, and proline from glutamine in a concentration-dependent manner, but had no effect on the formation of citrulline and arginine from ornithine. However, DHEA decreased the synthesis of proline from ornithine by 79%. DHEA had no effect on cellular ATP concentrations. These results provide the first line of evidence suggesting that glucose metabolism via pentose cycle plays an important role in providing NADPH for the conversion of glutamine into pyrroline-5-carboxylate in porcine enterocytes, which may explain the glucose-dependent synthesis of citrulline and proline from glutamine in these cells.


Androgen receptor and 5alpha-reductase are expressed in pelvic endometriosis.
The aim of this study was to evaluate whether androgen receptor (AR) and the enzymes that convert testosterone into the more potent androgen dihydrotestosterone, 5alpha-reductases (5alpha-R1 and 5alpha-R2) are expressed in pelvic endometriosis. The study involved 21 infertile women who underwent laparoscopy and were divided into two groups: control (n= 13) and endometriosis (n= 8) according to the histological and laparoscopic findings. Endometrial and endometriotic implant biopsies were performed. By reverse transcription polymerase chain reaction and immunohistochemistry, AR, 5alpha-R1 and 5alpha-R2 messenger RNA and protein were detected in biopsies of pelvic endometriosis, as well as in the eutopic endometrium of both groups. These findings suggest that active androgens may be formed within the endometriotic tissue and that both local and systemic androgens have the potential to act on endometriotic cells.


Thrombopoietin stimulates Hoxb4 expression: an explanation for the favorable effects of TPO on hematopoietic stem cells.
Thrombopoietin (TPO), the primary regulator of platelet production, also plays an important role in hematopoietic stem cell (HSC) biology. In previous studies we demonstrated that the self-renewal and expansion of HSCs is 10 to 20 times less robust in tpo-/- mice than in controls. To explore the molecular basis of this effect, we postulated that Hoxb4 might mediate at least part of the TPO effect on these cells. We first analyzed the effects of TPO on Hoxb4 expression in primitive hematopoietic cell lines; TPO increased expression of the gene 2- to 3-fold in EML and UT-7/TPO cells. We also compared Hoxb4 levels in a candidate HSC population derived from tpo-/- and control mice; Hoxb4 expression was 2- to 5-fold lower in null HSCs. Of the numerous signal transduction molecules induced by TPO, we found that p38 mitogen-activated protein kinase (MAPK) was responsible for the TPO-induced Hoxb4 elevation. We also demonstrated that upstream stimulating factor 1 (USF-1), a transcription factor previously shown to regulate Hoxb4 expression, is also induced by TPO in a p38-dependent manner. Together, these data provide a molecular pathway by which a growth factor can modulate a transcription factor and thereby help direct a critical developmental process.


Multi-layer graphene pirani pressure sensors.
The operating principle of Pirani pressure sensors is based on the pressure dependence of a suspended strip's electrical conductivity, caused by the thermal conductance of the surrounding gas which changes the Joule heating of the strip. To realize such sensors, not only materials with high temperature dependent electrical conductivity are required, but also minimization of the suspended strip dimensions is essential to maximize the responsivity and minimize the power consumption. Due to this, nanomaterials are especially attractive for this application. Here, we demonstrate the use of a multi-layer suspended graphene strip as a Pirani pressure sensor and compare its behavior with existing models. A clear pressure dependence of the strip's electrical resistance is observed, with a maximum relative change of 2.75% between 1 and 1000 mbar and a power consumption of 8.5 mW. The use of graphene enables miniaturization of the device footprint by 100 times compared to state-of-the-art. Moreover, miniaturization allows for lower power consumption and/or higher responsivity and the sensor's nanogap enables operation near atmospheric pressure that can be used in applications such as barometers for altitude measurement. Furthermore, we demonstrate that the sensor response depends on the type of gas molecules, which opens up the way to selective gas sensing applications. Finally, the graphene synthesis technology is compatible with wafer-scale fabrication, potentially enabling future chip-level integration with readout electronics.


A functional floxed allele of Pkd1 that can be conditionally inactivated in vivo.
Gene targeting has been used to create a variety of lines of mice with Pkd1 mutations that share many common features. Homozygous Pkd1 mutants invariably develop pancreatic and renal cysts if they survive to day 15.5 post coitum and die in either the fetal or the perinatal period. In contrast, mice with heterozygous mutations of Pkd1 are generally normal and have few if any renal cysts. These features have limited the utility of these models as tools to study the pathogenesis of cyst formation and the effect of various therapeutic interventions on disease progression. This report describes a new line of mice with a floxed allele of Pkd1 (Pkd1(cond)) that has an FRT-flanked neomycin cassette inserted into intron 1 and lox P sites inserted into intron 1 and intron 4. The Pkd1(cond) allele is fully functional, and homozygotes are viable and healthy. It is shown that the lox P and FRT sites can be selectively induced to recombine to produce two new alleles, Pkd1(del2-4) and Pkd1(cond-Deltaneo), by crossing to animals that express either the cre or FLPe recombinase, respectively. It is found that Pkd1(del2-4) allele functions as a true null, whereas presence or absence of the neomycin gene has no functional effects. It also is shown that somatic loss of Pkd1 results in renal and hepatic cysts. This new line of mice will be invaluable in the study of Pkd1 biology and serve as a powerful new tool that can be used to study the pathogenesis of autosomal dominant polycystic kidney disease.


Activation of the mammalian target of rapamycin complex 1 is both necessary and sufficient to stimulate eukaryotic initiation factor 2Bvarepsilon mRNA translation and protein synthesis.
In a previous study we demonstrated a requirement for activation of mTORC1 in the stimulation of eIF2Bepsilon mRNA translation in skeletal muscle in response to resistance exercise. Although that study established the necessity of mTORC1 activation, the experimental model used did not lend itself readily to address the question of whether or not mTORC1 activation was sufficient to produce the response. Therefore, the present study was designed to address the sufficiency of mTORC1 activation, using cultures of Rat2 fibroblasts in which mTORC1 signaling was repressed by serum/leucine-depletion and stimulated by repletion of leucine and/or IGF-1. Repletion with leucine and IGF-1 caused a shift of eIF2Bepsilon mRNA into actively translating polysomes and a stimulation of new eIF2Bepsilon protein synthesis, but had no effect on mRNAs encoding the other four eIF2B subunits. Stimulation of eIF2Bepsilon translation was reversed by pre-treatment with the mTORC1 inhibitor rapamycin. Exogenous overexpression of FLAG-Rheb, a proximal activator of mTORC1, also caused a re-distribution of eIF2Bepsilon mRNA into polysomes and a stimulation of eIF2Bepsilon protein synthesis. The stimulation of eIF2Bepsilon mRNA translation occurred in the absence of any effect on eIF2Bepsilon mRNA abundance. RNAi-mediated knockdown of eIF2Bepsilon resulted in reduced cellular proliferation, a result that phenocopied the known cytostatic effect of mTORC1 repression. Overall the results demonstrate that activation of mTORC1 is both necessary and sufficient to stimulate eIF2Bepsilon mRNA translation and that this response may represent a novel mechanism through which mTORC1 can affect mRNA translation initiation, rates of protein synthesis, and cellular growth/proliferation.


The deubiquitinating enzyme USP17 is highly expressed in tumor biopsies, is cell cycle regulated, and is required for G1-S progression.
Ubiquitination is a reversible posttranslational modification that is essential for cell cycle control, and it is becoming increasingly clear that the removal of ubiquitin from proteins by deubiquitinating enzymes (DUB) is equally important. In this study, we have identified high levels of the DUB USP17 in several tumor-derived cell lines and primary lung, colon, esophagus, and cervix tumor biopsies. We also report that USP17 is tightly regulated during the cell cycle in all the cells examined, being abundantly evident in G(1) and absent in S phase. Moreover, regulated USP17 expression was necessary for cell cycle progression because its depletion significantly impaired G(1)-S transition and blocked cell proliferation. Previously, we have shown that USP17 regulates the intracellular translocation and activation of the GTPase Ras by controlling Ras-converting enzyme 1 (RCE1) activation. RCE1 also regulates the processing of other proteins with a CAAX motif, including Rho family GTPases. We now show that USP17 depletion blocks Ras and RhoA localization and activation. Moreover, our results confirm that USP17-depleted cells have constitutively elevated levels of the cyclin-dependent kinase inhibitors p21(cip1) and p27(kip1), known downstream targets of Ras and RhoA signaling. These observations clearly show that USP17 is tightly regulated during cell division and that its expression is necessary to coordinate cell cycle progression, and thus, it may be considered a promising novel cancer therapeutic target.


Validation of the Brazilian version of the World Health Organization Disability Assessment Schedule 2.0 for individuals with HIV/AIDS.
The WHODAS 2.0 (World Health Organization Disability Assessment Schedule) is an instrument developed by the WHO (World Health Organization) for functioning and disability assessment based on the biopsychosocial framework, fully supported by the theoretical-conceptual framework of the ICF (International Classification of Functioning, Disability and Health). To validate the Brazilian version of the WHODAS 2.0 for individuals with HIV/AIDS. 100 individuals with diagnosis of HIV/AIDS participated in the study. Two assessment instruments were used: the 36-item version of WHODAS 2.0 and the WHOQOL-HIV-BREF (World Health Organization Quality of Life assessment in persons infected with HIV, shorter version). The psychometric properties tested were internal consistency and criterion validity. Internal consistency was adequate for all domains, with the exception of Life Activities (α = 0.69) and Self-care (α = 0.32). Criterion validity was adequate, with moderate correlations between the WHODAS 2.0 and the WHOQOL-HIV-BREF domains. The results indicated the WHODAS 2.0 instrument as a valid tool for assessing functioning of individuals with HIV/AIDS. The use of data from the Self-care domain should be carefully considered.


Spatio-temporal patterns in rhizosphere oxygen profiles in the emergent plant species Acorus calamus.
Rhizosphere oxygen profiles are the key to understanding the role of wetland plants in ecological remediation. Though in situ determination of the rhizosphere oxygen profiles has been performed occasionally at certain growing stages within days, comprehensive study on individual roots during weeks is still missing. Seedlings of Acorus calamus, a wetland monocot, were cultivated in silty sediment and the rhizosphere oxygen profiles were characterized at regular intervals, using micro-optodes to examine the same root at four positions along the root axis. The rhizosphere oxygen saturation culminated at 42.9% around the middle part of the root and was at its lowest level, 3.3%, at the basal part of the root near the aboveground portion. As the plant grew, the oxygen saturation at the four positions remained nearly constant until shoot height reached 15 cm. When shoot height reached 60 cm, oxygen saturation was greatest at the point halfway along the root, followed by the point three-quarters of the way down the root, the tip of the root, and the point one-quarter of the way down. Both the internal and rhizosphere oxygen saturation steadily increased, as did the thickness of stably oxidized microzones, which ranged from 20 µm in younger seedlings to a maximum of 320 µm in older seedlings. The spatial patterns of rhizosphere oxygen profiles in sediment contrast with those from previous studies on radial oxygen loss in A. calamus that used conventional approaches. Rhizosphere oxygen saturation peaked around the middle part of roots and the thickness of stably oxidized zones increased as the roots grew.


[Characteristics of patients with systemic sclerosis who develop interstitial lung disease].
Systemic sclerosis associated-interstitial lung disease (SSc-ILD) show a high mortality. The factors associated SSc-ILD have shown variability in different populations. There are few studies in Mexican mestizos. To analyze the epidemiological, clinical and paraclinical factors associated with SSc-ILD. Cross-sectional study, where patients > 18 years of age with a diagnosis of SSc according to EULAR/ACR 2013 criteria and diagnosis of ILD by forced vital capacity (FVC) < 70% and > 5% of affected lung area on tomography were included. The strength of association of the factors for ILD was measured by odds ratio (OR) with 95% confidence intervals (95% CI). The significant variables were analyzed by multiple logistic regression with adjustment. Of the 80 patients with SSc, 38 (47.5%) had ILD. Risk factors such as smoking, higher activity index, lower FVC, anti-topoisomerase I antibodies, and protective factors such as a limited SSc, early capillaroscopic pattern, and anti-centromere antibodies (ACA) were associated with ILD. In the multivariate analysis, a higher activity index with OR 4.17, (95% CI 2.01-8.65) persisted as a risk factor, while ACA with OR 0.17, (95% CI 0.03-0.85) persisted as a protective factor associated with SSc-ILD. A higher index of activity and ACA persisted as factors associated with SSc-ILD.


Repurposing of the PDE5 Inhibitor Sildenafil for the Treatment of Persistent Pulmonary Hypertension in Neonates.
Nitric oxide (NO), an important endogenous signaling molecule released from vascular endothelial cells and nerves, activates the enzyme soluble guanylate cyclase to catalyze the production of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP, in turn, activates protein kinase G to phosphorylate a range of effector proteins in smooth muscle cells that reduce intracellular Ca2+ levels to inhibit both contractility and proliferation. The enzyme phosphodiesterase type 5 (PDE5) curtails the actions of cGMP by hydrolyzing it into inactive 5'-GMP. Small molecule PDE5 inhibitors (PDE5is), such as sildenafil, prolong the availability of cGMP and therefore, enhance NO-mediated signaling. PDE5is are the first-line treatment for erectile dysfunction but are also now approved for the treatment of pulmonary arterial hypertension (PAH) in adults. Persistent pulmonary hypertension in neonates (PPHN) is currently treated with inhaled NO, but this is an expensive option and around 1/3 of newborns are unresponsive, resulting in the need for alternative approaches. Here the development, chemistry and pharmacology of PDE5is, the use of sildenafil for erectile dysfunction and PAH, are summarized and then current evidence for the utility of further repurposing of sildenafil, as a treatment for PPHN, is critically reviewed.


Urinary stone disease in Dar es Salaam.
Forty four adult patients, 34 males and 10 females, with urinary stones were seen over a six-month-period at Muhimbili Medical Centre, Dar es Salaam. Most patients were peasants and semiskilled workers. 8 of the patients were Arabs, which suggests a high predisposition for this race. 12 of the patients had a history of having suffered from bilharzia. There was a high proportion of bladder (and urethral) stones (30%) but upper urinary tract stones were still predominant (70%). Of 20 patients whose stones were available for analysis, 8 were composed of calcium oxalate, 7 of calcium phosphate and 5 of mixed composition. The ratio of stone patients to all hospital admissions of 243 per 100,000 suggests the prevalence of urinary stone disease is comparable to that found in Western countries.


[Histological evaluation of esophageal stricture in children with caustic burn].
To analyze histological features of esophageal strictures in children with chemical burn following ingestion of household products containing sodium (potassium) hypochlorite, sodium (potassium) hydroxide. We analyzed 3 children with complicated caustic esophageal burns. Children at the time of swallowing the caustic were 26.3±4.1 months. Multiple dilatations of esophageal stricture were ineffective. Therefore, extirpation or subtotal resection of the esophagus and esophagocoloplasty were performed. We stained specimens using hematoxylin and eosin, as well as Masson's trichrome. Severe esophageal burns caused by sodium (potassium) hydroxide and/or sodium hypochlorite are followed by irreversible tissue lesions and non-dilatable stricture. Strictures are localized in the areas of physiological narrowing of the esophagus. The longest stricture follows ingestion of liquid substance. Histological properties include atrophy of glands and mucous membrane, muscle layer substitution by connective tissue and diffuse sclerosis of esophageal wall. Non-dilatable esophageal stricture following caustic burn in children is due to irreversible morphological lesion of esophageal wall with mucous layer atrophy and sclerosis of all layers.


Modeling precipitation and sorption of elements during mixing of river water and porewater in the Coeur d'Alene River basin.
Reddish brown flocs form along the edge of the Coeur d'Alene River when porewater drains into river water during the annual lowering of water level in the basin. The precipitates are efficient scavengers of dissolved elements and have characteristics that may make metals associated with them bioavailable. This work characterizes the geochemistry of the porewater and models the formation and composition of the flocs. Porewater is slightly acidic, has suboxic to anoxic characteristics, tends to have higher alkalinity, and contains elevated concentrations of many constituents relative to river water. Laboratory mixing experiments involving porewater and river water were done to produce the precipitates. Thermodynamic predictions using PHREEQC indicate that predicted amounts of ferrihydrite and gibbsite agree with removal of Fe and Al. Predictions of element removal by adsorption onto ferrihydrite are consistent with observed removal using a combination of surface complexation constants for the generalized two-layer model (As and Se), alternative surface constants derived from experiments at high sorbate-to-sorbent ratios (Cd, Co, Cu, Ni, Pb, and Zn), and adjusted surface constants to fit experimental data (Cr, Mo, and Sb). This new set of surface complexation constants needs further testing in other contaminated systems.


The influence of poly(ethylene glycol) 6000 on the properties of skeletal-muscle actin.
Poly(ethylene glycol) 6000 affected many of the properties of skeletal-muscle actin. It accelerated the rate and increased the extent of actin polymerization as measured by light-scattering and sedimentation studies respectively. Moreover, intrinsic-fluorescence measurements showed that addition of poly(ethylene glycol) 6000 decreased the rate of EDTA-induced denaturation of actin monomer and increased the temperature at which irreversible conformational changes occur in actin monomer. These effects occurred without any apparent direct binding interaction and are postulated to be a consequence of the effect of excluded volume on the thermodynamic activity of actin. A relationship based on spherical geometry was formulated which described the co-volume increment that occurs upon addition of a monomer to a long linear polymer in the presence of a space-filling macromolecule. The application of this relationship to the poly(ethylene glycol) 6000-actin system was not without assumption, but it permitted quantitative estimation of the co-volume increment which proved to be of the sign and magnitude required to explain the increased extent of actin polymerization found experimentally in the presence of various concentrations of poly(ethylene glycol) 6000. It is suggested that, in vivo, excluded volume may play a role in actin-filament formation and in the maintenance of the native G-actin structure.


Tuning High-Tc Superconductors via Multistage Intercalation.
Multistage intercalation has been used to tune the interaction between adjacent blocks of CuO(2) sheets in the bigh-T(c) (high superconducting transition temperature) superconductor Bi(2)Sr(2)CaCu(2)Ox. As revealed by atomic-resolution transmission electron microscopy images, foreign iodine atoms are intercalated into every nth BiO bilayer of the host crystal, resulting in structures of stoichiometry IBi2nSr2nCanCu2nOx with stage index n up to 4. An expansion of 3.6 angstroms for each intercalated BiO bilayer decouples the CuO(2) sheets in adjacent blocks. A comparison of the superconducting transition temperatures of the pristine host material and intercalated compounds of different stages suggests that the coupling between each pair of adjacent blocks contributes approximately 5 K to T(c) in Bi(2)Sr(2)CaCu(2)Ox.


Molecular analysis and genotype-phenotype correlation of Diamond-Blackfan anemia.
Diamond-Blackfan anemia (DBA) features hypoplastic anemia and congenital malformations, largely caused by mutations in various ribosomal proteins. The aim of this study was to characterize the spectrum of genetic lesions causing DBA and identify genotypes that correlate with phenotypes of clinical significance. Seventy-four patients with DBA from across Canada were included. Nucleotide-level mutations or large deletions were identified in 10 ribosomal genes in 45 cases. The RPS19 mutation group was associated with higher requirement for chronic treatment for anemia than other DBA groups. Patients with RPS19 mutations, however, were more likely to maintain long-term corticosteroid response without requirement for further chronic transfusions. Conversely, patients with RPL11 mutations were less likely to need chronic treatment. Birth defects, including cardiac, skeletal, hand, cleft lip or palate and genitourinary malformations, also varied among the various genetic groups. Patients with RPS19 mutations had the fewest number of defects, while patients with RPL5 had the greatest number of birth defects. This is the first study to show differences between DBA genetic groups with regards to treatment. Previously unreported differences in the rate and types of birth defects were also identified. These data allow better patient counseling, a more personalized monitoring plan, and may also suggest differential functions of DBA genes on ribosome and extra-ribosomal functions.


Effects of single administration of a phosphodiesterase III inhibitor during cardiopulmonary bypass: comparison of milrinone and amrinone.
The effects of phosphodiesterase III (PDE III) inhibitors administered after aortic declamping during cardiopulmonary bypass (CPB) for open heart surgery were investigated. Ten patients (group M) were administered milrinone (50 microg/kg) after aortic declamping during CPB, 10 patients were administered amrinone (1 mg/kg) at the same time during their surgery (group A), and 10 patients served as controls with no drug administered (group C). Soon after bolus infusion of the PDE III inhibitor, perfusion pressure dropped significantly in groups M and A. However, after release of CPB and at the end of surgery, there was no difference in aortic pressure between the 3 groups. There were also no differences between the groups in heart rate, pulmonary artery pressure, and pulmonary capillary wedge pressure. After weaning from CPB, the cardiac index was high and systemic vascular resistance index was low in groups M and A. There were no significant differences in the need for additional catecholamines and time for rewarming between groups. No adverse reactions were observed. A single administration of a PDE III inhibitor during CPB was useful for post-CPB management of patients undergoing open heart surgery. Amrinone reduced perfusion pressures more than milrinone, but cardiac indices and aortic pressures after weaning from CPB showed no differences between group M and group A patients.


The transcriptional coregulator RIP140 represses E2F1 activity and discriminates breast cancer subtypes.
Receptor-interacting protein of 140 kDa (RIP140) is a transcriptional cofactor for nuclear receptors involved in reproduction and energy homeostasis. Our aim was to investigate its role in the regulation of E2F1 activity and target genes both in breast cancer cell lines and in tumor biopsies. Glutathione S-transferase pull-down assays, coimmunoprecipitation experiments, and chromatin immunoprecipitation analysis were used to evidence interaction between RIP140 and E2F1. The effects of RIP140 expression on E2F1 activity were determined using transient transfection and quantification of E2F target mRNAs by quantitative real-time PCR. The effect on cell cycle was assessed by fluorescence-activated cell sorting analysis on cells overexpressing green fluorescent protein-tagged RIP140. A tumor microarray data set was used to investigate the expression of RIP140 and E2F1 target genes in 170 breast cancer patients. We first evidenced the complex interaction between RIP140 and E2F1 and showed that RIP140 represses E2F1 transactivation on various transiently transfected E2F target promoters and inhibits the expression of several E2F1 target genes (such as CCNE1 and CCNB2). In agreement with a role for RIP140 in the control of E2F activity, we show that increasing RIP140 levels results in a reduction in the proportion of cells in S phase in various human cell lines. Finally, analysis of human breast cancers shows that low RIP140 mRNA expression was associated with high E2F1 target gene levels and basal-like tumors. This study shows that RIP140 is a regulator of the E2F pathway, which discriminates luminal- and basal-like tumors, emphasizing the importance of these regulations for a clinical cancer phenotype.


Slip into something more functional: selection maintains ancient frameshifts in homopolymeric sequences.
Mutational hotspots offer significant sources of genetic variability upon which selection can act. However, with a few notable exceptions, we know little about the dynamics and fitness consequences of mutations in these regions. Here, we explore evolutionary forces shaping homopolymeric tracts that are especially vulnerable to slippage errors during replication and transcription. Such tracts are typically eliminated by selection from most bacterial sequences, yet persist in genomes of endosymbionts with small effective population sizes (N(e)) and biased base compositions. Focusing on Blochmannia, a bacterial endosymbiont of ants, we track the divergence of genes that contain frameshift mutations within long (9-11 bp) polyA or polyT tracts. Earlier experimental work documented that transcriptional slippage restores the reading frame in a fraction of messenger RNA molecules and thereby rescues the function of frameshifted genes. In this study, we demonstrate a surprising persistence of these frameshifts and associated tracts for millions of years. Across the genome of this ant mutualist, rates of indel mutation within homopolymeric tracts far exceed the synonymous mutation rate, indicating that long-term conservation of frameshifts within these tracts is inconsistent with neutrality. In addition, the homopolymeric tracts themselves are more conserved than expected by chance, given extensive neutral substitutions that occur elsewhere in the genes sampled. These data suggest an unexpected role for slippage-prone DNA tracts and highlight a new mechanism for their persistence. That is, when such tracts contain a frameshift, transcriptional slippage plays a critical role in rescuing gene function. In such cases, selection will purge nucleotide changes interrupting the slippery tract so that otherwise volatile sequences become frozen in evolutionary time. Although the advantage of the frameshift itself is less clear, it may offer a mechanism to lower effective gene expression by reducing but not eliminating transcripts that encode full-length proteins.


Content and Mechanism of Action of National Antimicrobial Stewardship Interventions on Management of Respiratory Tract Infections in Primary and Community Care.
A major modifiable factor contributing to antimicrobial resistance (AMR) is inappropriate use and overuse of antimicrobials, such as antibiotics. This study aimed to describe the content and mechanism of action of antimicrobial stewardship (AMS) interventions to improve appropriate antibiotic use for respiratory tract infections (RTI) in primary and community care. This study also aimed to describe who these interventions were aimed at and the specific behaviors targeted for change. Evidence-based guidelines, peer-review publications, and infection experts were consulted to identify behaviors relevant to AMS for RTI in primary care and interventions to target these behaviors. Behavior change tools were used to describe the content of interventions. Theoretical frameworks were used to describe mechanisms of action. A total of 32 behaviors targeting six different groups were identified (patients; prescribers; community pharmacists; providers; commissioners; providers and commissioners). Thirty-nine interventions targeting the behaviors were identified (patients = 15, prescribers = 22, community pharmacy staff = 8, providers = 18, and commissioners = 18). Interventions targeted a mean of 5.8 behaviors (range 1-27). Influences on behavior most frequently targeted by interventions were psychological capability (knowledge and skills); reflective motivation (beliefs about consequences, intentions, social/professional role and identity); and physical opportunity (environmental context and resources). Interventions were most commonly characterized as achieving change by training, enabling, or educating and were delivered mainly through guidelines, service provision, and communications & marketing. Interventions included a mean of four Behavior Change Techniques (BCTs) (range 1-14). We identified little intervention content targeting automatic motivation and social opportunity influences on behavior. The majority of interventions focussed on education and training, which target knowledge and skills though the provision of instructions on how to perform a behavior and information about health consequences. Interventions could be refined with the inclusion of relevant BCTs, such as goal-setting and action planning (identified in only a few interventions), to translate instruction on how to perform a behavior into action. This study provides a platform to refine content and plan evaluation of antimicrobial stewardship interventions.


Sleep, hunger, satiety, food cravings, and caloric intake in adolescents.
Prevalence of adolescent obesity has increased worldwide. Although diet and exercise patterns are major determinants of weight, recent studies with adults and children have shown that total amount of sleep is inversely associated with body mass index (BMI). The purpose of this study was to examine associations among total sleep time (TST), hunger, satiety, food cravings, and caloric intake in a sample of healthy adolescents. DESIGN-METHODS: Participants were recruited from the community and a local high school. Demographic data such as sleeping habits, pubertal status, food cravings, caloric intake, physical activity, height, and weight were collected between October 2006 and April 2007. Participants also completed a 7-day sleep-hunger-satiety diary. Descriptive and parametric procedures were used for data analyses (alpha=.05). The sample (N=85) included 56% females (n=48), 76% African American (n=65) adolescents. Mean age was 15.6+/-1.4 years and mean BMI was 24.3+/-5.4 kg/m(2). Mean reported 7-day cumulative nocturnal sleep was 52.9 (+/-6.0) hours; mean reported cumulative daytime sleep (or napping) was 3.7 (+/-3.4) hours. Multiple regression analyses showed age, gender, and race were associated with feelings of hunger, satiety, total food cravings and caloric intake. A greater total food-cravings score was associated with increased daytime sleep. These findings indicate an unexpected association between increased daytime sleep and eating behaviors that potentially lead to obesity. Longitudinal studies using objective measures of sleep, appetite regulation, and caloric intake are needed to better understand relationships between appetite and sleep in adolescents from varying racial and gender groups. By carefully considering adolescent sleep (especially daytime sleep), race, and gender, clinicians and school health nurses in the US and other countries are in a unique position to develop novel approaches to prevent and reduce obesity.


Conjunctival Implantation Cyst in the Orbicularis Oculi Muscle: Review of a Possible Origin From Displaced Stem Cells With a Differential Diagnosis.
To document a unique case of a corneal/conjunctival epithelial inclusion cyst located in the orbicularis oculi muscle with a comprehensive review of variant conjunctival cysts and simulating conditions. Clinicopathologic case report with detailed histopathologic and immunohistochemical evaluation for cytokeratins combined with a tabulation of mimicking lesions and relevant literature citations. A 59-year-old man experienced severe blunt left periorbital trauma that resulted in a limbal partial-thickness corneal wound with an associated epithelial abrasion and a full-thickness eyelid laceration extending from the superior fornix to the margin. Several months after surgical repair of the eyelid a cyst appeared in the superior pretarsal skin. Histopathologic and immunohistochemical investigations supplied data suggesting that the cyst had a high probability of a corneoscleral limbal stem cell origin. Distinctive features of the lesion are contrasted with those of allied or simulating cysts. Stem cells are now believed to be located at the corneoscleral limbus, in the inferior fornix, in the medial canthal region, and at the eyelid margin where transitions from conjunctival epithelium to epidermal epithelium occur. Due to their replicative, hardy and robust nature, stem cells displaced to alien environments are most likely to survive and produce cysts. The cyst's corneal-type cytologic characteristics, the absence of goblet cells, and the expression of a broad spectrum of cytokeratin biomarkers in the current case give support to the proposal that limbal stem cells in the region of the corneal laceration were displaced to the eyelid orbicularis muscle and were responsible for this most extraordinary cyst. Comparison with other epithelial cystic linings lends further evidence for this conclusion.


Evaluating the adaptive potential of the European eel: is the immunogenetic status recovering?
The recent increased integration of evolutionary theory into conservation programs has greatly improved our ability to protect endangered species. A common application of such theory links population dynamics and indices of genetic diversity, usually estimated from neutrally evolving markers. However, some studies have suggested that highly polymorphic adaptive genes, such as the immune genes of the Major Histocompatibility Complex (MHC), might be more sensitive to fluctuations in population dynamics. As such, the combination of neutrally- and adaptively-evolving genes may be informative in populations where reductions in abundance have been documented. The European eel (Anguilla anguilla) underwent a drastic and well-reported decline in abundance in the late 20th century and still displays low recruitment. Here we compared genetic diversity indices estimated from neutral (mitochondrial DNA and microsatellites) and adaptive markers (MHC) between two distinct generations of European eels. Our results revealed a clear discrepancy between signatures obtained for each class of markers. Although mtDNA and microsatellites showed no changes in diversity between the older and the younger generations, MHC diversity revealed a contemporary drop followed by a recent increase. Our results suggest ongoing gain of MHC genetic diversity resulting from the interplay between drift and selection and ultimately increasing the adaptive potential of the species.


Muscle hypertrophy due to scarring of the S1 nerve root.
Segmental muscle enlargement occurs in a variety of neurogenic conditions. We present a patient with calf hypertrophy, likely produced by continuous neuromuscular irritability and compensatory type 1 and type 2 muscle fiber hypertrophy. The underlying lesion of the S1 nerve root was caused by scarring, which could be demonstrated by Gadolinum enhanced, fat saturated magnetic resonance imaging. Thus, the application of this technique is recommended in otherwise etiologically unclear cases of neurogenic muscular lesions in order to detect chronic nerve root pathology.


Retroposons do jump: a B2 element recently integrated in an 18S rDNA gene.
Several cDNA clones were isolated from cDNA libraries constructed with mRNA longer than 28S RNA from the murine cell line PYS-2/12. The plasmids have inserts containing 1-1.2 kb of the ribosomal 5' external transcribed spacer followed by nearly 700 nt of sequence for 18S rRNA and ending with a B2 element (retroposon). The cloned sequence differed in a few positions from published ribosomal sequences. The 3' adjacent genomic sequence was obtained by polymerase chain reaction (PCR) and showed that the B2 element has a poly(A) tail of about 50 nt and is surrounded by perfect direct repeats of 15 nt. Analysis of genomic DNA from several murine cell lines revealed that PYS cells contain at least one copy of 18S RNA with the B2 element which is not present in the genome of other murine cell lines derived from the same teratocarcinoma. Similarly, rRNA transcripts containing the B2 element were only detected in PYS cells. According to the publication dates of the different cell lines, the B2 element must have been integrated into an rRNA transcription unit during the years 1970 through 1974 thus proving that retroposons (SINEs) can still be inserted into the genome in our times.


Ecological factors predictive of wild spider monkey (Ateles belzebuth) foraging decisions in Yasuní, Ecuador.
Because fruiting trees are uncommon in tropical forests, frugivorous primates experience selective pressure to incorporate knowledge of where to find feeding trees, what to expect when they arrive there, and when they can return after depleting a tree. I investigated these abilities in wild spider monkeys (Ateles belzebuth) in Yasuní, Ecuador, by analyzing the characteristics of feeding trees that drive foraging decisions. Foraging data were derived from four 2-week follows of focal adult females, conducted between May and December 1999, during which I measured and mapped all trees in which the focal subject fed, feeding bout duration, and the number of conspecifics feeding simultaneously with the focal. Taking into account the order in which feeding trees were visited across each follow, I analyzed each foraging decision from the second week of a follow, treating all previously visited trees as options for visits. I scored each option tree in terms of nine ecological variables, including the distance from the decision to each location tree, DBH, recent feeding time and mean feeding times for the focal and other monkeys present, and the interval in hours between the foraging decision and the most recent visit to each option tree. I then examined the predictive strength of the model using logistic regression analysis, comparing characteristics of selected trees to those not selected. The overall model successfully predicted trees selected by focal monkeys (r(2) = 0.27). Monkeys preferentially moved to nearby, large canopy trees, in which previous feeding success was high, and which were visited after an interval of 3.5 days. Interval mattered most for medium and large trees, but did not predict selection for trees <10 cm DBH. Despite the large home range and large numbers of trees, Yasuní spider monkeys appeared to integrate spatial, value, and temporal information when deciding where to feed.


Rhinoplasty Results Are Influenced by Non-nasal Features.
Rhinoplasty results are evaluated both objectively and subjectively following any procedure by plastic surgeons and nonplastic surgeons at meetings, in publications, and online. We aim to evaluate whether subjective aesthetics of non-nasal features, such as the eyes and lips, would influence the overall evaluation of rhinoplasty results. We matched pairs of photographs of patients who had undergone aesthetic rhinoplasty by sex, age, and skin tone. We transferred the eyes/eyebrows and lips from the photographs of the donor patient onto the photographs of the original patient to create composite photographs. Plastic surgeons were asked to rate the rhinoplasty results objectively, and non-plastic surgeons were asked to rate the overall attractiveness of 16 sets of photographs (8 originals and 8 composites). Postoperative photographs that were deemed to be more attractive were associated with higher ratings of rhinoplasty improvement. The objective nasal result may be influenced by non-nasal aesthetic factors as rhinoplasty surgeons gave higher ratings to more attractive faces. Greater emphasis on neutralizing non-nasal factors in pre- and postoperative photographs should be considered.


Effect of cigarette smoke extract on lipopolysaccha-ride-activated mitogen-activated protein kinase signal transduction pathway in cultured cells.
Lipopolysaccharide (LPS) forms outer membrane of the wall of Gram-negative cells. LPS can directly cause damage to epithelia of respiratory tract and is the major factor responsible for the chronic inflammation of respiratory passage. The mitogen-activated protein kinase (MAPK) signal transduction pathway of the airway epithelia is intimately associated with the action of LPS. The chronic inflammation of respiratory tract and smoking are interrelated and entwined in the development and progression of chronic lung diseases. This study was designed to examine the effects of cigarette smoke extract (CSE) and LPS on MAPK signal transduction pathway in order to further understand the roles CSE and LPS play in chronic lung inflammation. Cultured primary human epithelial cells of airway were divided into four groups according to the stimulants used: blank control group, LPS-stimulation group, CSE-stimulation group and CSE plus LPS group. Western blotting was employed for the detection of phosphorylation level of extracellular-signal-regulated-kinase (ERK(1/2)), p38 MAPK and c-Jun N-terminal kinase (JNK). The expression of cytokines of MAPK transduction pathway (granulocyte-macrophage colony stimulating factor (GM-CSF) and mRNA of IL-8) in the primary epithelial cells of respiratory tract was also determined. Western blotting revealed that the phosphorylation levels of ERK(1/2), p38 MAPK and JNK were low and 2 hours after the LPS stimulation, the phosphorylation of ERK(1/2), p38 MAPK and JNK were all increased. There was a significant difference in the phosphorylation between the LPS-stimulation group and blank control group (P < 0.05); no significant difference was found between CSE-stimulation group and blank control group (P > 0.05); there was a significant difference between CSE + LPS group and blank control group and between CSE + LPS group and LPS group (P < 0.05). The phosphorylation of CSE-LPS group was higher than that of blank control group but lower than that of LPS group. In blank control group, the expression of IL-8 and GM-CSF mRNA was low in the epithelial cells of airway and the release of IL-8 and GM-CSF was also at a low level. One hour after LPS stimulation, the level of IL-8 mRNA increased (P < 0.05) and reached a peak after 2 hours. On the other hand, GM-CSF mRNA level increased 2 hours after the stimulation (P < 0.05) and reached the highest level 4 hours after the stimulation. Two hours after LPS stimulation, IL-8 and GM-CSF protein level began to rise (P < 0.05), and the level was the highest 8 hours after the stimulation (P < 0.01). Stimulation with CSE alone had no effect on the release of IL-8 and GM-CSF and expression of IL-8 mRNA (P > 0.05), but pre-treatment with CSE could delay the LPS-induced release of IL-8 and GM-CSF and the expression of IL-8 mRNA and its peak was lower. LPS stimulation can significantly increase the phosphorylation of ERK(1/2), p38 MAPK and JNK in the epithelial cells of airway and activate the MAPK transduction pathway, thereby can activate the downstream signal transduction pathway, and can ultimately result in the release of cytokines by the epithelial cells of airway. CSE can partially abolish the LPS-induced activation of MAPK signal transduction pathway and the expression of cytokines of the pathway, which might contribute to the development and progression of the inflammatory reactions in COPD patients.


Effect of nutritional status on response to treatment with artemisinin-based combination therapy in young Ugandan children with malaria.
The relationship between malnutrition and malaria in young children is under debate, and no studies evaluating the association between malnutrition and response to artemisinin-based combination therapies (ACTs) have been published. We evaluated the association between malnutrition and response to antimalarial therapy in Ugandan children treated with ACTs for repeated episodes of malaria. Children aged 4 to 12 months diagnosed with uncomplicated malaria were randomized to dihydroartemisinin-piperaquine (DP) or artemether-lumefantrine (AL) and followed for up to 2 years. All HIV-exposed and HIV-infected children received trimethoprim-sulfamethoxazole prophylaxis (TS). The primary exposure variables included height-for-age and weight-for-age z scores. Outcomes included parasite clearance at days 2 and 3 and risk of recurrent parasitemia after 42 days of follow-up. Two hundred ninety-two children were randomized to DP or AL, resulting in 2,013 malaria treatments. Fewer than 1% of patients had a positive blood smear by day 3 (DP, 0.2%; AL, 0.6% [P = 0.18]). There was no significant association between height-for-age or weight-for-age z scores and a positive blood smear 2 days following treatment. For children treated with DP but not on TS, decreasing height-for-age z scores of <-1 were associated with a higher risk of recurrent parasitemia than a height-for-age z score of >0 (hazard ratio [HR] for height-for-age z score of <-1 and ≥-2 = 2.89 [P = 0.039]; HR for height-for-age z score of <-2 = 3.18 [P = 0.022]). DP and AL are effective antimalarial therapies in chronically malnourished children in a high-transmission setting. However, children with mild to moderate chronic malnutrition not taking TS are at higher risk for recurrent parasitemia and may be considered a target for chemoprevention.


[Open lung biopsy in severely ill patients with unrecognized pulmonary infiltrates].
In three patients, a man aged 34 with aids, a woman aged 67 with recurrent major dyspnoea and a woman aged 73 with chronic lymphatic leukaemia, examination revealed progressive dyspnoea while the chest X-rays showed infiltrative lesions in both lungs. In view of the inadequate response to the treatment administered, an open lung biopsy was performed, following which the diagnosis could be made. Adequate treatment was then started and followed by clinical recovery. It is not clear if open lung biopsy carries higher risks of mortality and morbidity than biopsy by means of flexible bronchoscopy. Open lung biopsy more often leads to a classifying diagnosis. For collection of endobronchial or transbronchial biopsy samples in ununderstood diffuse interstitial lung diseases, flexible bronchoscopy is the method of first choice. Open lung biopsy is a justified supplementary examination, at any rate in severely ill, immunocompromised patients who require adequate therapy without delay.


Transport systems for polyamines in the established renal cell line LLC-PK. Polarized expression of an Na(+)-dependent transporter.
We present evidence for the existence of an Na(+)-dependent transporter and an Na(+)-independent transporter for polyamines in LLC-PK1 cells. Both transporters could be discriminated by their sensitivity to inhibitors, particularly rho-chloromercuriphenyl sulphate and various polycationic molecules. By using cell monolayers grown on a permeable filter support, we have found that the Na(+)-dependent polyamine uptake occurred preferentially from the basolateral side. The Na(+)-independent uptake, on the other hand, occurred to the same extent from either the apical or the basolateral side.


In vitro effect of malachite green on Candida albicans involves multiple pathways and transcriptional regulators UPC2 and STP2.
In this study, we show that a chemical dye, malachite green (MG), which is commonly used in the fish industry as an antifungal, antiparasitic, and antibacterial agent, could effectively kill Candida albicans and non-C. albicans species. We have demonstrated that Candida cells are susceptible to MG at a very low concentration (MIC that reduces growth by 50% [MIC(50)], 100 ng ml(-1)) and that the effect of MG is independent of known antifungal targets, such as ergosterol metabolism and major drug efflux pump proteins. Transcriptional profiling in response to MG treatment of C. albicans cells revealed that of a total of 207 responsive genes, 167 genes involved in oxidative stress, virulence, carbohydrate metabolism, heat shock, amino acid metabolism, etc., were upregulated, while 37 genes involved in iron acquisition, filamentous growth, mitochondrial respiration, etc., were downregulated. We confirmed experimentally that Candida cells exposed to MG resort to a fermentative mode of metabolism, perhaps due to defective respiration. In addition, we showed that MG triggers depletion of intracellular iron pools and enhances reactive oxygen species (ROS) levels. These effects could be reversed by the addition of iron or antioxidants, respectively. We provided evidence that the antifungal effect of MG is exerted through the transcription regulators UPC2 (regulating ergosterol biosynthesis and azole resistance) and STP2 (regulating amino acid permease genes). Taken together, our transcriptome, genetic, and biochemical results allowed us to decipher the multiple mechanisms by which MG exerts its anti-Candida effects, leading to a metabolic shift toward fermentation, increased generation of ROS, labile iron deprivation, and cell necrosis.


Genetic characteristics of P. falciparum parasites collected from 2012 to 2016 and anti-malaria resistance along the China-Myanmar border.
The therapeutic efficacy studies of DHA-PIP for uncomplicated Plasmodium falciparum patients were implemented from 2012 to 2016 along China (Yunnan province)-Myanmar border, which verified the high efficacy of DHA-PIP. With the samples collected in these studies, the genetic characteristics of P. falciparum parasites based on in vivo parasite clearance time (PCT) was investigated to explore if these parasites had developed resistance to DHA and PIP at molecular level. The genetic characteristics were investigated based on K13 genotypes, copy numbers of genes pfpm2 and pfmdr1, and nine microsatellite loci (Short Tandem Repeats, STR) flanking the K13 gene on chromosome 13. The PCT 50s were compared based on different K13 genotypes, sites, periods and copy numbers. In the NW (North-West Yunnan province bordering with Myanmar) region, F446I was the main K13 genotype. No significant differences for PCT 50s presented among three K13 genotypes. In SW (South-West Yunnan province bordering with Myanmar) region, only wild K13 genotype was detected in all parasite isolates whose PCT 50s was significantly longer than those in NW region. For the copy numbers of genes, parasite isolates containing multiple copies of pfmdr1 gene were found in both regions, but only single copy of pfpm2 gene was detected. Though the prevalence of parasite isolates with multiple copies of pfmdr1 gene in SW region was higher than that in NW region, no difference in PCT 50s were presented between isolates with single and multiple copies of pfmdr1 gene. The median He values of F446I group and Others (Non-F446I K13 mutation) group were 0.08 and 0.41 respectively. The mean He values of ML group (Menglian County in SW) and W (wild K13 genotype in NW) group were 0 and 0.69 respectively. The mean Fst values between ML and W groups were significantly higher than the other two K13 groups. P. falciparum isolates in NW and SW regions had very different genetic characteristics. The F446I was hypothesized to have independently appeared and spread in NW region from 2012 and 2016. The high susceptibility of PIP had ensured the efficacy of DHA-PIP in vivo. Multiple copy numbers of pfmdr1 gene might be a potential cause of prolonged clearance time of ACTs drugs along China-Myanmar border. Trial registration: ISRCTN, ISRCTN 11775446. Registered 17 April 2020-Retrospectively registered, the registered name was Investigating resistance to DHA-PIP for the treatment of Plasmodium falciparum malaria and chloroquine for the treatment of Plasmodium vivax malaria in Yunnan, China. http://www.isrctn.com/ISRCTN11775446.


Sequence analysis of two alleles reveals that intra-and intergenic recombination played a role in the evolution of the radish fertility restorer (Rfo).
Land plant genomes contain multiple members of a eukaryote-specific gene family encoding proteins with pentatricopeptide repeat (PPR) motifs. Some PPR proteins were shown to participate in post-transcriptional events involved in organellar gene expression, and this type of function is now thought to be their main biological role. Among PPR genes, restorers of fertility (Rf) of cytoplasmic male sterility systems constitute a peculiar subgroup that is thought to evolve in response to the presence of mitochondrial sterility-inducing genes. Rf genes encoding PPR proteins are associated with very close relatives on complex loci. We sequenced a non-restoring allele (L7rfo) of the Rfo radish locus whose restoring allele (D81Rfo) was previously described, and compared the two alleles and their PPR genes. We identified a ca 13 kb long fragment, likely originating from another part of the radish genome, inserted into the L7rfo sequence. The L7rfo allele carries two genes (PPR-1 and PPR-2) closely related to the three previously described PPR genes of the restorer D81Rfo allele (PPR-A, PPR-B, and PPR-C). Our results indicate that alleles of the Rfo locus have experienced complex evolutionary events, including recombination and insertion of extra-locus sequences, since they diverged. Our analyses strongly suggest that present coding sequences of Rfo PPR genes result from intragenic recombination. We found that the 10 C-terminal PPR repeats in Rfo PPR gene encoded proteins result from the tandem duplication of a 5 PPR repeat block. The Rfo locus appears to experience more complex evolution than its flanking sequences. The Rfo locus and PPR genes therein are likely to evolve as a result of intergenic and intragenic recombination. It is therefore not possible to determine which genes on the two alleles are direct orthologs. Our observations recall some previously reported data on pathogen resistance complex loci.


Vascular retinopathy in migraine.
After years of episodic monocular visual loss, two migraineurs suffered sudden, persisting loss of vision from retinal vascular occlusion. One was a 34-year-old woman with systemic lupus erythematosus who showed abnormalities of the cilioretinal arterial and retinal venous circulations. The other was a 62-year-old man with hypertension and arteriosclerosis who had a central retinal vein occlusion. Persisting monocular visual loss is a rare consequence of migraine. Our cases suggest a role for venous lesions. Occlusion of retinal vessels in some migraineurs may result from the synergistic effect of another vascular disorder with the migraine.