Dual Bioorthogonal Labeling of the Amyloid-β Protein Precursor Facilitates Simultaneous Visualization of the Protein and Its Cleavage Products.
The amyloid-β protein precursor (AβPP) is critical in the pathophysiology of Alzheimer's disease (AD), since two-step proteolytic processing of AβPP generates the neurotoxic amyloid-β peptide (Aβ). We developed a dual fluorescence labeling system to study the exact subcellular location of γ-secretase cleavage of AβPP. The C-terminal tail of AβPP was fluorescently labeled using a SNAP-tag, while the Aβ region of AβPP was fluorescently tagged with a dye at a genetically-encoded noncanonical amino acid (ncAA). The ncAA was introduced at specific positions in AβPP using a genetic code expansion strategy and afterwards, the reactive side-chain of the ncAA was coupled to the dye using a bioorthogonal labeling chemistry. In proof-of-concept experiments, HEK293T cells were transfected with plasmids containing engineered AβPP harboring an amber mutation and an amber codon suppression system with an evolved tRNA synthetase/tRNA pair and grown in the presence of a lysine-derived ncAA. Processing of the AβPP variants was validated with ELISA and immunoblotting, and seven AβPP mutants that showed similar cleavage pattern as wild-type AβPP were identified. The AβPP mutant was fluorescently labeled with 6-methyl-tetrazine-BDP-FL and TMR-Star at the ncAA and SNAP-tag, respectively. Using this approach, AβPP was fluorescently labeled at two sites in living cells with minimal background to allow monitoring of Aβ and C-terminal cleavage products simultaneously. The method described provides a powerful tool to label Aβ with minimal perturbations of its processing, thus enabling studies of the trafficking of the cleavage products of AβPP.


Complex population dynamics in mussels arising from density-linked stochasticity.
Population fluctuations are generally attributed to the deterministic consequences of strong non-linear interactions among organisms, or the effects of random stochastic environmental variation superimposed upon the deterministic skeleton describing population change. Analysis of the population dynamics of the mussel Mytilus californianus taken in 16 plots over 18-years found no evidence that these processes explained observed strong fluctuations. Instead, population fluctuations arose because environmental stochasticity varied with abundance, which we term density-linked stochasticity. This phenomenon arises from biologically relevant mechanisms: recruitment variation and transmission of disturbance among neighboring individuals. Density-linked stochasticity is probably present frequently in populations, as it arises naturally from several general ecological processes, including stage structure variation with density, ontogenetic niche shifts, and local transmission of stochastic perturbations. More thoroughly characterizing and interpreting deviations from the mean behavior of a system will lead to better ecological prediction and improved insight into the important processes affecting populations and ecosystems.


Occurrence and evolutionary significance of a California encephalitis-like virus in Aedes squamiger (Diptera: Culicidae).
More than 12,000 Aedes increpitus Dyar and 4,600 Aedes squamiger (Coquillett) were tested for the presence of arboviruses to test the hypothesis that there is a coevolutionary relationship between Aedes (Ochlerotatus) mosquitoes and California serogroup viruses. Five strains of a California encephalitis-like virus were isolated from adults reared from larvae of Ae. squamiger collected in January 1989 from a coastal salt marsh at Morro Bay, San Luis Obispo County, California. Viruses were isolated in Vero cell cultures and serotyped by cross-neutralization tests. These isolates represent the first arboviruses isolated from this species. On the basis of morphology, Aedes squamiger has been included in the Aedes stimulans group of the subgenus Ochlerotatus. Other species within the Ae. stimulans group are vectors of California (CAL) serogroup viruses elsewhere in North America. Analysis of isozyme variability supports the inclusion of Ae. squamiger in the Ae. stimulans group and suggests that coastal populations of Ae. increpitus are the closest California relatives of Ae. squamiger. Recovery of virus from Ae. squamiger reinforces the relationship between CAL serogroup viruses and Aedes (Ocherlotatus) mosquitoes. However, the failure to isolate virus from large samples of Ae. increpitus from coastal and low elevation inland habitats suggests a complex evolutionary history involving both vertical and horizontal transmission mechanisms.


Development and validation of a liquid chromatography-electrospray ionization-time-of-flight mass spectrometry method for induced changes in Nicotiana attenuata leaves during simulated herbivory.
A liquid chromatography-electrospray ionization-time-of-flight mass spectrometry (HPLC/ESI-TOF-MS) procedure was developed to characterize changes induced in Nicotiana attenuata leaves 1 h and 5 days after wounding and application of Manduca sexta elicitors. The constancy of the measurement conditions was first confirmed for 22 selected analytes spanning the entire chromatogram. Using the Profile Analysis software, we extracted 367 buckets, which were analyzed by principal component analysis and two-factorial ANOVA. One hundred seventy-three buckets were found to be statistically regulated, 128 due to time effects, and 85 due to treatment effects. In vivo 15N-isotope labeling was used to facilitate the annotation and the interpretation of the fragmentation pattern of nitrogen-containing metabolites, and a correlation analysis was performed to test mathematical relationships existing among potential in-source fragments. Additionally, tandem MS measurements of the most regulated ions are presented. Altogether, this study defines a framework for the mining and annotation of major herbivory-elicited changes in Nicotiana attenuata.


Ninety-five percent insulin independence rate 3 years after pancreas transplantation alone with portal-enteric drainage.
Portal-enteric drainage (PED) might be particularly suitable for pancreas transplantation alone (PTA), since it has been associated with an immunologic advantage and achieves excellent metabolic results. We describe our experience with a consecutive series of 40 PTAs with PED. Between April 2001 and March 2004, 40 consecutive PTAs were performed with PED. Recipients were selected according to the American Diabetic Association recommendations. Donors were selected according to standard criteria irrespective of HLA match, although matching for A and B loci was considered at the time of graft allocation. Immunosuppression consisted of induction treatment with basiliximab (n = 34) or thymoglobulin (n = 6), and maintenance therapy with steroids, mycophenolate mofetil, and tacrolimus. After a mean cold ischemia time of 690 minutes (range, 517-965 min) all pancreases functioned immediately. Three grafts were lost due to hyperacute or accelerated rejection. No graft was lost to vascular thrombosis, although 5 (12.5%) nonocclusive thromboses were identified and the grafts were rescued with intravenous heparin infusion. A repeat laparotomy was required in 7 recipients (17.5%) No patient required multiple repeat laparotomies, and none died. After a mean follow-up of 16.4 months (range, 1-36 mo), 2 recipients were diagnosed with rejection episodes, which were reversed with steroid boluses. Actuarial 3-year patient, and graft survival rates were 100% and 94.9%, respectively. The following parameters showed significant improvement compared with pretransplantation evaluation: hemoglobin A1C concentration, total and high-density lipoprotein cholesterol levels, arterial blood pressure, cardiac performance, retinopathy, proteinuria, and neuropathy. Pancreas transplantation alone with PED provides high rates of long-term insulin-independence.


Quantification and Assessment of the Chemical Form of Residual Gadolinium in the Brain After Repeated Administration of Gadolinium-Based Contrast Agents: Comparative Study in Rats.
Multiple clinical and preclinical studies have reported a signal intensity increase and the presence of gadolinium (Gd) in the brain after repeated administration of Gd-based contrast agents (GBCAs). This bioanalytical study in rat brain tissue was initiated to investigate whether the residual Gd is present as intact GBCA or in other chemical forms by using tissue fractionation and chromatography. Rats were divided randomly in 6 groups of 10 animals each. They received 10 daily injections of 2.5 mmol/kg bodyweight of 1 of 5 different GBCAs: linear GBCAs such as gadodiamide (Omniscan; GE Healthcare), gadopentetate dimeglumine (Gd-DTPA, Magnevist; Bayer), or gadobenate dimeglumine (Multihance; Bracco) and macrocyclic GBCAs such as gadobutrol (Gadovist; Bayer) and gadoterate meglumine (Gd-DOTA, Dotarem; Guerbet) or saline. On days 3 and 24 after the last injection (p.i.), 5 randomly chosen animals of each group were killed by exsanguination, and their brains were excised and divided into cerebrum, pons, and cerebellum. The brain sections were homogenized by sonication in ice-cold buffer at pH 7.4. Soluble and insoluble fractions were separated by centrifugation, and the soluble fractions were further separated by gel permeation chromatography (GPC). The Gd concentration in all tissue fractions and in the GPC eluate was measured by inductively coupled plasma-mass spectrometry. In a recovery control experiment, all GBCAs were spiked to blank brain tissue and more than 94% recovery of Gd in the tissue fractions was demonstrated. Only traces of the administered Gd were found in the rat brain tissue on day 3 and day 24 p.i. In the animals treated with macrocyclic GBCAs, Gd was found only in the soluble brain fraction and was present solely as low molecular weight molecules, most likely the intact GBCA. In the animals treated with linear GBCAs Gd was found to a large extent in the insoluble tissue fraction. The Gd concentration in the soluble fraction was comparable to the macrocyclic agents. According to GPC, a smaller portion of the Gd in the soluble fraction of the linear GBCAs groups was bound to macromolecules larger than 250 to 300 kDa. The nature of the Gd-containing macromolecules and the insoluble species were not determined, but they appeared to be saturable with Gd. The excretion of the soluble Gd species in the linear and macrocyclic GBCA groups was still ongoing between days 3 and 24 p.i. This was also observed for the macromolecular Gd species in the linear GBCA groups, but at a slower rate. The residual Gd found in the rat brain after repeated administration of all 3 linear GBCAs was present in at least 3 distinctive forms-soluble small molecules, including the intact GBCA, soluble macromolecules, and to a large extent in insoluble form. The latter 2 are most likely responsible for the prolonged signal intensity enhancement in brain structures observed in magnetic resonance imaging. No relevant differences between the 3 linear GBCAs were observed. The Gd concentrations in the brain after administration of macrocyclic GBCAs are lower, and the Gd is only present in soluble small molecules, which were slowly excreted. This underlines the crucial importance of the kinetic inertness of macrocyclic agents in the prevention of potential retention of Gd in the brain compared with the 3 linear, kinetically less restricted GBCAs.


Translation of the Diabetes Prevention Program to Ethnic Communities in the United States.
The Diabetes Prevention Program (DPP), an evidenced-based lifestyle intervention for type 2 diabetes (T2D), has been translated for use with ethnic minority communities throughout the United States that are disproportionately at-risk for T2D. The present paper sought to critically review ethnic translation studies of the DPP with respect to translation methods utilized, the success of these methods, and alternative or supplemental methodologies for future translation efforts. Manuscripts reviewed were found by searching PubMed and PsycINFO, using the terms: "diabetes prevention program" AND ["translation" or "ethnic"]. Of 89 papers found, only 6 described ethnic translations of the DPP in the United States, and were included in this review. Translations of the DPP to African American, Hispanic/Latino, Native Hawaiian and Other Pacific Islander, Arab American, and American Indian and Native Alaskan communities were identified and reviewed. The most common translation strategies included group-based delivery and use of bilingual study personnel. Generally, these factors appeared to increase acceptability of the intervention within the ethnic communities reviewed, and should be considered in future efforts to implement and translate the DPP to ethnic communities in the United States.


Perceived factors to providing palliative care for patients with cancer - a qualitative systematic review.
Palliative care (PC) is one of the necessary cares given throughout a patient's experience with cancer. The aim of this study was to identify the perceived factors to providing PC for patients with cancer. Our study was a systematic review of qualitative literature. To this end, electronic databases, including CINAHL, PubMed, PsycINFO, Ovid, and Web of Science as well as Persian databases were searched and qualitative studies on the role of PC in patients with cancer published between Jan 2008 and Dec 2017 were selected. Generally, 12 studies were reviewed. A thematic synthesis approach was used to analyze the data. Exploring the selected articles, the findings on the perceived factors to providing PC for patients with cancer were categorized into three themes, including organizational factors, ethical factors, and psychological factors. This qualitative systematic review expands our knowledge about factors influencing the provision of PC for patients with cancer. It is necessary for health system managers and caregivers to pay attention to all aforesaid factors in order to improve PC for cancer patients.


Changes in unintentional cannabis exposures in children 6 months to 5 years reported to United States poison centers during the first nine months of the coronavirus-19 pandemic.
Almost half of exposures reported to United States (US) poison centers are exploratory ingestions in children under the age of 5 years. Pediatric cannabis exposures reported to US poison centers have risen over the last twenty years, with greater increases in the last 5 years. In 2020, the Coronavirus disease 2019 (COVID-19) pandemic resulted in widespread stay-at-home orders and subsequent changes in work, education, and daycare. This study describes the changes in pediatric cannabis exposures during the first nine months of the COVID-19 pandemic relative to the three years before the pandemic. Cases were identified from the National Poison Data System. Inclusion criteria was unintentional cannabis exposure in children aged 6 months to 5 years between January 1, 2017 and December 31, 2020. Analysis was performed with segmented regression of interrupted time series analysis comparing January 2017-March 2020 (pre-COVID-19) to April 2020-December 2020 (COVID-19 period). Autocorrelation was assessed using Dubin-Watson test. There were 7,679 unintentional pediatric exposures from January 1, 2017 through December 31, 2020. There was a significant increase of 3.1% per month during the pre-COVID-19 period (p < .0001). A statistically significant immediate increase in number of exposures per month occurred in April 2020 (58.4%; p < .0001). The slope in the COVID-19 period was -0.01% (p = .99). No autocorrelation was detected. Unintentional cannabis exposures in children aged 6 months to 5 years reported to United States poison centers increased significantly after the initial COVID-19 stay-at-home orders. This trend may be associated with COVID-19 quarantines, increased time children are spending at home, increased availability of cannabis products in homes, or other reasons. Future efforts should evaluate specific factors that resulted in the observed increases in pediatric exposures.


Mutational analysis of substrate interactions with the active site of dialkylglycine decarboxylase.
Pyridoxal phosphate (PLP)-dependent enzymes catalyze many different types of reactions at the alpha-, beta-, and gamma-carbons of amine and amino acid substrates. Dialkylglycine decarboxylase (DGD) is an unusual PLP-dependent enzyme that catalyzes two reaction types, decarboxylation and transamination, in the same active site. A structurally based, functional model has been proposed for the DGD active site, which maintains that R406 is important in determining substrate specificity through interactions with the substrate carboxylate while W138 provides specificity for short-chain alkyl groups. The mechanistic roles of R406 and W138 were investigated using site-directed mutagenesis, alternate substrates, and analysis of steady-state and half-reaction kinetics. Experiments with the R406M and R406K mutants confirm the importance of R406 in substrate binding. Surprisingly, this work also shows that the positive charge of R406 facilitates catalysis of decarboxylation. The W138F mutant demonstrates that W138 indeed acts to limit the size of the subsite C binding pocket, determining specificity for 2,2-dialkylglycines with small side chains as predicted by the model. Finally, work with the double mutant W138F/M141R shows that these mutations expand substrate specificity to include l-glutamate and lead to an increase in specificity for l-glutamate over 2-aminoisobutyrate of approximately 8 orders of magnitude compared to that of wild-type DGD.


Survey of Nutrition Management Practices in Centers for Pediatric Intestinal Rehabilitation.
Nutrition management of pediatric intestinal failure (IF) requires interdisciplinary coordination of parenteral nutrition (PN) and enteral nutrition (EN) support. Nutrition strategies used by specialists in pediatric intestinal rehabilitation to promote gut adaptation and manage complications have not been previously summarized. A practice survey was distributed to members of the dietitian subgroup of the American Society for Parenteral and Enteral Nutrition Pediatric Intestinal Failure Section. The survey included 24 open-ended questions related to PN and enteral feeding strategies, nutrition management of PN-associated liver disease, and laboratory monitoring. Dietitians from 14 centers completed the survey. Management components for patients at risk for cholestasis were consistent and included fat minimization, trace element modification, avoiding PN overfeeding, and providing EN. Parenteral amino acid solutions designed for infants/young children are used in patients <1 or 2 years of age. Trace minerals are dosed individually in 10 of 14 centers. Eleven centers prescribe a continuous infusion of breast milk or elemental formula 1-2 weeks after resection while 3 centers determine the formula type by the extent of resection. Most (86%) centers do not have a protocol for initiating oral/motor therapy. Laboratory panel composition varied widely by center. The selection and frequency of use depended on clinical variables, including cholestatic status, exclusive vs partial PN dependence, postrepletion verification vs routine monitoring, intestinal anatomy, and acuity of care. EN and PN management strategies are relatively consistent among U.S. centers. Collaborative initiatives are necessary to define better practices and establish laboratory monitoring guidelines.


Systematic analysis of alternative exon-dependent interactome remodeling reveals multitasking functions of gene regulatory factors.
Alternative splicing significantly expands biological complexity, particularly in the vertebrate nervous system. Increasing evidence indicates that developmental and tissue-dependent alternative exons often control protein-protein interactions; yet, only a minor fraction of these events have been characterized. Using affinity purification-mass spectrometry (AP-MS), we show that approximately 60% of analyzed neural-differential exons in proteins previously implicated in transcriptional regulation result in the gain or loss of interaction partners, which in some cases form unexpected links with coupled processes. Notably, a neural exon in Chtop regulates its interaction with the Prmt1 methyltransferase and DExD-Box helicases Ddx39b/a, affecting its methylation and activity in promoting RNA export. Additionally, a neural exon in Sap30bp affects interactions with RNA processing factors, modulating a critical function of Sap30bp in promoting the splicing of <100 nt "mini-introns" that control nuclear RNA levels. AP-MS is thus a powerful approach for elucidating the multifaceted functions of proteins imparted by context-dependent alternative exons.


Management of concomitant coronary and bilateral carotid artery disease: a case report.
Patients with severe coexistent coronary and carotid artery stenosis represent a difficult and high-risk population. Herein we describe management of a patient with concomitant coronary artery and bilateral carotid artery disease. Firstly, left carotid artery stenting was done using a self-expandable monorail stent and a neurological protective device. Post-stent angiogram revealed satisfactory dilatation in the left carotid artery. Later, coronary artery bypass grafting to the four coronary arteries was done. Then right carotid endarterectomy was done. He had no neurological complication during or after any of the operation and he remains in good health since his last operation. We think the staged treatment, consisting of carotid artery stenting plus coronary artery bypass grafting plus carotid endarterectomy, in a patient with concomitant severe coronary artery and bilateral carotid artery disease is feasible, safe, and may be an alternative to combined coronary artery bypass grafting plus carotid endarterectomy.


Renal effects of targeted anticancer therapies.
The use of novel targeted anticancer agents has led to overall improvement in the prognosis of many patients affected by various malignancies, but has also been associated with an increased risk of poorly characterized toxic effects to different organs, including the kidneys. The high prevalence of kidney impairment in the general population complicates the issue further. Nephrologists most frequently work with patients with cancer when they are asked to investigate kidney function to assess the need for dose adjustments in anticancer therapy. A thorough knowledge of the renal safety profile of novel life-prolonging anticancer therapies, specific features of their metabolism, and pharmacokinetic and pharmacodynamic properties (under normal circumstances as well as in the setting of renal replacement therapy) is, therefore, necessary to preserve kidney function as far as possible and to ensure optimum treatment. In this Review we summarize the present knowledge of renal toxic effects from novel targeted anticancer agents and discuss whether the management of patients' treatment needs to be modified. We also advocate the development of a new onconephrology subspeciality.


Tobacco smoke overload and ethnic, state, gender, and temporal cancer mortality disparities in Asian-Americans and Pacific Islander-Americans.
Asians and Pacific Islanders (APIs) are important populations nationally and globally. So we assessed cumulative tobacco smoke overexposure (smoke overload)/cancer mortality associations across states, ethnicities, years, and genders among API-Americans. Death rates were adjusted to the 2000 United States age standard, lung cancer death rates used as a smoke overload bio-index, and lung/non-lung cancer death rate linear regressions run. Cancer death rate smoking-attributable fractions (SAFs) are equal to 1--estimated unexposed rate/observed rate. The two lowest smoke overload and non-lung cancer death rates were in South Asian (Indo)-Californian females and males. The highest were in Korean-Californian males. Non-lung cancer death rates were tightly and steeply associated with smoke overload across ethnicity, state, year, or gender. Cancer death rate smoking-attributable fractions ranged from 0 in female and 6% in male Indo-Californians, to 39% in female and 57% in male API-Americans in 2002, to 71% in Korean-Californian and 69% in API Hawaiian males. Many API American cancer death rate disparities across genders, ethnicities, states, or years can be explained by smoke overload disparities. Tobacco control may greatly reduce cancer death rates and disparities among API-Americans and, likely, others.


From Solution to Surface: Persistence of the Diradical Character of a Diindenoanthracene Derivative on a Metallic Substrate.
Organic diradicals are envisioned as elementary building blocks for designing a new generation of spintronic devices and have been used in constructing prototypical field effect transistors and nonlinear optical devices. Open-shell systems, however, are also reactive, thus requiring design strategies to "protect" their radical character from the environment, especially when they are embedded in solid-state devices. Here, we report the persistence on a metallic surface of the diradical character of a diindeno[b,i]anthracene (DIAn) core protected by bulky end-groups. Our scanning tunneling spectroscopy measurements on single-molecules detected singlet-triplet excitations that were absent for DIAn species packed in assembled structures. Density functional theory simulations unravel that the molecular geometry on the metal substrate can crucially modify the value of the singlet-triplet gap via the delocalization of the radical sites. The persistence of the diradical character over metallic substrates is a promising finding for integrating radical-based materials into functional devices.


Biochemical and structural analyses suggest that plasminogen activators coevolved with their cognate protein substrates and inhibitors.
Protein sequences of members of the plasminogen activation system are present throughout the entire vertebrate phylum. This important and well-described proteolytic cascade is governed by numerous protease-substrate and protease-inhibitor interactions whose conservation is crucial to maintaining unchanged protein function throughout evolution. The pressure to preserve protein-protein interactions may lead to either co-conservation or covariation of binding interfaces. Here, we combined covariation analysis and structure-based prediction to analyze the binding interfaces of urokinase (uPA):plasminogen activator inhibitor-1 (PAI-1) and uPA:plasminogen complexes. We detected correlated variation between the S3-pocket-lining residues of uPA and the P3 residue of both PAI-1 and plasminogen. These residues are known to form numerous polar interactions in the human uPA:PAI-1 Michaelis complex. To test the effect of mutations that correlate with each other and have occurred during mammalian diversification on protein-protein interactions, we produced uPA, PAI-1, and plasminogen from human and zebrafish to represent mammalian and nonmammalian orthologs. Using single amino acid point substitutions in these proteins, we found that the binding interfaces of uPA:plasminogen and uPA:PAI-1 may have coevolved to maintain tight interactions. Moreover, we conclude that although the interaction areas between protease-substrate and protease-inhibitor are shared, the two interactions are mechanistically different. Compared with a protease cleaving its natural substrate, the interaction between a protease and its inhibitor is more complex and involves a more fine-tuned mechanism. Understanding the effects of evolution on specific protein interactions may help further pharmacological interventions of the plasminogen activation system and other proteolytic systems.


[Hepatocellular carcinoma: interdisciplinary treatment concept].
In most cases hepatocellular carcinoma develops in a cirrhotic liver. The stage of the cirrhosis and the number and size of the liver tumors are decisive for the prognosis and the individual treatment possibilities. For each therapeutic procedure there are specific contraindications which have to be considered. In a prospective comparative study of different established methods of treatment, i.e. hepatic resection, percutaneous ethanol instillation, transcatheter arterial embolisation and tamoxifen therapy, tumor response, survival time, complications and factors, determining prognosis are analysed. The therapeutic concept of the study can thereby be used as a model for the interdisciplinary treatment of hepatocellular carcinoma.


Evaluation of an organic light-emitting diode display for precise visual stimulation.
A new type of visual display for presentation of a visual stimulus with high quality was assessed. The characteristics of an organic light-emitting diode (OLED) display (Sony PVM-2541, 24.5 in.; Sony Corporation, Tokyo, Japan) were measured in detail from the viewpoint of its applicability to visual psychophysics. We found the new display to be superior to other display types in terms of spatial uniformity, color gamut, and contrast ratio. Changes in the intensity of luminance were sharper on the OLED display than those on a liquid crystal display. Therefore, such OLED displays could replace conventional cathode ray tube displays in vision research for high quality stimulus presentation. Benefits of using OLED displays in vision research were especially apparent in the fields of low-level vision, where precise control and description of the stimulus are needed, e.g., in mesopic or scotopic vision, color vision, and motion perception.


Impact of new technologies on the clinical and functional outcome of Altemeier's procedure: a randomized, controlled trial.
A randomized study was performed to assess whether new technologies offer advantages over the conventional technique on the clinical and functional outcome of patients with full-thickness rectal prolapse and fecal incontinence, submitted to Altemeier's procedure with levatorplasty. Between January 1999 and December 2003, 58 patients (55 females; mean age, 70.9 +/- 11.3 years) with full-thickness rectal prolapse were evaluated with continence score, colonoscopy, anorectal manometry, anal electromyography, and sacral reflex latency; 40 of them were selected and randomly assigned to two groups: 20 patients (Group 1; 19 females, 73.4 +/- 10.4 years) were submitted to a conventional operation with monopolar electrocautery and handsewn anastomosis, and 20 (Group 2; 18 females, 71.5 +/- 12.2 years) using harmonic scalpel and circular stapler. Patients were followed up with clinical examination, anorectal manometry, and anal electromyography, with mean follow-up 29.3 +/- 8.5 and 27.5 +/- 9.2 months in Groups 1 and 2, respectively. Operative time, blood loss, and hospital stay were significantly reduced in Group 2 (P < 0.001), whereas no differences were found in pain score, time to return to normal activity, morbidity, and mortality. Complications were two (10 percent) stenosis in Group 1. Fecal continence score significantly improved in both groups (P < 0.01), whereas anorectal manometry and neurophysiologic data were not significantly modified by the operation. Recurrence rates were 15 and 10 percent in Groups 1 and 2, respectively (P= not significant). The clinical and functional long-term results of perineal rectosigmoidectomy with levatorplasty are not influenced by surgical instruments and type of coloanal anastomosis. The clinical relevance of the short-term results in high-risk patients should be specifically investigated.


Concepts in caregiver research.
To clarify and delineate conceptualizations of the effects of caregiving for nursing research and practice with family caregivers. The biopsychosocial (psychosocial and physiological) sequelae, both negative and positive, associated with providing care for a relative or friend with a chronic illness. Literature reviewed was obtained via searches of CINAHL, MEDLINE, and PsycInfo computerized databases through mid-2002. Key words for the searches were caregiver, caregiving, family caregiving, caregiver burden, and caregiver appraisal. Reports of both earlier reviews of literature and original research were included. Negative concepts included caregiver burden, hassles, strain, and stress. Positive concepts included caregiver esteem, uplifts of caregiving, caregiver satisfaction, finding or making meaning through caregiving, and gain in the caregiving experience. A neutral concept for describing the caregiving process is caregiver appraisal. Although earlier studies were focused on negative aspects of caregiving, more recent research has also included positive aspects. More attention should be given to (a) gender and cultural differences in caregiving, (b) development of flexible interventions, and (c) the biophysical sequelae of caregiving.


[Frequency of fecal incontinence and its impact on the quality of life of the hospitalized geriatric patient].
To determine the frequency of fecal incontinence and the impact on the quality of life of hospitalized geriatric patients in a sample from a level two hospital in Monterrey, Nuevo Leon, Mexico. Hospitalized patients over 60 years of age or their caregivers were questioned about the presence of fecal incontinence. Those who responded affirmatively and could respond were given the following questionnaires and scales: Mini-Mental, Rockwood quality of life for fecal incontinence and Wexner scale modified for severity of incontinence; in addition to clinical data. The frequency was calculated based on a sample and associations were determined between degree of incontinence and quality of life. A total of 234 patients were questioned, of whom 135 (57.69%) were women and 99 (42.31%) men. A total of 34 patients with fecal incontinence were documented, this represents a frequency of 14.53% (95% CI, 10.28-19.71%) in this population. A positive correlation of the severity of incontinence was found with the lifestyle dimension (relation (r) = -0.61, p = 0.04), shame (r = -0.70, p = 0.01), behavior (r = -0.73, p = 0.001) and the average of the four dimensions (r = -0.67, p = 0.02) but not with the depression dimension of the quality of life questionnaire in fecal incontinence. When compared with other national and international studies, the frequency of fecal incontinence found was lower than that documented in other series. The quality of life of hospitalized elderly patients with fecal incontinence in this sample was diminished and its impact on quality of life correlated with the severity of fecal incontinence.


In vitro development of inner cell masses isolated immunosurgically from mouse blastocysts. I. Inner cell masses from 3.5-day p.c. blastocysts incubated for 24 h before immunosurgery.
This paper describes the in vitro development of inner cell masses isolated immunosurgically from mouse blastocysts which had been collected on 3.5 days p.c. and then incubated for 24 h. The inner cell masses continue to grow in culture and develop through a series of stages with increasing complexity of internal organization. By day 1 all of the cultured ICMs have an outer layer of endoderm, and by day 3 some of them have two distinct kinds of inside cells; a columnar epithelial layer and a thin hemisphere of elongated cells. Later, mesodermal cells appear to delaminate from a limited region of the columnar layer, close to where it forms a junction with the thinner cells. By day 5, about 25% of the cultured ICMs have a striking resemblance to normal 7.5-day p.c. C3H embryos, with embryonic ectoderm, extra-embryonic ectoderm and chorion, embryonic and extra-embryonic mesoderm, and visceral endoderm. When mechanically disrupted and grown as attached clumps of cells in a tissue dish, these embryo-like structures give rise to trophoblast-like giant cells. These results suggest that the inner cell mass of 4.5-day p.c. blastocysts contains cells which can give rise to trophoblast derivates in culture.


Egg Parasitoids Survey of Spodoptera frugiperda (Smith) (Lepidoptera: Noctuidae) in Maize and Sorghum in Central Mexico.
Spodoptera frugiperda (Smith) is the main maize pest in America and was recently detected as an invasive pest in some countries in Asia and Africa. Among its natural enemies presented in Mexico, Trichogramma pretiosum Riley is the only egg parasitoid used in Integrated Pest Management (IPM) programs regardless of its effectiveness. A search for natural enemies of S. frugiperda was then carried out to determine whether this parasitoid has been established, and to detect native egg parasitoids or predators associated with this pest. The sentinel technique (egg masses) was used, and then placed in maize and sorghum fields in the state of Guanajuato, Mexico. Trichogramma atopovirilia Oatman and Platner, an egg parasitoid, and Chelonus insularis Cresson egg-larva parasitoid were recovered from field surveys. Among the natural enemies that preyed on eggs of S. frugiperda, we found mites of the genus Balaustium, and Dermaptera of the genus Doru, both species in great abundance. Laboratory tests were performed to compare the potential parasitism of T. atopovirilia against T. pretiosum. T. atopovirilia obtained 70.14% parasitism while T. pretiosum, 29.23%. In field cages, three doses of the parasitoids were tested. Total parasitism did not exceed 8% in any of the two species, but T. atopovirilia parasitized a greater number of hosts using two and three parasitoids per pest egg. Then, the use of Trichogramma species needs to be reevaluated in biological control programs against S. frugiperda.


Three-Dimensional Multimodality Image Reconstruction as Teaching Tool for Case-based learning among medical postgraduates: a focus on primary pelvic bone Tumour Education.
Postgraduate medical education in oncology orthopedics confronts obstacles when instructing on pelvic tumors, primarily due to their intricate anatomy and the limitations of conventional teaching techniques. The employment of Three-dimensional multimodality imaging (3DMMI) can be considered a valuable teaching tool, as it gracefully elucidates the intricacies of pelvic anatomical structures and the interactions between tumors and surrounding tissues through three-dimensional imaging, thereby providing a comprehensive and nuanced perspective. This study aimed to assess the feasibility and effectiveness of incorporating 3DMMI in combination with a Case-Based Learning (CBL) approach for postgraduate education. The study encompassed a 10-week course involving 90 surgical postgraduates, focusing on common pelvic tumor diseases. Students were assigned representative clinical cases, and each group created a PowerPoint presentation based on these cases. The core educational content included fundamental knowledge of pelvic anatomy, as well as clinical presentations, radiological features, and treatment principles of common pelvic tumor diseases. The research compared two groups: a traditional CBL group (n = 45) and a 3DMMI-CBL group (n = 45). The 3DMMI-CBL group had access to advanced imaging technology for better visualization. Various evaluations, including image interpretation, theoretical knowledge, and questionnaires, were used to assess the learning outcomes. The 3DMMI-CBL group outperformed the CBL group not only in the imaging diagnosis of common pelvic diseases but also in their mastery of the related theoretical knowledge. Student questionnaires indicated higher scores for the 3DMMI-CBL group in basic pelvic anatomy knowledge (8.08 vs. 6.62, p < 0.01), image interpretation (8.15 vs. 6.69, p < 0.01), learning efficiency (8.07 vs. 7.00, p < 0.01), clinical reasoning (7.57 vs. 6.77, p < 0.01), and learning interest (8.46 vs. 7.00, p < 0.01). Teacher questionnaires revealed that 3DMMI technology enhanced teachers' clinical knowledge, facilitated instruction, and increased overall satisfaction and interest in teaching. Our study introduced an enhancement to the conventional Case-Based Learning (CBL) model by incorporating 3DMMI technology for visualizing pelvic anatomy. In contrast to pure CBL, this adaptation improved teacher instruction, substantially heightened student engagement, ignited greater interest in learning, and boosted overall efficiency, ultimately leading to positive learning outcomes. Consequently, our study demonstrated the potential feasibility and acceptability of the 3DMMI-CBL teaching method for postgraduates in pelvic bone tumor education.


The impact of the Prime Time Sister Circles® (PTSC) on blood pressure of low-income mid-life African American women in the United States.
There is a pressing need to develop and evaluate culturally tailored, community-based interventions that address hypertension management among low-income African American women. We employed a randomized controlled trial to test the effectiveness of the Prime Time Sister Circles® Program in reducing blood pressure and body mass index among low-income African American women ages with hypertension. Study participants (N = 339) were African American women aged 40-75 years who were diagnosed with hypertension and received their primary care at government funded health centers in Washington, D.C. Compared to the usual care group, Prime Time Sister Circles® participation was associated with a reduction in systolic BP by - 2.45 (CI - 6.13, 1.23) mmHg, a reduction in diastolic BP by - 3.66 mmHg (CI - 6.32, - 0.99), and a change in BMI by - 0.26 (CI - 2.00, 1.48) from baseline to 15 months. The results suggest that culturally tailored community-based interventions can improve hypertension management in low-income women.


Molecular recognition and drug-lead identification: what can molecular simulations tell us?
Molecular recognition and ligand binding involving proteins underlie the most important life processes within the cell, such as substrate transport, catalysis, signal transmission, receptor trafficking, gene regulation, switching on and off of biochemical pathways. Despite recent successes in predicting the structures of many protein-substrate complexes, the dynamic aspects of binding have been largely neglected by computational/theoretical investigations. Recently, several groups have started tackling these problems with the use of experimental and simulation methods and developed models describing the variation of protein dynamics upon complex formation, shedding light on how substrate or inhibitor binding can alter protein flexibility and function. The study of ligand-induced dynamic variations has also been exploited to review the concept of allosteric changes, in the absence of major conformational changes. In this context, the study of the influence of protein motions on signal transduction and on catalytic activities has been used to develop pharmacophore models based on ensembles of protein conformations. These models, taking flexibility explicitly into account, are able to distinguish active inhibitors versus nonactive drug-like compounds, to define new molecular motifs and to preferentially identify specific ligands for a certain protein target. The application of these methods holds great promise in advancing structure-based drug discovery and medicinal chemistry in general, opening up the possibility to explore broader chemical spaces than is normally done in an efficient way. In this review, examples illustrating the extent to which simulations can be used to understand these phenomena will be presented along with examples of methodological developments to increase physical understanding of the processes and improve the possibility to rationally design new molecules.


Fostering multiple healthy lifestyle behaviors for primary prevention of cancer.
The odds of developing cancer are increased by specific lifestyle behaviors (tobacco use, excess energy and alcohol intakes, low fruit and vegetable intake, physical inactivity, risky sexual behaviors, and inadequate sun protection) that are established risk factors for developing cancer. These behaviors are largely absent in childhood, emerge and tend to cluster over the life span, and show an increased prevalence among those disadvantaged by low education, low income, or minority status. Even though these risk behaviors are modifiable, few are diminishing in the population over time. We review the prevalence and population distribution of these behaviors and apply an ecological model to describe effective or promising healthy lifestyle interventions targeted to the individual, the sociocultural context, or environmental and policy influences. We suggest that implementing multiple health behavior change interventions across these levels could substantially reduce the prevalence of cancer and the burden it places on the public and the health care system. We note important still-unresolved questions about which behaviors can be intervened upon simultaneously in order to maximize positive behavioral synergies, minimize negative ones, and effectively engage underserved populations. We conclude that interprofessional collaboration is needed to appropriately determine and convey the value of primary prevention of cancer and other chronic diseases.


Different approaches in the assessment of audiological rehabilitation: a meta-theoretical perspective.
The aim of this article is to highlight some elements (e.g. the view on truth, causality, context and methods) in three different meta-theoretical approaches to assessment and to discuss their implications: external realism, critical realism, and anti-realism. Although there are many differences between external realism and anti-realism, their main shortcoming is the failure to answer one of the basic questions in assessment research: 'What works for whom in what circumstances?' In order to answer this question, one needs a deep-structure ontology and a theory including mechanisms and contexts, which one finds in critical realism. An adequate approach to an evaluation process can be described as follows. The point of departure is a theory describing how mechanisms work in context and what the expected outcomes are. Hypotheses are formulated suggesting answers to the question 'What might work for whom in what circumstances? Data are collected in order to answer the question. Different methods are used which can shed light on the phenomenon. The outcome of the evaluation process is to find the conditions under which a specific outcome is produced.


[Functional assessment in rehabilitation].
The Norwegian Ministry of Health and Care Services currently defines rehabilitation as: a well planned, goal-oriented, time-limited process, where several professions or services cooperate in assisting individuals to use their own efforts to achieve best possible functioning and coping capabilities, to become independent and to participate in society. This understanding of rehabilitation includes some important changes compared to previous definitions. One is an acknowledgement of the disabled person as an expert on his/her life, who should be involved in decisions concerning rehabilitation goals and interventions. Another is an increased focus on activity and participation in community as important goals. Continuous evaluation of the content, process and outcomes of rehabilitation is needed. An important step towards an evidence-based practice in this field is the implementation of valid and systematic assessments in clinical practice. This conceptualisation of rehabilitation requires use of individualised instruments that capture the patients' priorities and evaluations.


Modulation of intracellular Na+ activity and cardiac force by norepinephrine and Ca2+.
The actions of norepinephrine and high calcium on the electrical, mechanical, and intracellular sodium ion activities were studied in electrically driven canine cardiac Purkinje fibers under different conditions. It was found that norepinephrine and high calcium decrease intracellular sodium ion activity (aiNa). The exposure to either agent is followed by a transient decline of force that correlates with the lower aiNa. Inhibition of the Na+ -K+ pump by strophanthidin reduces or abolishes the decrease in aiNa by norepinephrine but not that by high calcium. It is concluded that norepinephrine and high calcium both decrease aiNa and thereby the contractile force but (unlike high calcium) norepinephrine acts through the stimulation of the Na+ -K+ pump.


Media and social media attention to retracted articles according to Altmetric.
The number of retracted articles has grown fast. However, the extent to which researchers and the public are made adequately aware of these retractions and how the media and social media respond to them remains unknown. Here, we aimed to evaluate the media and social media attention received by retracted articles and assess also the attention they receive post-retraction versus pre-retraction. We downloaded all records of retracted literature maintained by the Retraction Watch Database and originally published between January 1, 2010 to December 31, 2015. For all 3,008 retracted articles with a separate DOI for the original and its retraction, we downloaded the respective Altmetric Attention Score (AAS) (from Altmetric) and citation count (from Crossref), for the original article and its retraction notice on June 6, 2018. We also compared the AAS of a random sample of 572 retracted full journal articles available on PubMed to that of unretracted full articles matched from the same issue and journal. 1,687 (56.1%) of retracted research articles received some amount of Altmetric attention, and 165 (5.5%) were even considered popular (AAS>20). 31 (1.0%) of 2,953 with a record on Crossref received >100 citations by June 6, 2018. Popular articles received substantially more attention than their retraction, even after adjusting for attention received post-retraction (Median difference, 29; 95% CI, 17-61). Unreliable results were the most frequent reason for retraction of popular articles (32; 19%), while fake peer review was the most common reason (421; 15%) for the retraction of other articles. In comparison to matched articles, retracted articles tended to receive more Altmetric attention (23/31 matched groups; P-value, 0.01), even after adjusting for attention received post-retraction. Our findings reveal that retracted articles may receive high attention from media and social media and that for popular articles, pre-retraction attention far outweighs post-retraction attention.


Pharmit: interactive exploration of chemical space.
Pharmit (http://pharmit.csb.pitt.edu) provides an online, interactive environment for the virtual screening of large compound databases using pharmacophores, molecular shape and energy minimization. Users can import, create and edit virtual screening queries in an interactive browser-based interface. Queries are specified in terms of a pharmacophore, a spatial arrangement of the essential features of an interaction, and molecular shape. Search results can be further ranked and filtered using energy minimization. In addition to a number of pre-built databases of popular compound libraries, users may submit their own compound libraries for screening. Pharmit uses state-of-the-art sub-linear algorithms to provide interactive screening of millions of compounds. Queries typically take a few seconds to a few minutes depending on their complexity. This allows users to iteratively refine their search during a single session. The easy access to large chemical datasets provided by Pharmit simplifies and accelerates structure-based drug design. Pharmit is available under a dual BSD/GPL open-source license.


Leucocyte cytokines dominate platelet cytokines overtime in non-leucoreduced platelet components.
Leucoreduction of blood components, including platelet components, is strongly encouraged but not yet universal, especially outside high income countries. As both leucocytes and platelets secrete copious amounts of pro-inflammatory cytokines/chemokines under various conditions and during storage, we investigated the potential of the respective secretory programmes of these cells in order to evaluate their subsequent pathophysiological effects. A total of 158 individual non-leucoreduced platelet components were obtained from Tunisian donors and tested for characteristic biological response modifiers (BRM) of leukocytes (IL-1β, IL-8), platelets (sCD62P, sCD40L) and both cell types (TNF-α, RANTES) in the presence or absence of thrombin stimulation and after different periods of storage (up to 5 days). BRM levels were determined using enzyme-linked immunosorbent assays and Luminex technology. Platelet-leucocyte aggregate formation during storage was analysed using flow cytometry. Leucocyte- and platelet-associated BRM had clearly distinct profiles both at the onset (day 0) and termination (day 5) of the observation period but altered during the intermediate period so that their respective importance was inverted; in fact, the profiles were merged and indistinguishable on days 2-3. The leucocyte-derived BRM largely dominated over platelet-derived ones and further altered the BRM platelet secretion programme. This study contributes substantial, new information on leucocyte/platelet interactions and their likely role in transfusion when leucodepletion cannot be performed or is only partially achieved.


Nanohaloarchaea as beneficiaries of xylan degradation by haloarchaea.
Climate change, desertification, salinisation of soils and the changing hydrology of the Earth are creating or modifying microbial habitats at all scales including the oceans, saline groundwaters and brine lakes. In environments that are saline or hypersaline, the biodegradation of recalcitrant plant and animal polysaccharides can be inhibited by salt-induced microbial stress and/or by limitation of the metabolic capabilities of halophilic microbes. We recently demonstrated that the chitinolytic haloarchaeon Halomicrobium can serve as the host for an ectosymbiont, nanohaloarchaeon 'Candidatus Nanohalobium constans'. Here, we consider whether nanohaloarchaea can benefit from the haloarchaea-mediated degradation of xylan, a major hemicellulose component of wood. Using samples of natural evaporitic brines and anthropogenic solar salterns, we describe genome-inferred trophic relations in two extremely halophilic xylan-degrading three-member consortia. We succeeded in genome assembly and closure for all members of both xylan-degrading cultures and elucidated the respective food chains within these consortia. We provide evidence that ectosymbiontic nanohaloarchaea is an active ecophysiological component of extremely halophilic xylan-degrading communities (although by proxy) in hypersaline environments. In each consortium, nanohaloarchaea occur as ectosymbionts of Haloferax, which in turn act as scavenger of oligosaccharides produced by xylan-hydrolysing Halorhabdus. We further obtained and characterised the nanohaloarchaea-host associations using microscopy, multi-omics and cultivation approaches. The current study also doubled culturable nanohaloarchaeal symbionts and demonstrated that these enigmatic nano-sized archaea can be readily isolated in binary co-cultures using an appropriate enrichment strategy. We discuss the implications of xylan degradation by halophiles in biotechnology and for the United Nation's Sustainable Development Goals.


3-aryl-indolinones derivatives as antiplasmodial agents: synthesis, biological activity and computational analysis.
Malaria is an infectious illness, affecting vulnerable populations in Third World countries. Inspired by natural products, indole alkaloids have been used as a nucleus to design new antimalarial drugs. So, eighteen oxindole derivatives, aza analogues were obtained with moderate to excellent yields. Also, the saturated derivatives of oxindole and aza derivatives via H2/Pd/C reduction were obtained in good yields, leading to racemic mixtures of each compound. Next, the inhibitory activity against P. falciparum of 18 compounds were tested, founding six compounds with IC50 < 20 µM. The most active of these compounds was 8c; however, their unsaturated derivative 7c was inactive. Then, a structure-activity relationship analysis was done, founding that focused LUMO lobe on the specific molecular zone is related to inhibitory activity against P. falciparum. Finally, we found a potential inhibition of lactate dehydrogenase by oxindole derivatives, using molecular docking virtual screening.


The Effect of Bulky Substituents on Two π-Conjugated Mesogenic Fluorophores. Their Organic Polymers and Zinc-Bridged Luminescent Networks.
From a dicyano-phenylenevinylene (PV) and an azobenzene (AB) skeleton, two new symmetrical salen dyes were obtained. Terminal bulky substituents able to reduce intermolecular interactions and flexible tails to guarantee solubility were added to the fluorogenic cores. Photochemical performances were investigated on the small molecules in solution, as neat crystals and as dopants in polymeric matrixes. High fluorescence quantum yield in the orange-red region was observed for the brightest emissive films (88% yield). The spectra of absorption and fluorescence were predicted by Density Functional Theory (DFT) calculations. The predicted energy levels of the frontier orbitals are in good agreement with voltammetry and molecular spectroscopy measures. Employing the two dyes as dopants of a nematic polymer led to remarkable orange or yellow luminescence, which dramatically decreases in on-off switch mode after liquid crystal (LC) order was lost. The fluorogenic cores were also embedded in organic polymers and self-assembly zinc coordination networks to transfer the emission properties to a macro-system. The final polymers emit from red to yellow both in solution and in the solid state and their photoluminescence (PL) performance are, in some cases, enhanced when compared to the fluorogenic cores.


Comparison of Clinical Examination and Various Imaging Modalities in the Diagnosis of Head and Neck Cancer.
Introduction Squamous cell Carcinoma of the Head and Neck (HNSCC) is the most common tumor entity of malignant processes in the head and neck area. Due to the metastasizing behavior of these tumors, the staging is indispensable for the treatment planning and requires imaging techniques, which are sensitive, specific, and as far as possible cost-effective, to benefit ultimately the patient and to ensure optimal care. Objectives The aim of the present study is to compare the clinical examination including palpation, ultrasound and computed tomography (CT)/magnetic resonance imaging (MRI) for the diagnosis of neck metastases to make the correct indication for a neck dissection. Methods Data from 286 patients with HNSCC were analyzed for neck metastases to determine which diagnostic tool is the best to answer the question if a neck dissection is necessary or not. Each study method was examined retrospectively by comparing sensitivity, specificity, the positive/negative predictive value, the positive likelihood ratio and the diagnostic accuracy. Results The ultrasound showed a sensitivity of 91.52%, a specificity of 61.67%, a positive/negative predictive value of 76.65%/84.09%, a positive likelihood ratio of 2.39 and a diagnostic accuracy of 78.95%. The clinical examination showed a sensitivity of 75.76%, a specificity of 66.12%, a positive/negative predictive value of 75.30%/66.67%, a positive likelihood ratio of 2.24 and a diagnostic accuracy of 71.68%. The CT/MRI showed a sensitivity of 78.66%, a specificity of 62.50%, a positive/negative predictive value of 74.14%/68.18%, a positive likelihood ratio of 2.10 and a diagnostic accuracy of 71.83%. Radiographically, ultrasound, as well as the clinical examination, could be judged to be free from radiation load and side effects from the contrast medium. The high dependence on the investigator when using ultrasound made reproducibility of the results difficult. Conclusions It could be shown that ultrasound was the diagnostic tool with the highest sensitivity, positive/negative predictive value, positive likelihood ratio and diagnostic accuracy by detecting and interpreting metastases in the head and neck region correctly. Whether a neck dissection should be performed depends to a large extent on the ultrasound findings.


Automatic tracing of vocal-fold motion from high-speed digital images.
Defining characteristics of the phonatory vocal fold vibration is essential for studies that aim to understand the mechanism of voice production and for clinical diagnosis of voice disorders. The application of high-speed digital imaging techniques to these studies makes it possible to capture sequences of images of the vibrating vocal folds at a frequency that can resolve the actual vocal fold vibrations of a patient. The objective of this study is to introduce a new approach for automatic tracing of vocal fold motion from image sequences acquired from high-speed digital imaging of the larynx. The approach involves three process steps. 1) Global thresholding--the threshold value is selected on the basis of the histogram of the image, which is assumed to follow Rayleigh distribution; 2) applying a morphology operator to remove the isolated object regions; 3) using region-growing to delineate the object, or the vocal fold opening region, and to obtain the area of the glottis; the segmented object obtained after global threshold and the morphological operation is used as a seed region for the final region-growing operation. The performance, effectiveness and validation of our approach is demonstrated using representative, high-speed imaging recordings of subjects having normal and pathological voices.


Probiotics for treatment of Clostridium difficile-associated colitis in adults.
Probiotics are live microorganisms consisting of non-pathogenic yeast and bacteria that are believed to restore the microbial balance of the gastrointestinal tract altered by infection with Clostridium difficile (C. difficile). To assess the efficacy of probiotics in the treatment of antibiotic associated C. difficile colitis. The databases MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and Cochrane IBD/FBD Specialized Trials register were searched to locate all published reports from 1966 to 2007. Randomized, prospective studies using probiotics alone or in conjunction with conventional antibiotics for the treatment of documented C. difficile colitis were eligible for inclusion. Data extraction and analysis was done independently by two authors. Four studies met the inclusion criteria and were included in the review. The four studies examined the use of probiotics in conjunction with conventional antibiotics (vancomycin or metronidazole) for the treatment of recurrence or an initial episode of C. difficile colitis in adults. The studies were small in size and had methodological problems. A statistically significant benefit for probiotics combined with antibiotics was found in one study. McFarland 1994 found that patients receiving S. boulardii were significantly less likely than patients receiving placebo to experience recurrence of C. difficile diarrhea (RR 0.59; 95% CI 0.35 to 0.98). No benefit of probiotics treatment was found in the other studies. There is insufficient evidence to recommend probiotic therapy as an adjunct to antibiotic therapy for C. difficile colitis. There is no evidence to support the use of probiotics alone in the treatment of C. difficile colitis.


Systolically gated 3D phase contrast MRA of mesenteric arteries in suspected mesenteric ischemia.
Our goal was to assess the value of MRA for detecting stenoses in the celiac (CA) and superior mesenteric (SMA) arteries in patients suspected of having chronic mesenteric ischemia, using an optimized systolically gated 3D phase contrast technique. In an initial study in 24 patients who underwent conventional angiography of the abdominal vessels for different clinical indications, a 3D phase contrast MRA technique (3D-PCA) was evaluated and optimized to image the CAs and SMAs. Subsequently, a prospective study was performed to assess the value of systolically gated 3D-PCA in evaluation of the mesenteric arteries in 10 patients with signs and symptoms of chronic mesenteric ischemia. Intraarterial digital subtraction angiography and surgical findings were used as the reference standard. In the initial study, systolic gating appeared to be essential in imaging the SMA on 3D-PCA. In 10 patients suspected of mesenteric ischemia, systolically gated 3D-PCA identified significant proximal disease in the two mesenteric vessels in 4 patients. These patients underwent sucessful reconstruction of their stenotic vessels. Cardiac-gated MRA may become a useful tool in selection of patients suspected of having mesenteric ischemia who may benefit from surgery.


Forming and shaping of professional identity within pre-registration physiotherapy curricular: A scoping review.
The purpose of this review was to explore how professional identity is formed and shaped within pre-registration physiotherapy curricular. A scoping review using the PRISMA guidelines from the Joanna Briggs Institute to capture a range of evidence describing how professional identity has been formed and shaped in pre-registration physiotherapy curricular. Databases searched included: PubMed 1996-Present, Embase 1974-Present, CINAHL 1961-Present, ProQuest Health and Medical Collection 1938-Present and Google Scholar (2004-Present). Additional studies were identified by scanning reference lists and hand searching for relevant articles. The research team collaboratively designed the data charting table and two project leads independently extracted and screened the data as per guidance from the Joanna Briggs Institute Reviewers Manual. A meta-synthesis was conducted in this scoping review to identify common themes from qualitative research to provide a deeper understanding of literature. To ensure feasibility of collating results, components of pre-registration curricular in physiotherapy students describing associations of forming and shaping professional identity were charted. A total of 21 articles were reviewed. Articles were categorised into three categories of shaping (5, 24%), forming (9, 43%) or forming and shaping (7, 33%). Five themes emerged from the meta-synthesis pertaining to forming and shaping professional identity: self, skills, curriculum, program, location. This scoping review illustrates the evidence for multidimensional components of physiotherapy curricular involved to assist in shaping and forming professional identity in pre-registration physiotherapy students. The results of this review can provide a foundation level into the understanding of what professional identity is, although further research is required to understand how it could be best implemented in pre-registration physiotherapy curricular.


Cholesterol and Dementia: A Long and Complicated Relationship.
There is a huge demand for efficient strategies for maintaining cognitive wellbeing with age, especially in the context of population aging. Dementia constitutes the main reason for disability and dependency in the elderly. Identification of potential risk and protective factors, as well as determinants of conversion from MCI to dementia, is therefore crucial. In case of Alzheimer's disease, the most prevalent dementia syndrome amongst the members of modern societies, neurodegenerative processes in the brain can begin many years before first clinical symptoms appear. First functional changes typically mean advanced neuron loss, therefore, the earliest possible diagnosis is critical for implementation of promising early pharmaceutical interventions. The study aimed to discuss the relationships between both circulating and brain cholesterol with cognition, and explore its potential role in early diagnosis of cognitive disorders. Literature review. The causal role of high cholesterol levels in AD or MCI has not been confirmed. It has been postulated that plasma levels of 24(S)-OHC can potentially be used as an early biochemical marker of altered cholesterol homeostasis in the CNS. Some studies brought conflicting results, finding normal or lowered levels of 24(S)-OHC in dementia patients compared to controls. In spite of decades of research on the relationship between cholesterol and dementia, so far, no single trusted indicator of an early cognitive deterioration has been identified. The current state of knowledge makes the use of cholesterol markers of cognitive decline in clinical practice impossible.


Molecular characterization of ligand selectivity of the sex peptide receptors of Drosophila melanogaster and Aedes aegypti.
Drosophila melanogaster sex peptide receptor (DrmSPR) is a G protein-coupled receptor (GPCR) with 'dual ligand selectivity' towards sex peptide (SP) and myoinhibitory peptides (MIPs), which are only remotely related to one another. SPR is conserved in almost all the sequenced lophotrochozoan and ecdysozoan genomes. SPRs from non-drosophilid taxa, such as those from the mosquitoes Aedes aegypti (AeaSPR), Anopheles gambiae (AngSPR), and the sea slug Aplysia californica (ApcSPR), are highly sensitive to MIP, but not to SP. To understand how Drosophila SPRs evolved their SP sensitivity while maintaining MIP sensitivity, we examined ligand selectivity in a series of chimeric GPCRs that combine domains from the SP-sensitive DrmSPR and the SP-insensitive AeaSPR. We found replacement of Pro 238 (P238) in DrmSPR with the corresponding residue from AeaSPR (L310) reduced its SP sensitivity 2.7 fold without altering its MIP sensitivity. The P238 residue located in the third extracellular loop (ECL3) is conserved in Drosophila SPRs and in SPR from the moth Bombyx mori (BomSPR), which is considerably more sensitive to SP than AeaSPR, AngSPR, or ApcSPR. We found, however, that rather than improving AeaSPR's sensitivity to SP, replacement of L310 in AeaSPR with Pro significantly reduces its MIP sensitivity. Thus, our identification of a single amino acid residue critical for SP sensitivity, but not for MIP sensitivity is an important step in clarifying how DrmSPR evolved the ability to detect SP.


Reciprocal and nonreciprocal recombination in diploid clones from Bacillus subtilis protoplast fusion: Association with the replication origin and terminus.
The primary heterodiploid bacteria regenerated after Bacillus subtilis fusion, although generally noncomplementing diploids, behave in pedigree analysis as multipotential systems. Individual diploid colonies yielding complete reciprocal recombinant (RR) progeny-often accompanied by one or both parents-constitute 10-30% of the total recombinant-forming units. The RR (reciprocal for 8-11 genes) usually occur in equivalent numbers both among and within individual colonies. Novel for bacteria, they demonstrate that entire parental genomes brought together within a diploid protoplast are retained as two independent replicons able to undergo classical recombination characteristic of eukaryotic gametogenesis. Parental or recombinant genomes are also subject to multiple rounds of recombination without obligate segregation and often not reciprocal. Diploid recombinant clones, sharing streptomycin resistance but reciprocal for auxotrophic markers, have displayed a partial ability to make a facultative shift in chromosome expression. They have also produced two types of prototrophs: a stable one (presumably haploid and recombinant) and an unstable one, (diploid and temporarily complementing at low frequency). It follows that chromosome extinction may affect both parental and recombinant chromosomes and does not interfere with recombination. Analysis of the number and chromosomal distribution of crossovers in all recombinants and those from single diploid clones shows increased frequency of exchange in the regions of the replication origin and terminus, possibly a result of the association of these sites with the cell wall or membrane.


Mitochondrial proteomics of the acetic acid - induced programmed cell death response in a highly tolerant Zygosaccharomyces bailii - derived hybrid strain.
Very high concentrations of acetic acid at low pH induce programmed cell death (PCD) in both the experimental model Saccharomyces cerevisiae and in Zygosaccharomyces bailii, the latter being considered the most problematic acidic food spoilage yeast due to its remarkable intrinsic resistance to this food preservative. However, while the mechanisms underlying S. cerevisiae PCD induced by acetic acid have been previously examined, the corresponding molecular players remain largely unknown in Z. bailii. Also, the reason why acetic acid concentrations known to be necrotic for S. cerevisiae induce PCD with an apoptotic phenotype in Z. bailii remains to be elucidated. In this study, a 2-DE-based expression mitochondrial proteomic analysis was explored to obtain new insights into the mechanisms involved in PCD in the Z. bailii derived hybrid strain ISA1307. This allowed the quantitative assessment of expression of protein species derived from each of the parental strains, with special emphasis on the processes taking place in the mitochondria known to play a key role in acetic acid - induced PCD. A marked decrease in the content of proteins involved in mitochondrial metabolism, in particular, in respiratory metabolism (Cor1, Rip1, Lpd1, Lat1 and Pdb1), with a concomitant increase in the abundance of proteins involved in fermentation (Pdc1, Ald4, Dld3) was registered. Other differentially expressed identified proteins also suggest the involvement of the oxidative stress response, protein translation, amino acid and nucleotide metabolism, among other processes, in the PCD response. Overall, the results strengthen the emerging concept of the importance of metabolic regulation of yeast PCD.


Recent advances in organic mechanofluorochromic materials.
Mechanofluorochromic materials, which are dependent on changes in physical molecular packing modes, have attracted considerable interest over the past ten years. In this review, recent progress in the area of pure organic mechanofluorochromism is summarized, and majority of the reported organic mechanofluorochromic systems are discussed, along with their derived structure-property relationships. The existence of a structural relationship between aggregation-induced emission compounds and mechanofluorochromism is recognized based on our recent results, which considered aggregation-induced emission compounds as a well of mechanofluorochromic materials. The established structure-property relationship will guide researchers in identifying and synthesizing more mechanofluorochromic materials.


Anionic constitution of 1-atmosphere silicate melts: implications for the structure of igneous melts.
A structural model is proposed for the polymeric units in silicate melts quenched at 1 atmosphere. The anionic units that have been identified by the use of Raman spectroscopy are SiO(4)(4-) monomers, Si(2)O(7)(6-) dimers, SiO(3)(2-) chains or rings, Si(2)O(5)(2-) sheets, and SiO(2) three-dimensional units. The coexisting anionic species are related to specific ranges of the ratio of nonbridging oxygens to tetrahedrally coordinated cations (NBO/Si). In melts with 2.0 < NBO/Si < approximately 4.0, the equilibrium is of the type [See equation in the PDF file]. In melts with NBO/Si approximately 1.0 to 2.0, the equilibrium anionic species are given by [See equation in the PDF file]. In alkali-silicate melts with NBO/Si <~ 1.3 and in aluminosilicate melts with NBO/T < 1.0, where T is (Si + Al), the anionic species in equilibrium are given by [See equation in the PDF file]. In multicomponent melts with compositions corresponding to those of the major igneous rocks, the anionic species are TO(2), T(2)O(5), T(2)O(6), and TO(4), and the coexisting polymeric units are determined by the second and third of these disproportionation reactions.


Double-blind, placebo-controlled, fixed dose trial of minaprine in patients with major depression.
Minaprine dihydrochloride is a novel psychotropic drug possessing both antidepressant and psycho-stimulant properties. Prior clinical studies have shown minaprine to be as effective as standard antidepressant agents in the treatment of endogenous depression. The present study examined the safety and efficacy of minaprine at four different doses compared to placebo in 190 outpatients with major depression. Overall, minaprine demonstrated a significant antidepressant action compared to placebo, which was most evident at the maximum dose of 400 mg daily. These data, together with a favorable side effects profile, suggest that minaprine may be an effective antidepressant agent for the treatment of major depression.


Music interventions in patients during coronary angiographic procedures: a randomized controlled study of the effect on patients' anxiety and well-being.
A cardiac catheterization laboratory can be a frightening environment and music can be a supportive source of environmental sound that stimulates and maintains relaxation. To test the effects of patient focused music versus loudspeaker music versus standard sound on patient's experiences of anxiety and well-being during coronary angiographic procedures. A prospective, randomized, controlled trial of 98 subjects undergoing elective coronary angiogram and/or percutaneous coronary intervention. The subjects were randomly allocated to three different groups of sound environments: a control group (the usual sound environment), a patient focused music group (audio pillow) or to a loudspeaker music group. Anxiety decreased significantly and well-being increased significantly in the two music groups compared to the control group. There was a significantly more positive impression of the sound environment in the patient focused music group compared to the two other groups. This study showed that the use of a specially designed music reduced anxiety and increased well-being in patients during coronary angiographic procedures. However, patient focused music seemed to be more preferable. The sound environment was rated more positively by the subjects listening to music via audio pillow. The music delivered via loudspeakers seemed to distract the staff during the examination at the cardiac catheterization laboratory.


Stress hyperglycemia: an essential survival response!
Stress hyperglycemia is common in critically ill patients and appears to be a marker of disease severity. Furthermore, both the admission as well as the mean glucose level during the hospital stay is strongly associated with patient outcomes. Clinicians, researchers and policy makers have assumed this association to be causal with the widespread adoption of protocols and programs for tight in-hospital glycemic control. However, a critical appraisal of the literature has demonstrated that attempts at tight glycemic control in both ICU and non-ICU patients do not improve health care outcomes. We suggest that hyperglycemia and insulin resistance in the setting of acute illness is an evolutionarily preserved adaptive responsive that increases the host's chances of survival. Furthermore, attempts to interfere with this exceedingly complex multi-system adaptive response may be harmful. This paper reviews the pathophysiology of stress hyperglycemia and insulin resistance and the protective role of stress hyperglycemia during acute illness.


[Bone marrow scanning (author's transl)].
Personal experience of Technetium-99m-sulfur colloid in the scintiscanning of bone marrow is reported. The method offers technical advantages over other methods and superior protection, while its only limitation is that it does not permit a dynamic study of hematopoiesis. Four pathologic scans typical of four groups of diseases may be distinguished. Further, metastatic bone marrow localisations can be diagnosed much earlier and more precisely than by radiography.


Janice Drew's work on diet and cancer.
Obesity and associated reduced consumption of plant derived foods are linked to increased risk of colon cancer as well as a number of other organ specific cancers. Inflammatory processes are a contributing factor but the precise mechanisms remain elusive. Obesity and cancer incidence are increasing worldwide, presenting bleak prospects for reducing, or preventing, obesity related cancers. The incidence of these preventable cancers can be achieved with greater understanding of the molecular mechanisms linking diet and carcinogenesis. Janice Drew has developed a research program over recent years to investigate molecular mechanisms related to consumption of anti-inflammatory metabolites generated from consumption of plant based diets, the impact of high fat diets and associated altered metabolism and obesity on regulation of colon inflammatory responses and processes regulating the colon epithelium. Comprehensive strategies have been developed incorporating transcriptomics, including the novel gene expression technology, the GenomeLab System and proteomics, together with biochemical analyses of plasma and tissue samples to assess correlated changes in oxidative stress, inflammation and pathology. The approaches developed have achieved success in establishing antioxidant and anti-inflammatory activity of dietary antioxidants and associated genes and pathways that interact to modulate redox status in the colon. Cellular processes and genes altered in response to obesity and high fat diets have provided evidence of molecular mechanisms that are implicated in obesity related cancer.


Polyphenol composition and antioxidant capacity from different extracts of Aster scaber.
Phenolic contents and antioxidant capacities from different solvent extracts (petroleum ether, ethyl acetate, methanol, butanol and water) of Aster scaber leaf were investigated. Antioxidant activity was evaluated by three different methods, namely DPPH radical scavenging activity, reducing power assay and phosphomolybdenum activity. A total of twenty-three polyphenolic compounds were identified and quantified from A. scaber leaf extracts, including hydroxybenzoic acids, hydroxycinnamic acids, flavonols and other groups of phenolic compounds. Ultra high performance liquid chromatography (UHPLC) analysis of the leaf extract revealed that myricetin (4850.45 μg/g) was the most dominant flavonols, compared to quercetin and kaempferol. Caffeic acid was the dominant phenolic compound in A. scaber leaf extracts, it constituted about 104.20 μg/g, followed by gentisic acid (84.50 μg/g), gallic acid (61.05 μg/g) and homogentisic acid (55.65 μg/g). The total phenolic and flavonoid content was the highest in ethyl acetate extract (322.43 and 6.51 mg/g). The decreasing order of antioxidant activity among the A. scaber leaf extracts assayed through all the three methods was found to be ethyl acetate > butanol > methanol > petroleum ether > water extract.


Video event recognition using kernel methods with multilevel temporal alignment.
In this work, we systematically study the problem of event recognition in unconstrained news video sequences. We adopt the discriminative kernel-based method for which video clip similarity plays an important role. First, we represent a video clip as a bag of orderless descriptors extracted from all of the constituent frames and apply the earth mover's distance (EMD) to integrate similarities among frames from two clips. Observing that a video clip is usually comprised of multiple subclips corresponding to event evolution over time, we further build a multilevel temporal pyramid. At each pyramid level, we integrate the information from different subclips with Integer-value-constrained EMD to explicitly align the subclips. By fusing the information from the different pyramid levels, we develop Temporally Aligned Pyramid Matching (TAPM) for measuring video similarity. We conduct comprehensive experiments on the TRECVID 2005 corpus, which contains more than 6,800 clips. Our experiments demonstrate that 1) the TAPM multilevel method clearly outperforms single-level EMD (SLEMD) and 2) SLEMD outperforms keyframe and multiframe-based detection methods by a large margin. In addition, we conduct in-depth investigation of various aspects of the proposed techniques such as weight selection in SLEMD, sensitivity to temporal clustering, the effect of temporal alignment, and possible approaches for speed up. Extensive analysis of the results also reveals intuitive interpretation of video event recognition through video subclip alignment at different levels.


Glucuronidation Pathways of 5- and 7-Hydroxypropranolol: Determination of Glucuronide Structures and Enzyme Selectivity.
Propranolol, a non-selective beta-blocker medication, has been utilized in the treatment of cardiovascular diseases for several decades. Its hydroxynaphthyl metabolites have been recognized to possess varying degrees of beta-blocker activity due to the unaltered side-chain. This study achieved the successful separation and identification of diastereomeric glucuronic metabolites derived from 4-, 5-, and 7-hydroxypropranolol (4-OHP, 5-OHP, and 7-OHP) in human urine. Subsequently, reaction phenotyping of 5- and 7-hydroxypropranolol by different uridine 5'-diphospho-glucuronosyltransferases (UGTs) was carried out, with a comparison to the glucuronidation of 4-hydroxypropranolol (4-OHP). Among the 19 UGT enzymes examined, UGT1A1, UGT1A3, UGT1A7, UGT1A8, UGT1A9, UGT1A10, UGT2A1, and UGT2A2 were found to be involved in the glucuronidation of 5-OHP. Furthermore, UGT1A6 exhibited glucuronidation activity towards 7-OHP, along with the aforementioned eight UGTs. Results obtained by glucuronidation of corresponding methoxypropranolols and MS/MS analysis of 1,2-dimethylimidazole-4-sulfonyl (DMIS) derivatives of hydroxypropranolol glucuronides suggest that both the aromatic and aliphatic hydroxy groups of the hydroxypropranolols may be glucuronidated in vitro. However, the analysis of human urine samples collected after the administration of propranolol leads us to conclude that aromatic-linked glucuronidation is the preferred pathway under physiological conditions.


Deep ROC Analysis and AUC as Balanced Average Accuracy, for Improved Classifier Selection, Audit and Explanation.
Optimal performance is desired for decision-making in any field with binary classifiers and diagnostic tests, however common performance measures lack depth in information. The area under the receiver operating characteristic curve (AUC) and the area under the precision recall curve are too general because they evaluate all decision thresholds including unrealistic ones. Conversely, accuracy, sensitivity, specificity, positive predictive value and the F1 score are too specific-they are measured at a single threshold that is optimal for some instances, but not others, which is not equitable. In between both approaches, we propose deep ROC analysis to measure performance in multiple groups of predicted risk (like calibration), or groups of true positive rate or false positive rate. In each group, we measure the group AUC (properly), normalized group AUC, and averages of: sensitivity, specificity, positive and negative predictive value, and likelihood ratio positive and negative. The measurements can be compared between groups, to whole measures, to point measures and between models. We also provide a new interpretation of AUC in whole or part, as balanced average accuracy, relevant to individuals instead of pairs. We evaluate models in three case studies using our method and Python toolkit and confirm its utility.


The oesophageal obturator airway: A study of cadaver lund ventilation through obturator airways and tracheal tubes.
Ventilation of cadaver lungs using a Pneupac ventilator through oesophageal obturator airways (EOA), oesophageal gastric tube airways (EGTA), and tracheal tubes was studied in 23 subjects. The mean tidal volume obtained through tracheal tubes was 381 ml compared with a mean tidal volume of 156 ml obtained through the EOA and a mean tidal volume of 237 ml through the EGTA. Considerable leakage occurred at the pressure relief valve of the ventilator and at the face mask. With the pressure relief valve occluded and better mask fit achieved by observation of maximum possible tidal volume, the mean tidal volume obtained through obturator gastric airways was 606 ml compared with 906 ml obtained through tracheal tubes. This represents adequate ventilation in these very stiff lungs. Subject to modification of the device and prevention of leakage the oesophageal gastric tube airway is a useful alternative to tracheal intubation in certain adverse conditions.


Going Along With It: Neonatal Intensive Care Nurses' Views of a Donor Milk Practice Change.
Donor human milk (DHM) is used when a mother's own milk is not available. Donor human milk is available as a frozen pasteurized or commercially sterilized product. An abrupt change in practice in use of donor milk products raised concerns among nurses caring for infants in the neonatal intensive care unit (NICU). The change in practice occurred without the input of nurses and without the sharing of supportive evidence with them. The purpose of this study was to explore NICU nurses' perceptions of the practice change from using frozen pasteurized DHM to using sterilized DHM in this context. A grounded theory study was conducted in a 38-bed Level III NICU. Nurse participants were interviewed using open-ended questions aimed at eliciting their perceptions of using pasteurized and sterilized DHM. There were nine nurse participants. They described their perceptions of feeling confident about pasteurized DHM to feeling uncertain about sterilized DHM. The core category of going along with it was linked to judging DHM based upon attributes, questioning benefits of sterilized DHM, and preferring past practice of using pasteurized DHM. Nurses noted that they could move from feeling uncertain about the practice change to feeling certain if they had evidence to support the practice change. Barriers to seeking evidence were time, knowledge, and waiting for someone else to do it. Practice change without interprofessional collaboration is threatened by uncertainty and lack of support for the new practice. Nurses want to give evidence-based care, but they often face barriers to seeking evidence. Removing barriers to evidence-based practice and including nurses as stakeholders in practice change decisions are suggested.


Regular Exposure to Cowbells Affects the Behavioral Reactivity to a Noise Stimulus in Dairy Cows.
In alpine regions, cows are often equipped with bells during pasture season to ensure that farmers can locate them. Constant exposure to the chime of a bell may affect cows' acoustic perception in general. The aim of this study is to test whether routine bell exposure affects the reactivity to a noise stimulus and might be associated with hearing impairment in cows. For the assessment, behavioral and cardiac indicators were used as indirect measures of hearing capacity. Cows that were either used to wearing a bell or not were exposed to a playback of low and high amplitude (=varying loudness). In addition, we tested whether wearing earplugs, mimicking hearing impairment, reduced the cows' reactivity toward the playback. On 24 farms, half of them routinely using cowbells, 96 Brown Swiss cows were tested in a 2 × 2 factorial cross-over design (65 or 85 dB, without or with earplugs) in a balanced order. The effects of bell experience, amplitude, and earplugs on the latency to the first behavioral and cardiac response to a 5-s playback were analyzed using linear mixed-effects models, considering dependencies within the data set. Cows reacted faster without earplugs and when they were exposed to 85 dB compared with 65 dB. The proportion of cows leaving the feeding rack after onset of the playback was reduced by bell experience and earplugs and was increased when exposed to 85 dB compared with 65 dB. Exposure without earplugs to 85 dB but not to 65 dB increased heart rate. Heart rate and heart rate variability indicated increased sympathetic activation during the exposure to 85 dB compared with 65 dB. In general, behavioral and cardiac indicators did not indicate severe hearing impairment due to routine bell exposure. The 85-dB stimulus increased arousal and avoidance compared with the 65-dB stimulus, with bell experience and earplugs leading to a general decrease in avoidance of the stimulus. This may reflect an altered acoustic perception of the playback stimulus in dairy cows that are routinely exposed to bells.


Improved applications of the tetracycline-regulated gene depletion system.
Tightly controlled expression of transgenes in mammalian cells is an important tool for biological research, drug discovery, and future genetic therapies. The tetracycline-regulated gene depletion (Tet-Off) system has been widely used to control gene activities in mammalian cells, because it allows strict regulation of transgenes but no pleiotropic effects of prokaryotic regulatory proteins. However, the Tet-Off system is not compatible with every cell type and this is the main remaining obstacle left for this system. Recently, we overcame this problem by inserting an internal ribosome entry site (IRES) to drive a selectable marker from the same tetracycline-responsive promoter for the transgene. We also employed a CMV immediate early enhancer/beta-actin (CAG) promoter to express a Tet-controlled transactivator. Indeed, the Tet-Off system with these technical modifications was applied successfully to the human pre-B Nalm-6 cell line in which conventional Tet-Off systems had not worked efficiently. These methodological improvements should be applicable for many other mammalian proliferating cells. In this review we give an overview and introduce a new method for the improved application of the Tet-Off system.


[Birth weight of children born without congenital defects. I. Birthweight percentiles by gestational age].
We studied the birthweight by gestational age and sex from a population of 14,097 liveborns without congenital defects who were monitored by the Spanish Collaborative Study of Congenital Malformations (ECEMC). We have calculated the curves of percentiles for gestational age in males and females. As our sample size is very large, and it includes births from almost the whole country, we think these curves are enoughly representative of the Spanish population, fitter than the Denver's (1) which are widely utilized. On the other hand, we stress our attention in making curves of birthweight for malformed and not malformed babies separately.


Metabolic Reprogramming of Macrophages Exposed to Silk, Poly(lactic-co-glycolic acid), and Silica Nanoparticles.
Monitoring macrophage metabolism in response to nanoparticle exposure provides new insights into biological outcomes, such as inflammation or toxicity, and supports the design of tailored nanomedicines. This paper describes the metabolic signature of macrophages exposed to nanoparticles ranging in diameter from 100 to 125 nm and made from silk, poly(lactic-co-glycolic acid) or silica. Nanoparticles of this size and type are currently at various stages of preclinical and clinical development for drug delivery applications. 1 H NMR analysis of cell extracts and culture media is used to quantify the changes in the intracellular and extracellular metabolomes of macrophages in response to nanoparticle exposure. Increased glycolytic activity, an altered tricarboxylic acid cycle, and reduced ATP generation are consistent with a proinflammatory phenotype. Furthermore, amino acids possibly arising from autophagy, the creatine kinase/phosphocreatine system, and a few osmolytes and antioxidants emerge as important players in the metabolic reprogramming of macrophages exposed to nanoparticles. This metabolic signature is a common response to all nanoparticles tested; however, the direction and magnitude of some variations are clearly nanoparticle specific, indicating material-induced biological specificity. Overall, metabolic reprogramming of macrophages can be achieved with nanoparticle treatments, modulated through the choice of the material, and monitored using 1 H NMR metabolomics.


Current Treatment Strategies for Intracranial Aneurysms: An Overview.
Intracranial aneurysm is a leading cause of stroke. Its treatment has evolved over the past 2 decades. This review summarizes the treatment strategies for intracranial aneurysms from 3 different perspectives: open surgery approach, transluminal treatment approach, and new technologies being used or trialed. We introduce most of the available treatment techniques in detail, including contralateral clipping, wrapping and clipping, double catheters assisting coiling and waffle-cone technique, and so on. Data from major trials such as Analysis of Treatment by Endovascular approach of Non-ruptured Aneurysms (ATENA), Internal Subarachnoid Trial (ISAT), Clinical and Anatomical Results in the Treatment of Ruptured Intracranial Aneurysms (CLARITY), and Barrow Ruptured Aneurysm Trial (BRAT) as well as information from other clinical reports and local experience are reviewed to suggest a clinical pathway for treating different types of intracranial aneurysms. It will be a valuable supplement to the current existing guidelines. We hope it could help assisting real-time decision-making in clinical practices and also encourage advancements in managing the disease.


Somatotype Hormone Levels and Physical Fitness in Elite Young Soccer Players over a Two-Year Monitoring Period.
The effect of two soccer-training seasons on the growth, development and somatotype hormone concentrations of elite youth soccer players were evaluated. Eighteen elite soccer players and 18 age-matched non-athletic control subjects participated in the study. Anthropometric-measurements, aerobic and anaerobic performance tests and serum concentrations of insulin-like growth factor-1 (IGF-1), insulin-like growth factor binding protein-3 (IGFBP-3), and growth hormone (GH) were assessed at 5 time points across two competitive seasons. Soccer players revealed higher GH, IGF-1 and IGFBP-3 than the control group across all-time points. Significant moderate correlations were observed only in soccer players between hormonal concentrations (IGF-1 and IGFBP-3) and the jumping tests (r = 0.45-0.48; p < 0.01). Somatotropic axis hormones, anthropometric and physical parameters increased to a greater degree with growth and soccer training combined compared to growth alone. Results from this investigation revealed that intense training did not impair growth or development in these young soccer players across 2-year period.