Cumulative coffee consumption and reduced risk of oral and oropharyngeal cancer.
We examined the association between coffee consumption and oral cancer in a hospital-based case-control study comprising 143 patients with oral and oropharyngeal squamous cell carcinoma attended at 3 major hospitals in Sao Paulo, Brazil, and 240 controls without cancer, recruited from outpatient units of the same hospitals and matched with cases by sex and age. Associations were assessed by multivariate logistic regression conditioned on sociodemographic and behavioral characteristics. Tobacco smoking, alcohol drinking, and higher intake of bacon and deep-fried foods were directly related to disease; the inverse was observed to family income and salad intake. Coffee consumption and tobacco smoking were partially correlated (Spearman correlation coefficient 0.14 among cases, 0.31 among controls). When adjusted for all covariates, a cumulative coffee consumption higher than 18.0 daily liters × year during lifetime was indicated to be protective against disease (adjusted odds ratio 0.39, 95% confidence interval 0.16-0.94, P = 0.037). This observation may have pharmacological implications for clinical medication of these cancers and is relevant to programs aimed at reducing the burden of disease.


Individualised home-based rehabilitation after stroke in eastern Finland--the client's perspective.
Reintegration into society is one of the main purposes of post-stroke rehabilitation. The experiences of clients returning home after a stroke have been studied before. There is, however, little knowledge about activities carried out during home-based rehabilitation interventions and about the involvement of clients in the process. This study focused on clients' experiences of a 3-month individualised, home-based rehabilitation programme supervised by a multidisciplinary team. The data were collected in 2009-2010, and it was based on interviews with 14 clients (48-83 years of age) conducted approximately 7 months after stroke. In the thematic analysis, five main topics describing the goals and functions of the home-based rehabilitation were identified as follows: (i) learning strategies for solving problems in daily activities at home and in the community; (ii) receiving exercise coaching; (iii) exploring community services and facilities; (iv) having a dialogue with professionals; and (v) engaging in activities aimed at returning to work. Implementing rehabilitation activities in the home environment seemed to enhance the participants' active involvement and their ability to evaluate themselves and to set goals for their recovery. Work was an important goal for clients of working age, but work-related tasks were not sufficiently integrated with home-based rehabilitation. A challenge for local communities is to provide health promotion and recreation services that are also suitable for persons with limited functioning.


Molecular evolution in food allergy diagnosis.
Traditional allergological diagnostics often provide laboratory data that seem to correspond with similar positive results in different patients. However, with technological developments and the introduction of molecular diagnostics, it is possible to extract and highlight the differences in the serological laboratory data, to obtain detailed specificity on the various allergen components in different clinical settings. Allergological diagnostics prove to be increasingly useful in accurately distinguishing "cross-reactivity" and "cosensitization". This aspect is very important especially in patients who are, with a traditional diagnosis, polysensitized. Molecular diagnosis in allergology has expanded its range of applications thanks to the ability to IgE dose specific (in addition to classic total IgE serum) not only to allergens, food and inhalants, but also to the individual protein components which make up the allergenic source. It is essential to establish a correct diagnosis in order to determine the appropriate therapy. Therefore it is crucial to discern whether a patient is truly allergic because he presents specific IgE for molecules of a species or if the positivity is given from the structural homology between the different proteins. Molecular diagnostics emerges as a valuable tool for the discrimination of allergic patients and to differentiate between "true allergies" and "cross-reactivity". Molecular diagnostics should be used in a targeted manner for an accurate assessment and diagnosis, which would also reduce the use of oral challenges, to predict severe reactions and allergy persistence.


[Three new observational scales for use in Dutch nursing homes: scales from the Resident Assessment Instrument for Activities of Daily Living, cognition and depression].
The reliability and validity of three MDS scales for ADL, cognition and depression are described. The scales consist of items of the Minimum Data Set of the Resident Assessment Instrument and are available just after an MDS assessment. Data collection took place in nine Dutch nursing homes (N = 227) and consisted of three MDS assessments within one month to determine reliability. Several criterion measures were assessed in order to determine convergent validity. Intra- and inter-rater reliability and internal consistency were determined as well as correlation coefficients of the criterion measures and the MDS scales. All three MDS scales appear reliable, especially the ADL-Hierarchy has very good psychometric properties (intra- and inter-rater Intra Class Correlation were 0.81 and 0.83, respectively). Convergent validity of the ADL-Hierarchy and the Cognitive Performance Scale is good, the Depression Rating Scale appears valid in residents with moderate cognitive disorders at the most, but the results are more difficult to interpret in residents with severe cognitive disorders. The MDS scales appear useful in clinical practice and for research purposes in the Dutch nursing homes.


Proteome signatures of inflammatory activated primary human peripheral blood mononuclear cells.
Proteome profiling is the method of choice to identify marker proteins whose expression may be characteristic for certain diseases. The formation of such marker proteins results from disease-related pathophysiologic processes. In healthy individuals, peripheral blood mononuclear cells (PBMCs) circulate in a quiescent cell state monitoring potential immune-relevant events, but have the competence to respond quickly and efficiently in an inflammatory manner to any invasion of potential pathogens. Activation of these cells is most plausibly accompanied by characteristic proteome alterations. Therefore we investigated untreated and inflammatory activated primary human PBMCs by proteome profiling using a 'top down' 2D-PAGE approach in addition to a 'bottom up' LC-MS/MS-based shotgun approach. Furthermore, we purified primary human T-cells and monocytes and activated them separately. Comparative analysis allowed us to characterize a robust proteome signature including NAMPT and PAI2 which indicates the activation of PBMCs. The T-cell specific inflammation signature included IRF-4, GBP1 and the previously uncharacterized translation product of GBP5; the corresponding monocyte signature included PDCD5, IL1RN and IL1B. The involvement of inflammatory activated PBMCs in certain diseases as well as the responsiveness of these cells to anti-inflammatory drugs may be evaluated by quantification of these marker proteins. This article is part of a Special Issue entitled: Integrated omics.


Using concept maps in a modified team-based learning exercise.
Medical school education has traditionally been driven by single discipline teaching and assessment. Newer medical school curricula often implement an organ-based approach that fosters integration of basic science and clinical disciplines. Concept maps are widely used in education. Through diagrammatic depiction of a variety of concepts and their specific connections with other ideas, concept maps provide a unique perspective into learning and performance that can complement other assessment methods commonly used in medical schools. In this innovation, we describe using concepts maps as a vehicle for a modified a classic Team-Based Learning (TBL) exercise. Modifications to traditional TBL in our innovation included replacing an individual assessment using multiple-choice questions with concept maps as well as combining the group assessment and application exercise whereby teams created concept maps. These modifications were made to further assess understanding of content across the Fundamentals module (the introductory module of the preclerkship curriculum). While preliminary, student performance and feedback from faculty and students support the use of concept maps in TBL. Our findings suggest concept maps can provide a unique means of determining assessment of learning and generating feedback to students. Concept maps can also demonstrate knowledge acquisition, organization of prior and new knowledge, and synthesis of that knowledge across disciplines in a unique way providing an additional means of assessment in addition to traditional multiple-choice questions.


A feasibility study of photosensor charge signal transmission to preamplifier using long cable for development of hybrid PET-MRI.
A new positron emission tomography (PET) detector signal processing method, the charge signal transmission approach, is proposed for the development of a hybrid PET-magnetic resonance imaging (MRI). A number of experiments were performed to demonstrate that the Geiger-mode avalanche photodiode (GAPD) charge output could be transmitted to a preamplifier using a long cable without degrading the PET signal performance. A PET module consisted of LYSO and a GAPD with a 4 x 4 array. The GAPD output was transmitted to the preamplifier through flexible flat cables. The effect of the cable length on the PET performance was examined using seven different lengths ranging from 10 to 300 cm outside and inside the 7 T animal MRI. Four parameters (rise time, fall time, amplitude, and area of the preamplifier output) were measured as a function of the cable length using a 10 GS/s oscilloscope and three parameters (photopeak position, energy resolution, and time resolution) were measured using a 100 MS/s DAQ unit. The effect of the cable length on the MR phantom images was investigated. In addition, the effect of the PET module configuration on its temperature stability was assessed by acquiring the energy and time spectra. There were no significant changes in the PET module performance as a function of the cable length, both outside and inside MRI. The performance changes in energy information, such as the amplitude, area, photopeak position, and energy resolution, were <3% with cable lengths ranging from 10 to 300 cm and the change in the time resolution was <6%. There were no obvious artifacts or changes in the line profile in the MR phantom images. Moreover, no manifest changes in the photopeak position and coincidence counting rate were observed in the PET modules employing the charge signal transmission approach, whereas considerable degradation of the PET module performance was observed in the voltage signal transmission approach. This study demonstrated that it is feasible to design a hybrid PET-MRI using the charge signal transmission approach, which is expected to have more advantages than other approaches.


Effects of anandamide on polyamine levels and cell growth in human colon cancer cells.
Anandamide (AEA) is an endogenous agonist for cannabinoid receptor CB1-R and seems to be involved in the control of cancer growth. Polyamines are compounds that play an important role in cell proliferation and differentiation. Our aim was to investigate the effect of AEA on the polyamine levels (putrescine, spermidine and spermine) and cell growth of three human colon cancer cell lines, positive for CB1-R. After AEA treatment of DLD-1, HT-29 and SW620 cells, polyamine analysis was performed by high-performance liquid chromatography (HPLC) and cell growth was measured by 3-(4,5 di-methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test. CB1 gene expression was determined using reverse transcription and polymerase chain reaction (RT-PCR). AEA significantly reduced polyamine levels and cell proliferation dose-dependently when the tested cell lines were exposed for 24 h and 48 h. This inhibitory effect was mediated by CB1-R, since SR 1411716A, a selective CB-1 receptor antagonist, was able to entirely antagonize the effect of AEA. CB1-R mRNA levels were enhanced after AEA treatment in DLD-1 cells, whereas no induction was found in HT-29 and SW620 cells. It appears that mechanisms by which AEA may affect growth of colon cancer cells involve a decrease in cell proliferation rate by reducing the polyamine levels.


Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) in an Elderly Female: A Rare Case.
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is a rare hematologic malignancy derived from type 2 Dendritic cells (immature Plasmacytoid dendritic cells). It is an aggressive lymphoma and most commonly presents as nonpruritic cutaneous lesions. It can also involve the bone marrow, lymph nodes, or circulating peripheral blasts. Here we present a 61-year-old female with skin bruises all over her body for the last three months associated with fatigue, night sweats, and unintentional weight loss. Her initial diagnosis was Acute Myeloid Leukemia (AML), but later she was diagnosed with BPDCN on tumor biopsy consistent with CD56+ neoplasm. The patient was treated with cyclophosphamide with steroid bridge. She was follow-up every week for the disseminated intravascular coagulation panel and monitored for tumor lysis syndrome. The management of the BPDCN is still unclear due to the condition's rarity. tagraxofusp has been used for remission induction as it has a higher response rate with an acceptable toxicity profile than conventional chemotherapy. Allogeneic hematopoietic stem cell transplantation (HCT) is recommended in patients with the first remission. For patients with relapsed/refractory disease, tagraxofusp demonstrates a good overall response, followed by HCT.


Kveim test and mitochondrial antibodies in the differential diagnosis between primary biliary cirrhosis and sarcoidosis.
Intracutaneous Kveim test and measurement of serum mitochondrial antibodies were performed in a group of patients with primary biliary cirrhosis (PBC) and in a group of patients with sarcoidosis. There were 14 patients, 1 man and 13 women, age range 39-64 years, with clinical picture, laboratory tests and liver biopsy consistent with PBC. In the sarcoidosis group there were 38 patients, 18 men and 20 women, age range 22-76 years, with clinical, radiological and histopathological findings typical for sarcoidosis. In this group chest x-ray showed stage 0 in 3 patients, stage I in 7, stage II in 18 and 10 patients were in stage III. Kveim test was positive in 24 (63.2%) of the sarcoid patients and negative in all 14 patients with PBC. Mitochondrial antibodies were present in 13 of the PBC-patients but in none of the 38 examined sarcoid patients. Kveim test and analysis of mitochondrial antibodies seems to be of great value in the differential diagnosis between primary biliary cirrhosis and sarcoidosis.


A comparison of two long-acting vasoselective calcium antagonists in pulmonary hypertension secondary to COPD.
STUDY OBJECTIVES AND PATIENTS: Pulmonary hypertension (PH) is common in COPD and may predict mortality in this disorder. We have compared the pulmonary vasodilator effects, dose-response characteristics, and tolerability of two calcium channel blockers, amlodipine and extended-release (ER) felodipine, in 10 patients (seven men, age 68+/-4.8 [SD] years) with clinically stable COPD and PH. Drugs were given in equal single daily oral doses (2.5, 5, and 10 mg), increasing weekly for 3 weeks, in a randomized investigator-blinded crossover manner with a 1-week wash-out period between the two treatments. Doppler measurements of pulmonary hemodynamics were made on the seventh day of treatment at each drug dose. Lung function, arterial blood gases, and adverse events were also monitored weekly. A dose-dependent decline of pulmonary artery pressure (PAP) was observed with each drug. A dose of 2.5 mg produced a significant decrease in PAP compared with baseline (20% amlodipine, 17% felodipine ER). Additional decreases in PAP were observed at 5 mg and 10 mg that were similar for both drugs, but did not reach statistical significance compared with 2.5 mg. There was a dose-related decrease in pulmonary vascular resistance and increase in oxygen delivery with amlodipine and felodipine ER. Lung function and blood gas values were stable throughout. Side effects (headache and ankle edema) were less frequent during amlodipine treatment (p<0.05). Both amlodipine and felodipine ER, given as a single daily oral dose of > or = 2.5 mg, are effective pulmonary vasodilators in COPD patients with PH. Their dose-response characteristics are similar, but amlodipine treatment was associated with fewer side effects.


Increased autophagy blocks HER2-mediated breast tumorigenesis.
Allelic loss of the autophagy gene, beclin 1/BECN1, increases the risk of patients developing aggressive, including human epidermal growth factor receptor 2 (HER2)-positive, breast cancers; however, it is not known whether autophagy induction may be beneficial in preventing HER2-positive breast tumor growth. We explored the regulation of autophagy in breast cancer cells by HER2 in vitro and the effects of genetic and pharmacological strategies to increase autophagy on HER2-driven breast cancer growth in vivo. Our findings demonstrate that HER2 interacts with Beclin 1 in breast cancer cells and inhibits autophagy. Mice with increased basal autophagy due to a genetically engineered mutation in Becn1 are protected from HER2-driven mammary tumorigenesis, and HER2 fails to inhibit autophagy in primary cells derived from these mice. Moreover, treatment of mice with HER2-positive human breast cancer xenografts with the Tat-Beclin 1 autophagy-inducing peptide inhibits tumor growth as effectively as a clinically used HER2 tyrosine kinase inhibitor (TKI). This inhibition of tumor growth is associated with a robust induction of autophagy, a disruption of HER2/Beclin 1 binding, and a transcriptional signature in the tumors distinct from that observed with HER2 TKI treatment. Taken together, these findings indicate that the HER2-mediated inhibition of Beclin 1 and autophagy likely contributes to HER2-mediated tumorigenesis and that strategies to block HER2/Beclin 1 binding and/or increase autophagy may represent a new therapeutic approach for HER2-positive breast cancers.


Modeling open-set spoken word recognition in postlingually deafened adults after cochlear implantation: some preliminary results with the neighborhood activation model.
Do cochlear implants provide enough information to allow adult cochlear implant users to understand words in ways that are similar to listeners with acoustic hearing? Can we use a computational model to gain insight into the underlying mechanisms used by cochlear implant users to recognize spoken words? The Neighborhood Activation Model has been shown to be a reasonable model of word recognition for listeners with normal hearing. The Neighborhood Activation Model assumes that words are recognized in relation to other similar-sounding words in a listener's lexicon. The probability of correctly identifying a word is based on the phoneme perception probabilities from a listener's closed-set consonant and vowel confusion matrices modified by the relative frequency of occurrence of the target word compared with similar-sounding words (neighbors). Common words with few similar-sounding neighbors are more likely to be selected as responses than less common words with many similar-sounding neighbors. Recent studies have shown that several of the assumptions of the Neighborhood Activation Model also hold true for cochlear implant users. Closed-set consonant and vowel confusion matrices were obtained from 26 postlingually deafened adults who use cochlear implants. Confusion matrices were used to represent input errors to the Neighborhood Activation Model. Responses to the different stimuli were then generated by the Neighborhood Activation Model after incorporating the frequency of occurrence counts of the stimuli and their neighbors. Model outputs were compared with obtained performance measures on the Consonant-Vowel Nucleus-Consonant word test. Information transmission analysis was used to assess whether the Neighborhood Activation Model was able to successfully generate and predict word and individual phoneme recognition by cochlear implant users. The Neighborhood Activation Model predicted Consonant-Vowel Nucleus-Consonant test words at levels similar to those correctly identified by the cochlear implant users. The Neighborhood Activation Model also predicted phoneme feature information well. The results obtained suggest that the Neighborhood Activation Model provides a reasonable explanation of word recognition by postlingually deafened adults after cochlear implantation. It appears that multichannel cochlear implants give cochlear implant users access to their mental lexicons in a manner that is similar to listeners with acoustic hearing. The lexical properties of the test stimuli used to assess performance are important to spoken-word recognition and should be included in further models of the word recognition process.


[Pathomorphologic characteristics and classification of bronchitis in miners working on watered faces in coal mines].
The material obtained from the lungs of 83 miners who worked in coal faces for 2-27 years, has been studied. On the basis of pathomorphological data acute and chronic bronchitis were subdivided into three forms each. Acute bronchitis: catarrhal-desquamative, productive-infiltrative, destructive-necrotic; chronic ones: productive-destructive, hypertrophic, atrophic. Each form of acute and chronic bronchitis has its own morphological varieties. The signs of professional bronchitis are not characteristic of acute bronchitis; coal just decreases the resistance of the bronchial mucous membrane. Chronic bronchitis is characterized by a number of distinctive morphological features: hyalinosis of the basal membrane, restructuring of the vascular network of the bronchial tree, and rarely squamous-cell metaplasia of the bronchial epithelium.


An historical review of the legal and personal background to Jackson v. Indiana.
The landmark case of Jackson v. Indiana is well known to forensic psychiatrists, but little is known of the personal and legal background of this case. Mr. Jackson's state hospital records were reviewed, as were available transcripts and decisions of the Indiana court proceedings, before and after the U.S. Supreme Court decision, and local newspaper coverage, to understand how this case developed.


Macrophages as a source of HIV during opportunistic infections.
The source of increasing viremia that characterizes the latter stages of human immunodeficiency virus (HIV) disease has remained a paradox because it occurs at a time when lymphoid tissue is quantitatively and qualitatively impaired, and the patients' CD4 T lymphocytes are steadily declining. Here, macrophages, both infected and uninfected with common opportunistic pathogens of HIV disease such as Mycobacterium avium complex and Pneumocystis carinii, were identified as highly productive sources of HIV in coinfected lymph nodes. These observations indicate that tissue macrophages are not only infected with HIV, but that common pathogens of HIV disease can dramatically increase their production of virus. Thus, prevention or successful treatment of opportunistic coinfections, or both, potentially benefits the patient twofold by limiting the pathology caused by opportunistic infection and by controlling induction of HIV replication.


Computational models link cellular mechanisms of neuromodulation to large-scale neural dynamics.
Decades of neurobiological research have disclosed the diverse manners in which the response properties of neurons are dynamically modulated to support adaptive cognitive functions. This neuromodulation is achieved through alterations in the biophysical properties of the neuron. However, changes in cognitive function do not arise directly from the modulation of individual neurons, but are mediated by population dynamics in mesoscopic neural ensembles. Understanding this multiscale mapping is an important but nontrivial issue. Here, we bridge these different levels of description by showing how computational models parametrically map classic neuromodulatory processes onto systems-level models of neural activity. The ensuing critical balance of systems-level activity supports perception and action, although our knowledge of this mapping remains incomplete. In this way, quantitative models that link microscale neuronal neuromodulation to systems-level brain function highlight gaps in knowledge and suggest new directions for integrating theoretical and experimental work.


Epidermal growth factor: a potent vasoconstrictor in experimental hypertension.
We have tested the hypothesis that growth factor signaling pathways are augmented in hypertension, a disease associated with vascular smooth muscle cell growth. Thoracic aorta was dissected from deoxycorticosterone acetate-salt (DOCA-salt) and one kidney, one clip (1K, 1C) hypertensive rats and from sham normotensive rats for use in isolated tissue bath experiments. Systolic blood pressure was significantly higher in DOCA-salt and 1K, 1C than in normotensive sham rats: 192 +/- 7, 185 +/- 10, and 117 +/- 4 mmHg, respectively. Although virtually no contraction to epidermal growth factor (EGF) was observed in endothelium-denuded sham rat aorta [1 +/- 1% phenylephrine (PE) (10 micromol/l)-induced contraction], the maximal EGF-induced contraction was 45 +/- 7% in endothelium-denuded aorta from DOCA-salt hypertensive rats and 39 +/- 7% in aorta from 1K, 1C rats. Although slightly attenuated, a contraction to EGF was still observed in endothelium-intact aortic strips from 28-day DOCA-salt hypertensive rats. We also conducted concentration-response curves to EGF on days 1, 3, 5, 7, 14, and 21 of DOCA-salt therapy. A significant contraction to EGF in aorta from DOCA-salt rats was observed on day 14, when DOCA-salt rats had significantly higher blood pressure than sham rats: 188 +/- 6 and 122 +/- 3 mmHg, respectively. Transforming growth factor-alpha, an agonist of the EGF receptor, contracted DOCA-salt rat aorta (30 +/- 7% PE-induced contraction) but not sham aorta (3 +/- 3%). The EGF receptor tyrosine kinase inhibitor 4,5-dianilinophthalimide (10 micromol/l), the mitogen-activated protein kinase kinase inhibitor PD-098059 (10 micromol/l), and the L-type voltage-gated calcium channel inhibitor diltiazem (1 mol/l), but not the cyclooxygenase inhibitor indomethacin (10 micromol/l), virtually abolished EGF-induced contraction (85, 98, and 99% reduction, respectively). These data support a striking difference in EGF signaling between normotensive and hypertensive animals. Furthermore, they provide evidence that growth factors should be considered vasoconstrictors as well as growth modulators in hypertension.


PHF6 Expression Levels Impact Human Hematopoietic Stem Cell Differentiation.
Transcriptional control of hematopoiesis involves complex regulatory networks and functional perturbations in one of these components often results in malignancies. Loss-of-function mutations in PHF6, encoding a presumed epigenetic regulator, have been primarily described in T cell acute lymphoblastic leukemia (T-ALL) and the first insights into its function in normal hematopoiesis only recently emerged from mouse modeling experiments. Here, we investigated the role of PHF6 in human blood cell development by performing knockdown studies in cord blood and thymus-derived hematopoietic precursors to evaluate the impact on lineage differentiation in well-established in vitro models. Our findings reveal that PHF6 levels differentially impact the differentiation of human hematopoietic progenitor cells into various blood cell lineages, with prominent effects on lymphoid and erythroid differentiation. We show that loss of PHF6 results in accelerated human T cell development through reduced expression of NOTCH1 and its downstream target genes. This functional interaction in developing thymocytes was confirmed in vivo using a phf6-deficient zebrafish model that also displayed accelerated developmental kinetics upon reduced phf6 or notch1 activation. In summary, our work reveals that appropriate control of PHF6 expression is important for normal human hematopoiesis and provides clues towards the role of PHF6 in T-ALL development.


[Coronary artery spasm. Study of 66 patients].
We report the vasoactive effects of ergonovine maleate in 66 patients with chest pain and abnormal angiographic studies. In 42 patients this medication was injected directly in the coronary arteries, and in 24 in the aorta. We observed better vasospastic effect in the first group with the advantage of lesser dosage and less side effects. In 25 cases we deemed necessary the administration of intracoronary nitroglycerin due to evident positivity of the test (diameter reduction bigger than 60% or between 30 and 60% of any epicardial branch associated with chest pain and or ST segment shift on the electrocardiogram). Ergonovine and nitroglycerin solutions were prepared during the study without discernible morbidity. We discuss the indications of the ergonovine test: precordial pain with non-significant obstructive lesions, in patients without vasoactive medications for at least 24 hours.


Growth patterns and obesity development in overweight or normal-weight 13-year-old adolescents: the STRIP study.
Our goal was to study childhood growth patterns and development of overweight in children who were overweight or normal weight at 13 years of age. This study is part of a prospective atherosclerosis-prevention trial Special Turku Coronary Risk Factor Intervention Project for Children). At 7 months of age, 1062 children were randomly assigned to an intervention group (n = 540) receiving biannual fat-oriented dietary counseling or to a control group (n = 522). Height and weight of the children and their parents were monitored annually. Our study group comprised those children who participated in the 13-year study visit (n = 541). At 13 years of age, the child was classified as overweight (n = 84) if his or her BMI exceeded the international age- and gender-specific overweight criteria. In overweight girls, the annual weight gain increased from 2.8 kg during the third and fourth year of life to 7.5 kg during the 12th year of life, whereas the annual weight gain of the girls who were normal weight ranged from 2.1 to 4.8 kg during the same period. The annual weight gain was similar of overweight boys and in their normal-weight peers until the age of 5 years, but after that it increased from 3.5 to 7.9 kg in overweight and from 2.6 to 5.5 kg in normal-weight boys. The BMI of the girls and boys who were overweight at the age of 13 exceeded the international cutoff point for overweight from the age of 5 and 8 years onward, respectively. The mean BMIs of the mothers and fathers of the overweight children were higher than those of the parents of the normal-weight children. The STRIP intervention had no effect on the examined growth parameters or on parental BMI. The children who were overweight at 13 years of age gained more weight than their normal-weight peers by the age of 2 or 3 years onward. The girls became overweight by the age of 5 years, whereas the boys only after 8 years of age. Parental BMI and steep weight gain in early childhood indicate markedly increased risk for becoming overweight.


The ability of pseudorabies virus to grow in different hosts is affected by the duplication and translocation of sequences from the left end of the genome to the UL-US junction.
Pseudorabies virus is a herpesvirus which has a class 2 genome. However, under certain growth conditions it acquires a genome with class 3-like characteristics. In these variants, the leftmost sequences of the long (L) component of the viral genome have been duplicated and translocated to the right of the L component next to the short (S) component, resulting in an L component that is bracketed by inverted repeats. Consequently, the L component can invert and is found in two orientations relative to the S component. The translocation is accompanied invariably by a deletion of sequences that are normally present in the wild-type genome at the right end of the L component. The virion variants with an invertible L component have a growth advantage over wild-type virus in chicken embryo fibroblasts and chickens; they also have a growth disadvantage in mice or rabbit kidney cells. The changed growth characteristics of the variants reside entirely in the changed structure of the junction between the S and L components. Replacement of that region of the DNA with wild-type sequences restores the wild-type phenotype. To determine whether the modified growth characteristics of the variants are related to the translocation or to the deletion, mutants that have a deletion or that have a deletion as well as a translocation similar to those observed in the variants were constructed, and the growth characteristics of these mutants were determined. We show that the modified growth characteristics of the mutants with an invertible L component can be attributed to the translocation of the leftmost terminal sequences of the genome next to the inverted repeat; they are not related to the deletion of the sequences normally present at the right end of the L component. The translocation of the leftmost 325 bp of the genome is sufficient to confer upon the virus the modified cell-type-specific growth characteristics. Furthermore, the modified growth characteristics are contingent upon the presence of 68 bp spanning the internal junction between the L and S components.


Control of bacteriophage lambda CII activity by bacteriophage and host functions.
We have studied the regulation of the lambda cII gene in vivo using cloned lambda fragments. Lambda N protein stimulated cII expression. Surprisingly, although very high cII protein levels were detected by gel electrophoresis, little cII protein activity, measured as stimulation of the lambda pI and pE promoters, was observed. The half-life of cII protein depended critically on its initial level. At low concentrations its half-life was as short as 1.5 min, whereas at high cII protein levels, it could be as long as 22 min. The Escherichia coli mutant ER437 directs lambda towards lysogeny; cII protein was more stable in this strain than in the wild type. On the other hand, although cyclic AMP is required for efficient lysogeny, it did not appear to influence the synthesis, stability, or activity of cII protein.


Human Metapneumovirus: An Important Cause of Respiratory Disease in Children and Adults.
Human metapneumovirus is a paramyxovirus that was discovered in 2001 in the Netherlands. Epidemiologic studies have shown it to be a major cause of acute respiratory tract disease in normal infants and children worldwide, with a seasonal occurrence and spectrum of clinical illness most similar to the closely related respiratory syncytial virus. The greatest prevalence of severe disease requiring hospitalization in otherwise healthy children appears to be in those aged between 6 and 12 months, older than the peak age of hospitalizations for respiratory syncytial virus. Human metapneumovirus is also a significant cause of acute respiratory disease in adults, particularly the elderly and those with comorbid conditions such as chronic obstructive pulmonary disease, asthma, and cancer. Because there is no rapid diagnostic assay, reverse transcriptase polymerase chain reaction is most widely used. Animal models have been developed, and candidate live-attenuated vaccines are in preclinical trials, offering the potential for future interventions in high-risk groups.


Integrity rate of pronuclei after cryopreservation of pronuclear-zygotes as a criteria for subsequent embryo development and pregnancy.
The aim of this study was to examine whether the integrity rate of pronuclei, after cryopreservation of pronuclear zygotes, could be a predictor of future embryo development and implantation. Two-pronuclei stage zygotes (n = 862) were cryopreserved by aseptic rapid freezing in 15% ethylene glycol + 15% DMSO + 0.2 M sucrose with a 4-step exposure in 12% (v:v), 25, 50 and 100% rapid freezing solution for 2, 1, 1 min and 30-50 s, respectively, at room temperature, and then plunged into liquid nitrogen. Zygotes were rapidly warmed at a speed of 30,000 degrees C/min and subsequently expelled into a graded series of sucrose solutions (1.0, 0.5, 0.25, 0.12 and 0.06 M) at 2.5 min intervals and in vitro cultured for 5 days. If embryos had developed to blastocysts on the 5th day, they were transferred to the recipients. The rest of the embryos were fixed for evaluation of chromatin. Zygote development, up to the expanded blastocyst stage, after in vitro culture, was 40%, if the integrity rate of pronuclei was high, and 4% if the integrity rate was low (P < 0.05). The pregnancy rate after transfer of the 5-day blastocysts depended on the pronuclear integrity rate: 43% (125 pregnancies aftertransfer of 291 blastocysts) for those with a high integrity, and only 1 in 5 (20%) for the few blastocysts which had shown a pronuclear low integrity rate (P < 0.05). Integrity rate of pronuclei after cryopreservation of pronuclear zygotes was a predictor of future embryo development and implantation: high integrity rate resulted in high pregnancy rate, while zygotes with low integrity rate of pronuclei after cryopreservation had low developmental potential.


Comparison of four beta-lactamase inhibitors in combination with ampicillin against Mycobacterium tuberculosis.
The in-vitro activity of a beta-lactamase inhibitor (clavulanic acid, sulbactam, BL-P2013 or BL-P2090) in combination with ampicillin against 13 isolates of Mycobacterium tuberculosis was determined by broth dilution. The agents were tested in 1:1 molar ratio of ampicillin to beta-lactamase inhibitor. The beta-lactamase inhibitors alone did not inhibit growth at the highest concentration tested. The MIC90 for ampicillin alone was greater than 32 mg/l. Clavulanic acid plus ampicillin was the most active combination with an MIC90 of 11 microM (4 mg/l of ampicillin). The MIC90 of ampicillin in combination with sulbactam, BL-P2013 or BL-P2090 was 23 microM (8 mg/l of ampicillin). A 1:1 ratio of ampicillin to inhibitor was more active than was a 2:1 ratio. The addition of a beta-lactamase inhibitor to ampicillin greatly improves its in-vitro activity against M. tuberculosis.


[Patients' access to their medical records].
Until recently, the medical record was seen exclusively as being the property of health institutions and doctors. Its great technical and scientific components, as well as the personal characteristics attributed by each doctor, have been the reasons appointed for that control. However, nowadays throughout the world that paradigm has been changing. In Portugal, since 2007 patients are allowed full and direct access to their medical records. Nevertheless, the Deontological Code of the Portuguese Medical Association (2009) explicitly states that patients' access to their medical records should have a doctor as intermediary and that the records are each physician's intellectual property. Furthermore, several doctors and health institutions, receiving requests from patients to access their medical records, end up requesting the legal opinion of the Commission for access to administrative documents. Each and every time, that opinion goes in line with the notion of full and direct patient access. Sharing medical records with patients seems crucial and inevitable in the current patient-centred care model, having the potential to improve patient empowerment, health literacy, autonomy, self-efficacy and satisfaction with care. With the recent technological developments and the fast dissemination of Personal Health Records, it is foreseeable that a growing number of patients will want to access their medical records. Therefore, promoting awareness on this topic is essential, in order to allow an informed debate between all the stakeholders.


Gold nanoparticle effects in polymerase chain reaction: favoring of smaller products by polymerase adsorption.
Gold nanoparticles were recently reported to reduce the formation of nonspecific products in polymerase chain reaction (PCR) at remarkably low temperatures, with hypothesized mechanisms including adsorption of DNA and heat-transfer enhancement. In contrast to these reports, we report that gold nanoparticles do not enhance the specificity of PCR but rather suppress the amplification of longer products while favoring amplification of shorter products, independent of specificity. Gold nanoparticles bearing a self-assembled monolayer of hexadecanethiol did not affect PCR, suggesting that surface interactions play an essential role. This role was further confirmed by experiments in which a similar effect on PCR was observed for the same total surface area of particles over a 100-fold range of per-particle surface area. The effect was seen with Taq and Tfl polymerases but not with Vent polymerase, and the effects of nanoparticles can be reversed by increasing the polymerase concentration or by adding bovine serum albumin (BSA). Transient high-temperature nanoparticle pre-exposure of PCR mix containing polymerase but not template or primers, followed by nanoparticle removal, modified subsequent nanoparticle-free PCR. Interaction between polymerase and gold nanoparticles was confirmed by changes in nanoparticle absorption spectrum and electrophoretic mobility in the presence of polymerase. Taken together, these results suggest that the nanoparticles nonspecifically adsorb polymerase, thus effectively reducing polymerase concentration.


Altered cell cycle control at the G(2)/M phases in aryl hydrocarbon receptor-null embryo fibroblast.
The aryl hydrocarbon receptor (AHR) is known to mediate the toxic and carcinogenic effects of polycyclic aromatic hydrocarbons and dioxins. High-affinity AHR ligands, such as 2,3,7, 8-tetrachlorodibenzeno-p-dioxin, have been shown to modify cell proliferation and differentiation. However, the mechanisms by which AHR affects cell proliferation and differentiation are not fully understood. To investigate the role of AHR in cell proliferation, mouse embryonic fibroblasts (MEFs) derived from AHR-null mice were obtained and characterized. Compared with wild-type MEFs, AHR-null cells exhibited a lower proliferation rate with an accumulation of 4N DNA content and increased apoptosis. The expression levels of Cdc2 and Plk, two kinases important for G(2)/M phase of cell cycle, were down-regulated in AHR-null MEFs. In contrast, transforming growth factor-beta (TGF-beta), a proliferation inhibitor in several cell lines, was present at high levels in conditioned medium from AHR-null MEFs. Concomitant with G(2)/M cell accumulation, treatment of wild-type MEFs with TGF-beta3 also resulted in down-regulation of both Cdc2 and Plk. Thus, overproduction of TGF-beta in AHR-deficient cells appears to be the primary factor that causes low proliferation rates and increased apoptosis. Taken together, these results suggest that AHR influences TGF-beta production, leading to an alteration in cell cycle control.


[Medicinal chemistry and pharmacology focused on cannabidiol, a major component of the fiber-type cannabis].
Considerable attention has focused on cannabidiol (CBD), a major non-psychotropic constituent of fiber-type cannabis plant, and it has been reported to possess diverse biological activities. Although CBD is obtained from non-enzymatic decarboxylation of its parent molecule, cannabidiolic acid (CBDA), several studies have investigated whether CBDA itself is biologically active. In the present report, the author summarizes findings indicating that; 1) CBDA is a selective cyclooxygenase-2 (COX-2) inhibitor, and ii) CBDA possesses an anti-migrative potential for highly invasive cancer cells, apparently through a mechanism involving inhibition of cAMP-dependent protein kinase A, coupled with an activation of the small GTPase, RhoA. Further, the author introduces recent findings on the medicinal chemistry and pharmacology of the CBD derivative, CBD-2',6'-dimethyl ether (CBDD), that exhibits inhibitory activity toward 15-lipoxygenase (15-LOX), an enzyme responsible for the production of oxidized low-density lipoprotein (LDL). These studies establish CBD as both an important experimental tool and as a lead compound for pharmaceutical development. In this review, the author further discusses the potential uses of CBD and its derivatives in future medicines.


End-of-life care for older adults in ICUs.
This review was undertaken to present and critique the most recent (1990-2000) empirical evidence about end-of-life care for older adult patients in ICUs, their families, and care providers. The studies (including descriptive, correlational, longitudinal, and intervention) were found using a combination of these terms: (a) intensive care (units) or critical care (units), and (b) critical illness, critically ill patients, terminally ill, terminal care, life support care, or palliative care. The computerized databases searched were CINAHL and MEDLINE. Only published studies of persons 44 years of age or older, written in English, and conducted in the U.S. or Canada were included. Research was not limited to studies conducted by or written by nurses. Excluded were articles focused on physiology, for example, studies of treatment for specific conditions, and articles focused on predictors of ICU outcomes.


When parallel processing in visual word recognition is not enough: new evidence from naming.
Low-frequency irregular words are named more slowly and are more error prone than low-frequency regular words (the regularity effect). Rastle and Coltheart (1999) reported that this irregularity cost is modulated by the serial position of the irregular grapheme-phoneme correspondence, such that words with early irregularities exhibit a larger cost than words with late ones. They argued that these data implicate rule-based serial processing, and they also reported a successful simulation with a model that has a rule-based serial component--the DRC model of reading aloud (Coltheart, Rastle, Perry, Langdon, & Ziegler, 2001). However, Zorzi (2000) also simulated these data with a model that operates solely in parallel. Furthermore, Kwantes and Mewhort (1999) simulated these data with a serial processing model that has no rules for converting orthography to phonology. The human data reported by Rastle and Coltheart therefore neither require a serial processing account, nor successfully discriminate among a number of computational models of reading aloud. New data are presented wherein an interaction between the effects of regularity and serial position of irregularity is again reported for human readers. The DRC model simulated this interaction; no other implemented computational model does so. The present results are thus consistent with rule-based serial processing in reading aloud.


Deep Learning from Incomplete Data: Detecting Imminent Risk of Hospital-acquired Pneumonia in ICU Patients.
Hospital acquired pneumonia (HAP) is the second most common nosocomial infection in the ICU and costs an estimated $3.1 billion annually. The ability to predict HAP could improve patient outcomes and reduce costs. Traditional pneumonia risk prediction models rely on a small number of hand-chosen signs and symptoms and have been shown to poorly discriminate between low and high risk individuals. Consequently, we wanted to investigate whether modern data-driven techniques applied to respective pneumonia cohorts could provide more robust and discriminative prognostication of pneumonia risk. In this paper we present a deep learning system for predicting imminent pneumonia risk one or more days into the future using clinical observations documented in ICU notes for an at-risk population (n = 1, 467). We show how the system can be trained without direct supervision or feature engineering from sparse, noisy, and limited data to predict future pneumonia risk with 96% Sensitivity, 72% AUC, and 80% F1-measure, outperforming SVM approaches using the same features by 20% Accuracy (relative; 12% absolute).


Understanding knowledge of hypertension among affected individuals in low-Income (B40) communities in Malaysia: The RESPOND study.
Achieving optimal control of blood pressure is easier when those affected understand the risks and consequences of hypertension and the principles of management. It is particularly important in disadvantaged groups among whom blood pressure control is often poor. However, effective responses require evidence of the knowledge and beliefs of those affected. This was undertaken as part of a larger study of the therapeutic journeys followed by individuals living in B40 (bottom 40% by income) households in Malaysia, the Responsive and Equitable Health Systems-Partnership on Non- Communicable Diseases (RESPOND).This paper describes their reported knowledge of hypertension, health, and measures that can improve hypertensive control. The communities were selected from rural and urban populations in four peninsular states (Selangor, Kelantan, Perak, and Johor). Following a multistage sampling approach, communities in each stratum were selected according to probability proportional to the size and identified based on national census data by the community and administrative registers. Households were randomly selected. Eligible individuals were those aged between 35 and 70 years old, self-reported or identified as hypertensive at screening. Informed consent was taken. A survey using validated questionnaires was conducted. The total number of respondents was 579. The mean age was 59.0 (95%: 58.4, 59.7) and more were women (71.5%) than men (28.5%). Regarding respondents selfreported level of hypertension knowledge, 2.9% reported having no knowledge at all, 80.1% had little knowledge, and 17.9% were very familiar. Among all respondents, 56.2% (95% CI: 50.7, 61.6) correctly answered at least four out of five objective knowledge questions.Almost all (91.5%) were aware that hypertension could cause a stroke. However, one-fifth believed it could cause cancer. Almost threequarters said that people with high blood pressure generally felt well (72.1%) and recognized that they should not stop taking their medication (70.7%). Most of the respondents knew that people should take their medication even if they feel well (73.6%). Although more than half (66.0%) of the respondents rated their health as poor. Interestingly, most did not perceive themselves as having a long-term illness (95.0%). This study provides reassurance that individuals with hypertension in disadvantaged communities in Malaysia have a relatively good understanding of hypertension. Further research should explore the challenges they face on their therapeutic journeys.


WNT5A encodes two isoforms with distinct functions in cancers.
WNT5A, a member of the WNT family of secreted lipid-modified glycoproteins, is a critical regulator of a host of developmental processes, including limb formation, lung morphogenesis, intestinal elongation and mammary gland development. Altered WNT5A expression has been associated with a number of cancers. Interestingly, in certain types of cancers, such as hematological malignancies and colorectal carcinoma, WNT5A is inactivated and exerts a tumor suppressive function, while in other cancers, such as melanoma and gastric carcinoma, WNT5A is overexpressed and promotes tumor progression. The mechanism by which WNT5A achieves these distinct activities in cancers is poorly understood. Here, we provide evidence that the WNT5A gene produces two protein isoforms, WNT5A-long (WNT5A-L) and WNT5A-short (WNT5A-S). Amino-terminal sequencing and a WNT5A-L specific antibody demonstrate that the mature and secreted isoforms are distinct, with WNT5A-L carrying an additional 18 N-terminal amino acids. Biochemical analysis indicates that both purified proteins are similar with respect to their stability, hydrophobicity and WNT/β-catenin signaling activity. Nonetheless, modulation of these two WNT5A isoforms, either through ectopic expression or knockdown, demonstrates that they exert distinct activities in cancer cell lines: while WNT5A-L inhibits proliferation of tumor cell lines, WNT5A-S promotes their growth. Finally, we show that expression of these two WNT5A isoforms is altered in breast and cervix carcinomas, as well as in the most aggressive neuroblastoma tumors. In these cancers, WNT5A-L is frequently down-regulated, whereas WNT5A-S is found overexpressed in a significant fraction of tumors. Altogether, our study provides evidence that the distinct activities of WNT5A in cancer can be attributed to the production of two WNT5A isoforms.


Consumer knowledge and opinions of genetic testing for breast cancer risk.
Although clinical evidence shows the value of genetic testing for breast cancer risk, consumer opinion about the test-and its outcomes-may differ. We conducted focus groups with white and black women to assess consumer opinions about genetic testing for breast cancer risk. We conducted 5 focus groups with women between the ages of 30 and 79. Participants were not selected for personal or family history of breast cancer. The findings of these focus groups suggest that consumers' understandings of risk, genetics, and genetic testing can differ considerably from clinical definitions and interpretations. Clinical information appeared to be interpreted by participants based on personal experience and beliefs about genetics and disease causation. Our findings also suggest that many consumers have incomplete or erroneous knowledge about genetic testing (eg, whether the test should be repeated annually). Participants gave greater attention to the emotional and social consequences of positive test results than to their physical outcomes, suggesting that emotional and social issues may be more salient in decision making about whether to be tested. Sensitivity to the possibility that consumers may use nonclinical criteria to assess the value of genetic testing can help clinicians counsel women about testing and what actions to take after testing.


Studies of aging nonhuman primates illuminate the etiology of early-stage Alzheimer's-like neuropathology: An evolutionary perspective.
Tau pathology in Alzheimer's disease (AD) preferentially afflicts the limbic and recently enlarged association cortices, causing a progression of mnemonic and cognitive deficits. Although genetic mouse models have helped reveal mechanisms underlying the rare, autosomal-dominant forms of AD, the etiology of the more common, sporadic form of AD remains unknown, and is challenging to study in mice due to their limited association cortex and lifespan. It is also difficult to study in human brains, as early-stage tau phosphorylation can degrade postmortem. In contrast, rhesus monkeys have extensive association cortices, are long-lived, and can undergo perfusion fixation to capture early-stage tau phosphorylation in situ. Most importantly, rhesus monkeys naturally develop amyloid plaques, neurofibrillary tangles comprised of hyperphosphorylated tau, synaptic loss, and cognitive deficits with advancing age, and thus can be used to identify the early molecular events that initiate and propel neuropathology in the aging association cortices. Studies to date suggest that the particular molecular signaling events needed for higher cognition-for example, high levels of calcium to maintain persistent neuronal firing- lead to tau phosphorylation and inflammation when dysregulated with advancing age. The expression of NMDAR-NR2B (GluN2B)-the subunit that fluxes high levels of calcium-increases over the cortical hierarchy and with the expansion of association cortex in primate evolution, consistent with patterns of tau pathology. In the rhesus monkey dorsolateral prefrontal cortex, spines contain NMDAR-NR2B and the molecular machinery to magnify internal calcium release near the synapse, as well as phosphodiesterases, mGluR3, and calbindin to regulate calcium signaling. Loss of regulation with inflammation and/or aging appears to be a key factor in initiating tau pathology. The vast expansion in the numbers of these synapses over primate evolution is consistent with the degree of tau pathology seen across species: marmoset < rhesus monkey < chimpanzee < human, culminating in the vast neurodegeneration seen in humans with AD.


Heavy metals distribution in an Iowa suburban landscape.
This study investigated the degree to which human activities through urbanization influence heavy metal concentrations in a suburban landscape in Ankeny, IA. Residential areas from different years in nine time periods of development were identified from aerial photos. Soil cores were collected from the center of the front yard of 10 randomly selected homes. Cores were subdivided into 0- to 5-, 5- to 10-, and 10- to 20-cm increments from a composite of five cores. The soils were analyzed for organic C, pH, and total Cd, Co, Cr, Cu, Ni, Pb, and Zn. Results showed that organic C increased and pH decreased with time, and that there was a general decreasing trend in heavy metal concentrations from the pre-1939 period until 1983-1990, after which there was a sharp increase in the concentrations of most of the metals. The mean Cu concentration ranged from 21 mg kg(-1) for the pre-1939 time period of development to 14.9 mg kg(-1) for the recent period of development (2003-2005). Nickel concentrations increased significantly with depth with means of 21.3 mg kg(-1) at depth 0 to 5 cm, 22.5 mg kg(-1) at depth 5 to 10 cm, and 23.0 mg kg(-1) at depth 10 to 20 cm. The concentrations of heavy metals were significantly intercorrelated, except Zn, suggesting their coexistence as mineral constituents or common contamination source. The concentrations of Cu and Pb in some locations could be due to anthropogenic inputs or higher organic matter content in soils adjacent to older homes. There appears to have been a source that caused an increase in Cd, Cr, Co, Cu, Pb, and Ni concentrations in soil adjacent to homes built between 1983 and 1990.


Macrophage Uptake Behavior and Anti-inflammatory Response of Bovine Brain- or Soybean-derived Phosphatidylserine Liposomes.
Phosphatidylserine (PtdSer) is mainly derived from the bovine brain cortex or soybean lecithin. We investigated macrophage uptake behavior and the anti-inflammatory response induced by liposomes containing bovine brain- (B-PSL) or soybean-derived PtdSer (S-PSL). The size of B-PSL and S-PSL was very similar. There were no significant differences in the uptake of B-PSL and S-PSL by Raw 264.7 macrophage cells. Addition of B-PSL or S-PSL decreased the production of the inflammatory cytokines, IL-1α, IL-6 and TNF-α, in lipopolysaccharide-treated Raw 264.7 cells, but there were no differences between them. These results suggest that S-PSL may be used as an anti-inflammatory agent.


Therapeutic effect of microRNA-21 on differentially expressed hub genes in gastric cancer based on systems biology.
Gastric cancer (GC) is a leading cause of mortality for many people. Cancer's initiating factors are poorly understood. miR-21 has a crucial function in several malignancies, particularly GC. Furthermore, it has been shown that miR-21 is critical for the emergence and advancement of GC. This work intends to identify new genes which expression is associated with the activity of mir-21 in GC and to investigate the effect of downregulation of mir-21 on these genes and gastric tumorigenesis. We utilized the gene expression profiles of GCs from an Array database (GSE13911) from the Gene Expression Omnibus (GEO) dataset to find differentially expressed genes (DEGs) between control and gastric cancer groups. Using weighted gene correlation network analysis (WGCNA) in R, the Gene co-expression network was reconstructed. The microRNA-mRNA network was then reconstructed using the miRWalk database, and by investigating the microRNA-mRNA network, the genes that have an association with mir-21 were found. To implement the functional investigation, MKN and AGS cell lines were transfected with anti-miR-21 next. Subsequently, MTT proliferation was utilized to assess the cell's vitality. qRT-PCR was then used to evaluate the anticipated levels of gene expression in both GC cell lines. This study discovered and predicted CCL28, NR3C2, and SNYPO2 as the targets of miR-21 (GC), which are downregulated through gastric tumorigenesis, showing great potential as therapeutic and diagnostic targets. The suppression of miR-21 in gastric GC cells led to the inhibition of cell proliferation and decreased expression of CCL28, NR3C2, and SNYPO2 genes. This study established that miR-21, via downregulating these genes, contributes significantly to the development of GC. In addition, systems biology techniques identified CCL28, NR3C2, and SNYPO2 genes as possible GC surveillance and therapy components.


Study on the possible neurotransmitter of the non-adrenergic non-cholinergic innervation of the rat gastric fundus.
The neurotransmitter of the non-adrenergic non-cholinergic inhibitory innervation of the stomach is still unknown. We studied the effect of a series of neurotransmitter candidates, ATP, [Leu]enkephalin and [Met]enkephalin, somatostatin, neurotensin and VIP, in the rat gastric fundus and compared these effects with the response to electrical stimulation of the non-adrenergic non-cholinergic inhibitory neurons. Rats of both sexes were treated with reserpine (5 mg . kg-1 intraperitoneally) 24 h before killing. Longitudinal muscle strips of the gastric fundus were prepared and mounted between parallel platinum electrodes in Krebs solution containing atropine 10(-6) M and serotonin 3.10(-6) M. A maximal relaxatory response was obtained on transmural stimulation of the strips at supramaximal voltage, 1 msec and 5 Hz. ATP (10(-6)-10(-3) M) elicited a biphasic response, a small relaxation followed by a contraction. The maximal relaxatory response induced by ATP was much lower than that induced by transmural stimulation during 45 sec (37.3% versus 166.2%, where 100% is the maximal contractile response to ATP, n = 17). Desensitization to ATP did not influence the relaxation induced by transmural stimulation. [Met]enkephalin, [Leu]enkephalin and naloxone did not change the tone of the strips or the amplitude of the electrically induced relaxation. Somatostatin had no influence while neurotensin induced a concentration-dependent contraction from 10(-9) M or 10(-8) M on. VIP (10(-10)-3.10(-8) M) induced a concentration-dependent relaxation. The maximal relaxation induced by VIP was 120.8% of that induced by transmural stimulation (n = 16). The relaxation induced by VIP 10(-8) M, left in contact with the tissue for 10 min, was comparable to that induced by transmural stimulation during 10 min, except for a lag time of more than 10 sec after the addition of VIP. The relaxation induced by VIP was not influenced by tetrodotoxin, phentolamine or propranolol. The peptidase trypsin (10(-6) M) antagonized the relaxation by exogenously added VIP but did not influence the electrically induced relaxation. The results obtained in this study show that, of the substances tested, only VIP mimics the relaxation induced by stimulation of the inhibitory non-adrenergic non-cholinergic neurons in the rat gastric fundus; VIP therefore seems a reasonable candidate as neurotransmitter of these neurons.


ED utilization trends in sports-related traumatic brain injury.
Emergency department (ED) visits for sports-related traumatic brain injuries (TBIs) have risen. This study evaluated how the number and severity of admissions have changed as ED visits for sports-related TBIs have increased. A retrospective study of children aged 0 to 19 years at a level 1 trauma center was performed. Patients from 2002 to 2011 with a primary or secondary diagnosis of TBI were identified from the hospital's inpatient and outpatient trauma registries. Frequencies were used to characterize the population, χ(2) analysis was performed to determine differences between groups, and regression analysis looked at relationship between year and injury severity score or length of stay. Sport was responsible for injury in 3878 (15.4%) cases during the study period; 3506 (90.4%) were discharged from the hospital, and 372 (9.6%) were admitted. Seventy-three percent were male patients and 78% Caucasian; mean age was 13 ± 3.5 years. ED visits for sports-related TBIs increased 92% over the study period, yet there was no significant change (χ(2) = 9.8, df = 9, P = .37) in the percentage of children admitted. Mean injury severity score for those admitted decreased from 7.8 to 4.8 (β = -0.46; P = .006); length of stay trended downward (β = -0.05; P = .05). The percentage of children being admitted from the ED with sports-related TBI has not changed over the past 10 years. The severity of admitted sports-related TBI is decreasing. Additional research is needed to correlate these trends with other TBI mechanisms.


An ultralong CDRH2 in HCV neutralizing antibody demonstrates structural plasticity of antibodies against E2 glycoprotein.
A vaccine protective against diverse HCV variants is needed to control the HCV epidemic. Structures of E2 complexes with front layer-specific broadly neutralizing antibodies (bNAbs) isolated from HCV-infected individuals, revealed a disulfide bond-containing CDRH3 that adopts straight (individuals who clear infection) or bent (individuals with chronic infection) conformation. To investigate whether a straight versus bent disulfide bond-containing CDRH3 is specific to particular HCV-infected individuals, we solved a crystal structure of the HCV E2 ectodomain in complex with AR3X, a bNAb with an unusually long CDRH2 that was isolated from the chronically-infected individual from whom the bent CDRH3 bNAbs were derived. The structure revealed that AR3X utilizes both its ultralong CDRH2 and a disulfide motif-containing straight CDRH3 to recognize the E2 front layer. These results demonstrate that both the straight and bent CDRH3 classes of HCV bNAb can be elicited in a single individual, revealing a structural plasticity of VH1-69-derived bNAbs.


The Application of Seaweed Polysaccharides and Their Derived Products with Potential for the Treatment of Alzheimer's Disease.
Neurodegenerative diseases are among the most widespread diseases affecting humans, and the number of patients is only rising. Seaweed polysaccharide extracts show significant neuroprotective and reparative activities. Seaweed polysaccharides might provide the next big breakthrough in neurodegenerative disease treatment. This paper reviews the applications of seaweed polysaccharides as potential treatments of neurodegenerative diseases. The particular focus is on fucoidan, ulvan, and their derivatives as potential agents to treat Alzheimer's disease. This review provides a critical update on the progress in this important research area.


Stereospecific induction of nuclear factor-kappaB activation by isochamaejasmin.
The root of Stellera chamaejasme L. is a traditional Chinese herb termed Rui Xiang Lang Du and has been used to treat solid tumors, tuberculosis and psoriasis. Exactly how S. chamaejasme L. regulates cellular responses remains unclear. We examined four biflavonoids isolated from S. chamaejasme L., including isochamaejasmin, two of its stereo-isomers and a methyl derivative, in functional assays originally designed to screen ligands for the G protein-coupled formyl peptide receptor-like 1 (FPRL1). Isochamaejasmin was found to induce the expression of a nuclear factor (NF)-kappaB-directed reporter gene in transfected HeLa cells with an EC50 of 3.23 microM, independently of FPRL1. The isochamaejasmin-stimulated NF-kappaB reporter activity was accompanied by nuclear translocation of NF-kappaB proteins and was blocked by a dominant-negative construct of IkappaBalpha. Isochamaejasmin also induced time-dependent phosphorylation of the mitogen-activated protein kinases extracellular signal-regulated kinase 1/2 and p38, and a novel protein kinase C (PKCdelta). Likewise, inhibition of these kinases with the respective pharmacological inhibitors significantly reduced the isochamaejasmin-stimulated NF-kappaB activation. It is noteworthy that the two stereoisomers and the methyl derivative did not induce detectable activation of NF-kappaB and were more cytotoxic than isochamaejasmin, which could partially rescue cycloheximide-induced apoptosis. Inhibition of NF-kappaB activation reversed the anti-apoptotic effect of isochamaejasmin. These results provide the first evidence for a potential mechanism of action by S. chamaejasme L., and indicate that structurally similar compounds derived from S. chamaejasme L. may have different pharmacological properties.


Laser-Induced Breakdown Spectroscopy and Principal Component Analysis for the Classification of Spectra from Gold-Bearing Ores.
Laser-induced breakdown spectroscopy (LIBS) and principal component analysis (PCA) were applied to the classification of LIBS spectra from gold ores prepared as pressed pellets from pulverized bulk samples. For each sample, 5000 single-shot LIBS spectra were obtained. Although the gold concentrations in the samples were as high as 7.7 µg/g, Au emission lines were not observed in most single-shot LIBS spectra, rendering the application of the usual ensemble-averaging approach for spectral processing to be infeasible. Instead, a PCA approach was utilized to analyze the collection of single-shot LIBS spectra. Two spectral ranges of 21 nm and 0.15 nm wide were considered, and LIBS variables (i.e., wavelengths) reduced to no more than three principal components. Single-shot spectra containing Au emission lines (positive spectra) were discriminated by PCA from those without the spectral feature (negative spectra) in a spectral range of less than 1 nm wide around the Au(I) 267.59 nm emission line. Assuming a discrete gold distribution at very low concentration, LIBS sampling of gold particles seemed unlikely; therefore, positive spectra were considered as data outliers. Detection of data outliers was possible using two PCA statistical parameters, i.e., sample residual and Mahalanobis distance. Results from such a classification were compared with a standard database created with positive spectra identified with a filtering algorithm that rejected spectra with an Au intensity below the smallest detectable analytical LIBS signal (i.e., below the LIBS limit of detection). The PCA approach successfully identified 100% of the data outliers when compared with the standard database. False identifications in the multivariate approach were attributed to variations in shot-to-shot intensity and the presence of interfering emission lines.


Murine orthotopic model for the assessment of chemoradiotherapeutic interventions in rectal cancer.
A murine orthotopic model for the study of colon cancer has been described earlier. However, for the study of rectal cancer, three issues remain: (i) the relative sensitivity of the implanted tumors to ionizing radiation (IR); (ii) the location of the tumor for the delivery of external beam IR; and (iii) the assessment of a given modality over time before necropsy. In this protocol, we have modified an orthotopic model for colon cancer described earlier for the specific assessment of chemoradiation in rectal cancer by (i) cecal transplantation of tumors with a known response to IR; (ii) securing the tumor to the lateral abdominal wall with a permanent suture for the administration of IR; and (iii) transfection of cells with luciferase before tumor implantation for the assessment of the chemoradiotherapeutic interventions over time by bioluminescence imaging before the end on the study. This technique allows targeted delivery of IR in an intraperitoneal tumor. Imaging throughout the course of the treatment is possible such that the timing of chemoradiation can be determined and permits comparison between groups before the end of the treatment. This model represents a modified technique that allows the assessment of chemoradiotherapeutic interventions in rectal cancer.


An end-to-end test for MR-guided online adaptive radiotherapy.
In the evolving field of adaptive MR guided radiotherapy, the need for dedicated procedures for acceptance and quality assurance is increasing. Research has been devoted to MR compatible dosimeters and phantoms, but to date no end-to-end test has been presented that covers an MRgRT workflow. Such an end-to-end test should comprise each step of the workflow and include all associated uncertainties. The purpose of this study was to investigate the usability of an anthropomorphic deformable and multimodal pelvis (ADAM-pelvis) phantom in combination with film dosimetry for end-to-end testing of an MRgRT adaptive workflow. The ADAM-pelvis phantom included surrogates for muscle tissue, adipose and bone, as well as deformable silicone organs mimicking a prostate patient. At the interfaces of the critical structures (bladder and rectum), small pieces of GafChromic EBT3 films were placed to measure delivered dose. Pre-treatment MR imaging of the phantom was used to delineate the prostate, rectum and bladder and to generate a treatment plan to deliver 2 Gy to the prostate. Electron density (ED) map from CT imaging was used for dose calculation after deformable image registration (DIR) to the pre-treatment MR scan. At each fraction, bladder- and rectum filling was varied and a new adapted plan was generated. Dose calculation was performed using both a DIR-based ED map and a CT-based ED map after acquisition of a new CT scan of the phantom at each fraction. All dose calculations were performed taking into account the magnetic field. A good agreement between measured and calculated dose was found using both, the CT-derived and the DIR-based ED map (2.0% and 2.8% dose difference, respectively). The gamma index pass-rate (3%/2 mm) varied from 96.4% to 100%.The ADAM-pelvis phantom was suitable for end-to-end testing in MR-guided radiotherapy and a very good agreement with the calculated dose was achieved.


Anomalous variable-temperature photoluminescence of CsPbBr3 perovskite quantum dots embedded into an organic solid.
All-inorganic lead halide perovskite quantum dots (PQDs) of CsPbBr3 were synthesized at room temperature via a facile solution-based procedure. The cubic phase structure of the synthesized PQDs was judiciously identified through examining high-resolution transmission electron microscopy (TEM) images, selected area electronic diffraction (SAED) patterns and scanning TEM images of the PQDs. Variable-temperature photoluminescence (PL) spectra of the CsPbBr3 PQDs randomly embedded into a frozen solid of methylbenzene were measured in the temperature range of 5-180 K. It is found that both the linewidth and peak position of the measured PL spectra are abnormally almost temperature independent in the temperature range of interest. Some competing mechanisms, such as a competition between the bandgap blue shift induced by thermal lattice expansion and red shift induced by thermal escaping of localized excitons, and a competition between lineshape broadening by phonon scattering and narrowing by thermal escaping of localized excitons, are proposed to interpret the phenomena. Good agreement between the theoretical fitting and the experimental data leads to a state-of-the-art understanding of the temperature-dependent luminescence of the CsPbBr3 PQDs in a solid matrix.


A time- and voltage-dependent K+ current in single cardiac cells from bullfrog atrium.
Individual myocytes were isolated from bullfrog atrium by enzymatic and mechanical dispersion, and a one-microelectrode voltage clamp was used to record the slow outward K+ currents. In normal [K+]o (2.5 mM), the slow outward current tails reverse between -95 and -100 mV. This finding, and the observed 51-mV shift of Erev/10-fold change in [K+]o, strongly suggest that the "delayed rectifier" in bullfrog atrial cells is a K+ current. This current, IK, plays an important role in initiating repolarization, and it is distinct from the quasi-instantaneous, inwardly rectifying background current, IK. In atrial cells, IK does not exhibit inactivation, and very long depolarizing clamp steps (20 s) can be applied without producing extracellular K+ accumulation. The possibility of [K+]o accumulation contributing to these slow outward current changes was assessed by (a) comparing reversal potentials measured after short (2 s) and very long (15 s) activating prepulses, and (b) studying the kinetics of IK at various holding potentials and after systematically altering [K+]o. In the absence of [K+]o accumulation, the steady state activation curve (n infinity) and fully activated current-voltage (I-V) relation can be obtained directly. The threshold of the n infinity curve is near -50 mV, and it approaches a maximum at +20 mV; the half-activation point is approximately -16 mV. The fully activated I-V curve of IK is approximately linear in the range -40 to +30 mV. Semilog plots of the current tails show that each tail is a single-exponential function, which suggests that only one Hodgkin-Huxley conductance underlies this slow outward current. Quantitative analysis of the time course of onset of IK and of the corresponding envelope of tails demonstrate that the activation variable, n, must be raised to the second power to fit the sigmoid onset accurately. The voltage dependence of the kinetics of IK was studied by recording and curve-fitting activating and deactivating (tail) currents. The resulting 1/tau n curve is U-shaped and somewhat asymmetric; IK exhibits strong voltage dependence in the diastolic range of potentials. Changes in the [Ca2+]o in the superfusing Ringer's, and/or addition of La3+ to block the transmembrane Ca2+ current, show that the time course and magnitude of IK are not significantly modulated by transmembrane Ca2+ movements, i.e., by ICa. These experimentally measured voltage- and time-dependent descriptors of IK strongly suggest an important functional role for IK in atrial tissue: it initiates repolarization and can be an important determinant of rate-induced changes in action potential duration.


High-performance coils and yarns of polymeric piezoelectric nanofibers.
We report on highly stretchable piezoelectric structures of electrospun PVDF-TrFE nanofibers. We fabricated nanofibrous PVDF-TrFE yarns via twisting their electrospun ribbons. Our results show that the twisting process not only increases the failure strain but also increases overall strength and toughness. The nanofibrous yarns achieved a remarkable energy to failure of up to 98 J/g. Through overtwisting process, we fabricated polymeric coils out of twisted yarns that stretched up to ∼740% strain. This enhancement in mechanical properties is likely induced by increased interactions between nanofibers, contributed by friction and van der Waals interactions, as well as favorable surface charge (Columbic) interactions as a result of piezoelectric effect, for which we present a theoretical model. The fabricated yarns and coils show great promise for applications in high-performance lightweight structural materials and superstretchable piezoelectric devices and flexible energy harvesting applications.


Community factors, hospital characteristics and inter-regional outcome variations following acute myocardial infarction in Canada.
While various community and hospital characteristics have been demonstrated to have an impact on individual cardiovascular outcomes, the extent to which such factors account for inter-regional and interhospital outcome variations following acute myocardial infarction (AMI) remains unknown. To examine the impact of community and hospital factors on individual AMI outcomes and procedure use, and to determine the extent to which such characteristics account for inter-regional and interinstitutional AMI outcome and procedure variations across Canada. Patients hospitalized with AMI between April 1, 1997, and March 31, 2000, across Canada were examined. The community and hospital characteristics studied included three indicators of socioeconomic status, two indicators of ethnicity, rural-urban status of residence, hospital academic affiliation, and the presence or absence of on-site angiography or revascularization capabilities at the admitting institution. Outcomes included in-hospital mortality, one-year cardiac readmissions and 30-day revascularization rates post-AMI. All analyses were adjusted for age, sex and age-sex interaction. The relationships between community/hospital factors and individual outcomes were examined using random-effects hierarchical logistic regression analysis, while the relationships between community/hospital characteristics and inter-regional/hospital risk-adjusted outcomes were examined using least squares regression and the coefficient of determination (r2). After adjusting for demographic factors, a patient's neighbourhood socioeconomic status was inversely correlated with the likelihood of death and downstream cardiac readmissions (P<0.001); patients residing in lower educated regions were less likely to receive revascularization post-AMI (P<0.001). Patients living in regions with higher concentrations of new immigrants and/or visible minorities, as well as those admitted to academically affiliated hospitals or hospitals with on-site procedural capacity, had fewer cardiac readmissions (P<0.001) and greater use of revascularization post-AMI (P<0.001) after adjusting for age and sex. Despite their associations with outcomes on an individual patient level, community and hospital factors explained no more than 7% of the variation in the risk-adjusted outcomes across hospitals or regions. Finally, adjustments for community and hospital factors and procedure use, beyond adjustments for age and sex alone, had marginal impact on a province's risk-adjusted outcomes. While community and hospital factors are important determinants of individual outcomes after AMI, they account for only a minimal degree of outcome variation across regions. Further studies are required to examine whether AMI outcome variations in Canada are explained by differences in patient clinical profiles and/or by differences in the decision-making behaviours of providers across jurisdictions.


A Weakly Supervised Segmentation Network Embedding Cross-scale Attention Guidance and Noise-sensitive Constraint for Detecting Tertiary Lymphoid Structures of Pancreatic Tumors.
The presence of tertiary lymphoid structures (TLSs) on pancreatic pathological images is an important prognostic indicator of pancreatic tumors. Therefore, TLSs detection on pancreatic pathological images plays a crucial role in diagnosis and treatment for patients with pancreatic tumors. However, fully supervised detection algorithms based on deep learning usually require a large number of manual annotations, which is time-consuming and labor-intensive. In this paper, we aim to detect the TLSs in a manner of few-shot learning by proposing a weakly supervised segmentation network. We firstly obtain the lymphocyte density maps by combining a pretrained model for nuclei segmentation and a domain adversarial network for lymphocyte nuclei recognition. Then, we establish a cross-scale attention guidance mechanism by jointly learning the coarse-scale features from the original histopathology images and fine-scale features from our designed lymphocyte density attention. A noise-sensitive constraint is introduced by an embedding signed distance function loss in the training procedure to reduce tiny prediction errors. Experimental results on two collected datasets demonstrate that our proposed method significantly outperforms the state-of-the-art segmentation-based algorithms in terms of TLSs detection accuracy. Additionally, we apply our method to study the congruent relationship between the density of TLSs and peripancreatic vascular invasion and obtain some clinically statistical results.


Mediators of anaphylaxis but not activated neutrophils augment cholinergic responses of equine small airways.
Neutrophilic inflammation in small airways (SA) and bronchospasm mediated via muscarinic receptors are features of chronic obstructive pulmonary disease in horses (COPD). Histamine, serotonin, and leukotrienes (LTs) are reported to be involved in the exacerbation of COPD, and currently, histamine has been shown to increase tension response to electrical field simulation (EFS) in equine SA. We tested the effects of these mediators and the effects of activated neutrophils on the cholinergic responses in SA. Histamine, serotonin, and LTD4 had a synergistic effect on EFS responses and only an additive effect on the tension response to exogenous ACh or methacholine. Atropine and TTX entirely eliminated the EFS-induced tension response in the presence of all three inflammatory mediators, indicating that augmentation of the EFS response applies only to the endogenous cholinergic response. Neutrophils isolated from control and COPD-affected horses were activated by zymosan, producing 18.1 +/- 2.3 and 25.0 +/- 2.3 nmol superoxide. 10(6) cells-1. 30 min-1, respectively. However, in contrast to the profound effect of mediators, incubation of SA for over 1 h in a suspension of up to 30 x 10(6) zymosan-treated neutrophils/ml did not significantly affect EFS responses of SA isolated from either control or COPD-affected horses. We conclude that in equine SA 1) the endogenous cholinergic responses are subject to strong facilitation by inflammatory mediators; 2) activated neutrophils do not affect cholinergic responses in SA; and 3) in acute bouts of equine COPD, histamine, LTD4, and serotonin (mediators primarily associated with type I allergic reaction) rather than mediators derived from neutrophils most likely contribute to increased cholinergic airway tone.


Preparation and characterization of a novel thermosensitive nanoparticle for drug delivery in combined hyperthermia and chemotherapy.
In the present research, a novel thermal sensitive amphiphilic polymer was synthesized by modification of chitosan with hydrophilic hydroxybutyl groups and hydrophobic deoxycholic acid moieties. By finetuning the hydrophobic/hydrophilic balance of deoxycholic acid decorated hydroxybutyl chitosan (DAHBC), the lower critical solution temperature (LCST) of this novel polymer could be adjusted to 38.2 °C, which is an appropriate temperature in hyperthermia therapy. The polymer could self-assemble into approximately spherical nanoparticles in aqueous solutions with an average diameter of 399.6 nm and a zeta potential value of -33.8 mV. The controlled release properties of the thermosensitive drug delivery system were evaluated by using doxorubicin (DOX) as a model drug. Compared with the drug release behavior at a temperature below the LCST, the release of doxorubicin was significantly accelerated when the nanoparticles were in an environmental temperature above the LCST of the polymer. According to the results of MTT assays, blank DAHBC nanoparticles showed no significant toxicity on mouse embryo fibroblasts at a concentration as high as 1 mg ml-1, and DOX-loaded nanocarriers exhibited an improved drug uptake by MCF-7 cells with the incubation temperature rising from 37 °C to 43 °C, which indicated that thermoresponsive and biocompatible DAHBC nanoparticles might have practical applications as drug carriers in combined hyperthermia and chemotherapy.


Glycopeptide export from mammalian microsomes is independent of calcium and is distinct from oligosaccharide export.
Glycopeptides are exported from the endoplasmic reticulum to the cytosol of eukaryotic membranes in an ATP- and cytosol-requiring process (Romisch and Ali, 1997, Proc. Natl. Acad. Sci. USA,94, 6730-6734). Oligosaccharides of the polymannose-type are also exported from the endoplasmic reticulum of mammalian cells to the cytosol in an ATP-dependent fashion. These findings raise the strong possibility that the two substrate classes are transported by the same mechanism but the precise identity of the trans-location machinery for each substrate class has not been fully defined. Here we have investigated the mechanism by which a glycopeptide is exported from rat liver microsomes, and compare this to the export of free polymannose oligosaccharides. Using EGTA and the endoplasmic reticulum calcium mobilizing agents thapsigargicin and calcium ionophores A23187 and ionomycin, we show that glycopeptides, in contrast to oligosaccharides, are exported by a calcium-independent mechanism. On the other hand, Mg(2+)is required in the assay for the transport of glycopeptide from mammalian microsomes which is in common with oligosaccharide export. Deoxynojirimycin and castanospermine, inhibitors of ER glucosidases, when added to rat liver microsomes prior to loading with peptide that bears an N -glycosylation sequon, had no effect on the release of glucosylated glycopeptides from membranes, indicating that removal of the alpha-glucose units from the oligomannose glycan structure of the glycopeptide is not required for export. In contrast to oligosaccharides, where transport is efficiently inhibited, mannosides were without effect or only weak inhibitors of glycopeptide export. Taken together, these data suggest that glycopeptides are exported by a distinct mechanism from oligosaccharides of the polymannose-type and that the peptide moiety is an important structural determinant for glycopeptide export and capable of directing translocation of substrates to a specific transport pathway.


Heritability of refractive error and familial aggregation of myopia in an elderly American population.
To determine the heritability of refractive error and the familial aggregation of myopia in an older population. Seven hundred fifty-nine siblings (mean age, 73.4 years) in 241 families were recruited from the Salisbury Eye Evaluation (SEE) Study in eastern Maryland. Refractive error was determined by noncycloplegic subjective refraction (if presenting distance visual acuity was < or =20/40) or lensometry (if best corrected visual acuity was >20/40 with spectacles). Participants were considered plano (refractive error of zero) if uncorrected visual acuity was >20/40. Preoperative refraction from medical records was used for pseudophakic subjects. Heritability of refractive error was calculated with multivariate linear regression and was estimated as twice the residual between-sibling correlation after adjusting for age, gender, and race. Logistic regression models were used to estimate the odds ratio (OR) of myopia, given a myopic sibling relative to having a nonmyopic sibling. The estimated heritability of refractive error was 61% (95% confidence interval [CI]: 34%-88%) in this population. The age-, race-, and sex-adjusted ORs of myopia were 2.65 (95% CI: 1.67-4.19), 2.25 (95% CI: 1.31-3.87), 3.00 (95% CI: 1.56-5.79), and 2.98 (95% CI: 1.51-5.87) for myopia thresholds of -0.50, -1.00, -1.50, and -2.00 D, respectively. Neither race nor gender was significantly associated with an increased risk of myopia. Refractive error and myopia are highly heritable in this elderly population.


Carbon allocation to root exudates is maintained in mature temperate tree species under drought.
Carbon (C) exuded via roots is proposed to increase under drought and facilitate important ecosystem functions. However, it is unknown how exudate quantities relate to the total C budget of a drought-stressed tree, that is, how much of net-C assimilation is allocated to exudation at the tree level. We calculated the proportion of daily C assimilation allocated to root exudation during early summer by collecting root exudates from mature Fagus sylvatica and Picea abies exposed to experimental drought, and combining above- and belowground C fluxes with leaf, stem and fine-root surface area. Exudation from individual roots increased exponentially with decreasing soil moisture, with the highest increase at the wilting point. Despite c. 50% reduced C assimilation under drought, exudation from fine-root systems was maintained and trees exuded 1.0% (F. sylvatica) to 2.5% (P. abies) of net C into the rhizosphere, increasing the proportion of C allocation to exudates two- to three-fold. Water-limited P. abies released two-thirds of its exudate C into the surface soil, whereas in droughted F. sylvatica it was only one-third. Across the entire root system, droughted trees maintained exudation similar to controls, suggesting drought-imposed belowground C investment, which could be beneficial for ecosystem resilience.


Handling of ammonium by the renal proximal tubule during acute metabolic acidosis.
The present studies were designed to assess the handling of ammonium (NH+4) by the proximal tubule during acute metabolic acidosis (AMA). After tubule fluid collections were obtained with micropuncture techniques and in situ pH was determined near the end of the proximal tubule, 0.2 N HCl was infused intravenously at 17 microliter X min-1 X 100 g body wt-1. Thirty to sixty minutes later, samples were obtained and pH measurements were made near the previous micropuncture sites. During AMA, urine pH fell and total acid excretion doubled due to an increase in NH+4 excretion from 581 +/- 63 to 1,153 +/- 61 nmol X min-1 X g kidney wt-1 (P less than 0.001). Acid excretion did not change in time controls. Tubule fluid NH+4 rose from 2.17 +/- 0.15 to 3.45 +/- 0.24 mM during acid infusion (P less than 0.001) and its delivery to the end of the proximal tubule nearly doubled (67.8 +/- 6.3 vs. 33.9 +/- 2.9 pmol X min X g kidney wt-1 before acid infusion, P less than 0.001). This increase in delivery during AMA was due to enhanced ammonia (NH3) entry into the proximal tubule. In situ pH determined near the end of the proximal tubule averaged 6.94 +/- 0.04 before acid infusion and did not change afterwards (6.87 +/- 0.05). These data are consistent with the hypothesis that in AMA the increase in NH+4 excretion is due primarily to an increase in the cortical production of NH3.


Are standard doses of piperacillin sufficient for critically ill patients with augmented creatinine clearance?
The aim of this study was to explore the impact of augmented creatinine clearance and differing minimum inhibitory concentrations (MIC) on piperacillin pharmacokinetic/pharmacodynamic (PK/PD) target attainment (time above MIC (fT>MIC)) in critically ill patients with sepsis receiving intermittent dosing. To be eligible for enrolment, critically ill patients with sepsis had to be receiving piperacillin-tazobactam 4.5 g intravenously (IV) by intermittent infusion every 6 hours for presumed or confirmed nosocomial infection without significant renal impairment (defined by a plasma creatinine concentration greater than 171 μmol/L or the need for renal replacement therapy). Over a single dosing interval, blood samples were drawn to determine unbound plasma piperacillin concentrations. Renal function was assessed by measuring creatinine clearance (CLCR). A population PK model was constructed, and the probability of target attainment (PTA) for 50% and 100% fT>MIC was calculated for varying MIC and CLCR values. In total, 48 patients provided data. Increasing CLCR values were associated with lower trough plasma piperacillin concentrations (P < 0.01), such that with an MIC of 16 mg/L, 100% fT>MIC would be achieved in only one-third (n = 16) of patients. Mean piperacillin clearance was approximately 1.5-fold higher than in healthy volunteers and correlated with CLCR (r = 0.58, P < 0.01). A reduced PTA for all MIC values, when targeting either 50% or 100% fT>MIC, was noted with increasing CLCR measures. Standard intermittent piperacillin-tazobactam dosing is unlikely to achieve optimal piperacillin exposures in a significant proportion of critically ill patients with sepsis, owing to elevated drug clearance. These data suggest that CLCR can be employed as a useful tool to determine whether piperacillin PK/PD target attainment is likely with a range of MIC values.


[Importance of cytological study in the diagnosis of phyllode tumor, sarcoma and carcinosarcoma of the breast].
The paper deals with the results of application of clinical, cytologic and complex clinico-cytologic procedures of diagnosis of fibroadenoma phylloides mammae (160), sarcoma developing from libroadenoma phylloides (17), carcinosarcoma (5) and stromal or primary sarcoma (7). All the cases were treated at the Institute in 1960-1980. The difficulties involved in clinical diagnosis of these tumors are discussed. Correct clinical diagnosis was made only in 17% whereas benign and malignant tumors were identified in 94.7%. Cytological examination serves to improve the differential diagnosis between such neoplasms. Due to its application, the histological pattern of tumor was established in 30.6% and the benign or malignant nature of tumor--in 81.5%. When a complex clinico-cytologic examination was conducted diagnosis was improved in nearly half the cases (44.9%).


Equine colitis "X", still an enigma?
Colitis "X" is a sporadic diarrheal disease of horses with clinical signs of dehydration, electrolyte imbalances and "shock"-like features. Macroscopic and microscopic findings include signs of disseminated intravascular coagulation, necrosis of colonic mucosa and presence of large numbers of bacteria in the devitalized parts of the intestine. Recently published work suggests that the causative agent may be Clostridium perfringens, Type A, but the bacteria are recoverable only in the preliminary stages of the disease. Excess protein and lack of cellulose content in the diet is thought to be the trigger for the multiplication of the clostridial organisms. The pathological findings are pathognomonic, but clinically, a number of differential diagnoses have to be considered, such as intestinal accidents, salmonellosis, heavy metal intoxication and occlusive verminous arteritis.