Recognition of patients with cardiovascular disease by artificial neural networks.
Artificial neural networks (ANNs) are computer algorithms inspired by the highly interactive processing of the human brain. When exposed to complex data sets, ANNs can learn the mechanisms that correlate different variables and perform complex classification tasks. A database, of 949 patients and 54 variables, was analysed to evaluate the capacity of ANNs to recognise patients with (VE+, n = 196) or without (VE-, n = 753) a history of vascular events on the basis of vascular risk factors (VRFs), carotid ultrasound variables (UVs) or both. The performance of ANN was assessed by calculating the percentage of correct identifications of VE+ and VE- patients (sensitivity and specificity, respectively) and the prediction accuracy (weighted mean between sensitivity and specificity). The results showed that ANNs can be trained to identify VE+ and VE- subjects more accurately than discriminant analyses. When VRFs and UVs were used as input variables, the prediction accuracies of the ANN providing the best results were 80.8% and 79.2%, respectively. The addition of gender, age, weight, height and body mass index to UVs increased accuracy of prediction to 83.0%. When the ANNs were allowed to choose the relevant input data automatically (I.S. system-Semeion), 37 variables were selected among 54, five of which were UVs. Using this set of variables as input data, the performance of the ANNs in the classification task reached a prediction accuracy of 85.0%. with the 92.0% correct classification of VE+ patients. Artificial neural network technology is highly promising in the development of accurate diagnostic tools designed to recognize patients at high risk of cardiovascular diseases.


Active site mapping of amylo-alpha-1,6-glucosidase in porcine liver glycogen debranching enzyme using fluorogenic 6-O-alpha-glucosyl-maltooligosaccharides.
Glycogen debranching enzyme (GDE) has two enzymatic activities, 4-alpha-glucanotransferase and amylo-alpha-1,6-glucosidase. Products with 6-O-alpha-glucosyl structures formed from phosphorylase limit dextrin by the 4-alpha-glucanotransferase activity are hydrolyzed to glucose by the amylo-alpha-1,6-glucosidase activity. Here, we probed the active site of amylo-alpha-1,6-glucosidase in porcine liver GDE using various 6-O-alpha-glucosyl-pyridylamino (PA)-maltooligosaccharides, with structures (Glcalpha1-4)(m)(Glcalpha1-6)Glcalpha1-4(Glcalpha1-4)(n)GlcPA (GlcPA, 1-deoxy-1-[(2-pyridyl)amino]-D-glucitol residue). Fluorogenic dextrins were prepared from 6-O-alpha-glucosyl-alpha-, beta-, or gamma-cyclodextrin through partial acid hydrolysis, followed by fluorescent tagging of the reducing-end residues of the hydrolysates and separation by gel filtration and reversed-phase HPLC. Porcine liver GDE hydrolyzed dextrins with the structure Glcalpha1-4(Glcalpha1-6)Glcalpha1-4Glc to glucose and the corresponding PA-maltooligosaccharides, whereas other dextrins were not hydrolyzed. Thus, substrates must have two glucosyl residues sandwiching the isomaltosyl moiety to be hydrolyzed. The rate of hydrolysis increased as m increased and reached maximum at m = 4. The rates were the highest when n = 1 but did not vary much with changes in n. Of the dextrins examined, Glcalpha1-4Glcalpha1-4Glcalpha1-4Glcalpha1-4(Glcalpha1-6)Glcalpha1-4Glcalpha1-4GlcPA (6(3)-O-alpha-glucosyl-PA-maltoheptaose) was hydrolyzed most rapidly, suggesting that it fits the best in the amylo-alpha-1,6-glucosidase active site. It is likely that the active site accommodates 6(2)-O-alpha-glucosyl-maltohexaose and that the interactions of seven glucosyl residues with the active site allow the most rapid hydrolysis of the alpha-1,6-glucosidic linkage of the isomaltosyl moiety.


Live-Birth Rate Associated With Repeat In Vitro Fertilization Treatment Cycles.
The likelihood of achieving a live birth with repeat in vitro fertilization (IVF) is unclear, yet treatment is commonly limited to 3 or 4 embryo transfers. To determine the live-birth rate per initiated ovarian stimulation IVF cycle and with repeated cycles. Prospective study of 156,947 UK women who received 257,398 IVF ovarian stimulation cycles between 2003 and 2010 and were followed up until June 2012. In vitro fertilization, with a cycle defined as an episode of ovarian stimulation and all subsequent separate fresh and frozen embryo transfers. Live-birth rate per IVF cycle and the cumulative live-birth rates across all cycles in all women and by age and treatment type. Optimal, prognosis-adjusted, and conservative cumulative live-birth rates were estimated, reflecting 0%, 30%, and 100%, respectively, of women who discontinued due to poor prognosis and having a live-birth rate of 0 had they continued. Among the 156,947 women, the median age at start of treatment was 35 years (interquartile range, 32-38; range, 18-55), and the median duration of infertility for all 257,398 cycles was 4 years (interquartile range, 2-6; range, <1-29). In all women, the live-birth rate for the first cycle was 29.5% (95% CI, 29.3%-29.7%). This remained above 20% up to and including the fourth cycle. The cumulative prognosis-adjusted live-birth rate across all cycles continued to increase up to the ninth cycle, with 65.3% (95% CI, 64.8%-65.8%) of women achieving a live birth by the sixth cycle. In women younger than 40 years using their own oocytes, the live-birth rate for the first cycle was 32.3% (95% CI, 32.0%-32.5%) and remained above 20% up to and including the fourth cycle. Six cycles achieved a cumulative prognosis-adjusted live-birth rate of 68.4% (95% CI, 67.8%-68.9%). For women aged 40 to 42 years, the live-birth rate for the first cycle was 12.3% (95% CI, 11.8%-12.8%), with 6 cycles achieving a cumulative prognosis-adjusted live-birth rate of 31.5% (95% CI, 29.7%-33.3%). For women older than 42 years, all rates within each cycle were less than 4%. No age differential was observed among women using donor oocytes. Rates were lower for women with untreated male partner-related infertility compared with those with any other cause, but treatment with either intracytoplasmic sperm injection or sperm donation removed this difference. Among women in the United Kingdom undergoing IVF, the cumulative prognosis-adjusted live-birth rate after 6 cycles was 65.3%, with variations by age and treatment type. These findings support the efficacy of extending the number of IVF cycles beyond 3 or 4.


Starvation proteins in Escherichia coli: kinetics of synthesis and role in starvation survival.
Starvation proteins synthesized by Escherichia coli at the onset of carbon starvation (R. G. Groat and A. Matin, J. Indust. Microbiol. 1:69-73, 1986) exhibited four temporal classes of synthesis in response to glucose or succinate starvation, indicating sequential expression of carbon starvation response (cst) genes. A cst mutant of E. coli showed greatly impaired carbon starvation survival. Thus, it appears that E. coli undergoes a significant molecular realignment in response to starvation, which increases its resistance to this stress. New polypeptides were also synthesized by E. coli in response to phosphate or nitrogen starvation. Some of these polypeptides were unique to a given starvation regimen, but at least 13 appeared to be synthesized regardless of the nutrient deprivation causing the starvation.


Dynamics of an ultrasonic transducer used for wire bonding.
The vibration displacement distributions along a transducer used in ultrasonic wire bonding were measured using a heterodyne interferometer, and many nodes and anti-nodes were found. A mechanical finite element method (FEM) was used to compute the resonant frequencies and vibration mode shapes. The displacement distributions of the dominant 2nd axial mode agreed well with the measured values. Undesirable nonaxial modes, including the higher order flexural and torsional modes, also were excited at frequencies very close to the working frequency (2nd axial mode) of the transducer. Hence, the measured displacements were the resultant of all the allowable modes being excited. However, the excitation of these nonaxial modes were small enough not to affect the formation of consistent and high quality wire bonds. Results of the present study were used to determine a suitable location for installing a piezoelectric sensor to monitor the bond quality.


Intraspecific DNA contamination distorts subtle population structure in a marine fish: Decontamination of herring samples before restriction-site associated sequencing and its effects on population genetic statistics.
Wild specimens are often collected in challenging field conditions, where samples may be contaminated with the DNA of conspecific individuals. This contamination can result in false genotype calls, which are difficult to detect, but may also cause inaccurate estimates of heterozygosity, allele frequencies and genetic differentiation. Marine broadcast spawners are especially problematic, because population genetic differentiation is low and samples are often collected in bulk and sometimes from active spawning aggregations. Here, we used contaminated and clean Pacific herring (Clupea pallasi) samples to test (a) the efficacy of bleach decontamination, (b) the effect of decontamination on RAD genotypes and (c) the consequences of contaminated samples on population genetic analyses. We collected fin tissue samples from actively spawning (and thus contaminated) wild herring and nonspawning (uncontaminated) herring. Samples were soaked for 10 min in bleach or left untreated, and extracted DNA was used to prepare DNA libraries using a restriction site-associated DNA (RAD) approach. Our results demonstrate that intraspecific DNA contamination affects patterns of individual and population variability, causes an excess of heterozygotes and biases estimates of population structure. Bleach decontamination was effective at removing intraspecific DNA contamination and compatible with RAD sequencing, producing high-quality sequences, reproducible genotypes and low levels of missing data. Although sperm contamination may be specific to broadcast spawners, intraspecific contamination of samples may be common and difficult to detect from high-throughput sequencing data and can impact downstream analyses.


Prompting Paramedics: The Effect of Simulation on Paramedics' Identification of Learning Objectives.
Simulation has emerged as a useful educational tool for the continued training of paramedics. Practicing paramedics are thought to learn through reflecting on their own actions in practice, and it is hoped that simulation could spur similar reflection, which could then lead to practice change. Despite this, there is limited data on how these practitioners use simulated experiences to set learning objectives. This study aimed to explore how simulation training affects self-identification of learning objectives in emergency medical services (EMS) providers (a.k.a. paramedics). Paramedics (primary care and advanced care) participated in a 30-minute simulated learning session. All participants filled out pre-post surveys identifying their own learning objectives immediately before and after the simulation. An inductive qualitative analysis of these responses were conducted by two authors (EJ, TC) using an interpretive description approach, yielding a list of key themes commonly found in the learning objectives. Pre-post learning objectives were individually compared by the level of specificity as determined by the authorship team. Simple descriptive statistics were generated to describe the number of times that the paramedics' learning objectives became more or less specific, different, or same. Thirty-five paramedics who completed the simulation and survey were included. Four major themes emerged in the learning objectives: 1) assessment and diagnostic; 2) communication and collaboration; 3) integration of knowledge; and 4) treatment and management. After simulation, the learning objectives became more specific in 6 (17.1%), less specific in 3 (8.6%), different in 22 (62.9%), and remained same in 4 (11.4%). Simulation training shows promise in refining perceived learning needs. The results from this study offer insight into paramedics' self-identification of learning objectives and gaps pre-post simulation experiences. Understanding the underlying psychology of paramedics participating in simulation may help educators better understand how to guide reflection and continuous improvement.


The effect of upper eyelid blepharoplasty on eyebrow position.
Although upper eyelid blepharoplasty is one of the most frequently performed facial plastic surgical procedures, there is no consensus of opinion about the effect of an upper eyelid blepharoplasty on the position of the eyebrows in a general population. This study was undertaken to determine this effect and to investigate whether preoperative compensatory rhytidosis of the forehead may cause a significantly greater postoperative lowering of the eyebrows. An evaluation of 140 consecutive patients with complaints of visual impairment was performed, who underwent an upper eyelid blepharoplasty. The position of the eyebrows was measured pre- and postoperatively at three positions for each eye. In addition, the role of compensatory rhytidosis on eyebrow position was determined by classifying horizontal forehead lines. The mean drop in eyebrow position for all patients ranged from 0.35% to 1.23%. In females (n = 126), there was no significant postoperative drop in eyebrow position. In males (n = 14), however, one out of six measured distances (centre of pupil, lateral iris and lateral canthus) displayed a significant lowering of the eyebrow (p = 0.005). Our results show that the position of the eyebrow is not lowered significantly after an upper eyelid blepharoplasty performed among women with dermatochalasis and functional complaints of visual impairment. Male patients showed a slight trend of lowering of the eyebrows postoperatively. Preoperative lifting of the eyebrows by means of frontalis muscle activity did not influence the position of the eyebrows postoperatively, although forehead lines did seem to diminish significantly.


Physiological responses of young cross-bred calves immediately after long-haul road transportation and after one week of habituation.
We investigated 10 suckling cross-bred calves (Japanese Black (Wagyu) x Holstein) and collected data on the physiological stress responses of the young calves to long-haul road transportation. All calves were male and 21-47 days of age. The calves were obtained at a livestock market and were transported from the market to the university in a commercial livestock vehicle. The total haul distance and time were 306.9 km and 7 h, respectively. The calves were deprived of food and water during transportation. Blood samples, electrocardiograms, and rectal temperatures were collected immediately after transportation and after one week of habituation at the university. Serum pH was significantly lower (P < 0.01), while serum triiodothyronine, aspartate aminotransferase, non-esterified fatty acids (all P < 0.05), and heart rate (P < 0.01) were significantly higher immediately after transportation. The concentrations of blood lactic acid (P = 0.08) and serum alanine aminotransferase (P = 0.06) tended to be higher after transportation. These physiological responses suggest that the stress caused by long-haul transportation causes significant effects on liver function in young calves.


[From guidelines for screening to their (poor) implementation: the case of the abdominal aortic aneurysm].
Following the evidence of benefits of ultrasound screening for abdominal aorta aneurysms (AAA), several guidelines support this screening in population. Beyond the prompt diagnosis of AAA prior to its rupture of grim vital prognosis, small AAA can beconsidered as a prognostic marker for cardiovascular diseases (CVD). Yet, its detection is an opportunity for secondary prevention to reduce CVD mortality. Despite, these guidelines are poorly applied: systematic screening campaigns are infrequent, making the screening of family physicians responsibility. While the major benefit from this screening strategy is to reduce AAA-related death (but only trivial effect on long-term total mortality), this explains only partially the lack of guidelines implementation. The reasons of the poor implementation of these guidelines are discussed herein.


Annular versus supra-annular sizing for TAVI in bicuspid aortic valve stenosis.
We sought to compare annular versus supra-annular sizing for transcatheter aortic valve implantation (TAVI) in patients with a bicuspid aortic valve (BAV). In this retrospective single-centre analysis, we measured the aortic annulus (Ann) and intercommissural distance (ICD) on multidetector computed tomography scans in 217 BAV patients. With annular sizing being the default method for prosthesis size selection in all cases, we determined clinically relevant sizing errors and assessed the hypothetical impact of supra-annular sizing. Overall there was no significant difference between ICD and Ann (25.1 [23.5; 27.3] vs. 25.4 [23.6; 27.1] mm; p=0.24); intra-individually, ICD was similar to Ann in 26.7%, smaller in 40.1%, and larger in 33.2%. Annular sizing was appropriate in 96.3%, oversized in 0.5%, and undersized in 3.2% of cases. Supra-annular sizing would have resulted in a divergent size selection in 38.7% (smaller: 17.5%, larger: 19.8%, ICD out of range for TAVI prostheses: 1.4%) with potential improvement in a few cases with annular sizing errors, but potential worsening due to improper size selection in a much larger proportion of patients. Annular sizing for TAVI in BAV is feasible and safe. The added value of supra-annular sizing is questionable.


DNA damage repair pathways in cancer stem cells.
The discovery of tumor-initiating cells endowed with stem-like features has added a further level of complexity to the pathobiology of neoplastic diseases. In the attempt of dissecting the functional properties of this uncommon cellular subpopulation, investigators are taking full advantage of a body of knowledge about adult stem cells, as the "cancer stem cell model" implies that tissue-resident stem cells are the target of the oncogenic process. It is emerging that a plethora of molecular mechanisms protect cancer stem cells (CSC) against chemotherapy- and radiotherapy-induced death stimuli. The ability of CSCs to survive stressful conditions is correlated, among others, with a multifaceted protection of genome integrity by a prompt activation of the DNA damage sensor and repair machinery. Nevertheless, many molecular-targeted agents directed against DNA repair effectors are in late preclinical or clinical development while the identification of predictive biomarkers of response coupled with the validation of robust assays for assessing biomarkers is paving the way for biology-driven clinical trials.


Optical coupling and emission of metal-insulator confined circular resonators.
We numerically investigate the direct and indirect optical interactions of pair circular resonators laterally confined by metal-insulator waveguide. The direct optical interaction shows the split of quality (Q) factors of bonding and antibonding states only happens for thick insulator. The indirect optical interaction through a waveguide is proposed to control the modes resonance and collect the output emissions. The Q factors of resonant modes versus the coupling distance (width of waveguide) are studied. The results show whispering gallery modes(WGMs) engaged into interaction are strongly coupled with the guided waves of waveguide once its width is close to the cut-off width of guided waves, while the coupled mode of two WGMs is not limited by this condition. High Q factor mode, combined with a robust wide emission waveguide(close to the cut-off width of second-order guided waves), can be realized from the bonding states of WGM and coupled WGM with an added wave envelope in waveguide. In addition to the pair resonators, the studies on four resonators interacted with each other through waveguide are also addressed and wide waveguide output is anticipated.


Interactions of platelets and leukocytes with vascular endothelium: in vitro studies.
Our studies suggest that the interactions of blood cells with cultured endothelial monolayers mimic in vivo phenomena, thus providing potentially useful in vitro experimental models. For example, normal endothelial cells in culture show little tendency to react with platelets, similar to their behavior in vivo. Production of anti-aggregatory prostaglandins, such as prostacyclin, by cultured endothelial cells does not appear to be necessary for their non-thrombogenicity. Significant changes in platelet reactivity can be observed when endothelial cells are altered by certain stimuli. Analogous alterations in vivo might constitute a form of endothelial dysfunction relevant to thrombosis and atherosclerosis. In contrast to platelets, PMN leukocytes appear to show a preferential adherence to cultured endothelial monolayers. As our data indicate, this basal adhesion, which is observed in the absence of exogenous chemotactic agents or other stimuli, is neither dependent upon endogenous cyclooxygenase derivatives of arachidonate, nor inhibited by exogenous prostacyclin. However, certain anti-inflammatory drugs and other agents, that can interfere with the metabolism of arachidonate via lipoxygenase pathways, do significantly reduce basal PMN leukocyte-endothelial interactions. Further definition of the cellular and biochemical sites of action of these compounds may provide new insights into the mechanisms of the inflammatory response. Finally, given the vast repertoire of biologically active substances that platelets and leukocytes can secrete or generate, the regulation of blood cell interaction with endothelium may represent a key locus for pharmacological intervention in the treatment and prevention of vascular diseases.


Eyelid lesions: incidence and comparison of benign and malignant lesions.
A retrospective study was undertaken to determine the relative incidence of all eyelid lesions (720 cases) submitted to the Wills ophthalmic pathology laboratory between July 1, 1980, and June 30, 1982. Data on age, sex, location, and diagnostic accuracy were also tabulated. One hundred twenty-five (17.4%) malignant lesions were found. The most common lesion of the eyelid was basal cell carcinoma, which represented 14.3% of the total and 82.4% of the malignant lesions. Differences between malignant and benign lesions were searched for. The data suggests that lesions occurring in the upper lid are much less likely to be malignant than those occurring elsewhere. Among the 125 malignant lesions, clinicians were 92.8% accurate in predicting malignancy.


The combination of micro-resonators with spatially resolved ferromagnetic resonance.
We present two new and complementary approaches to realize spatial resolution for ferromagnetic resonance (FMR) on the 100 nm-scale. Both experimental setups utilize lithographically fabricated micro-resonators. They offer a detection sensitivity that is increased by four orders of magnitude compared with resonator-based FMR. In the first setup, the magnetic properties are thermally modulated via the thermal near-field effect generated by the thermal probe of an atomic force microscope. In combination with lock-in detection of the absorbed microwave power in the micro-resonator, a spatial resolution of less than 100 nm is achieved. The second setup is a combination of a micro-resonator with a scanning transmission x-ray microscope (STXM). Here a conventional FMR is excited by the micro-resonator while focused x-rays are used for a time-resolved snap-shot detection of the FMR excitations via the x-ray magnetic circular dichroism effect. This technique allows a lateral resolution of nominally 35 nm given by the STXM. Both experimental setups combine the advantage of low-power FMR excitation in the linear regime with high spatial resolution to study single and coupled nanomagnets. As proof-of-principle experiments, two perpendicular magnetic micro-stripes (5 μm × 1 μm) were grown and their FMR excitations were investigated using both setups.


The placebogenic phenomenon: art in psychiatric nursing.
1. Nearly half of all orders for psychotropic medications are written "as needed" (PRN); therefore, the nurse must assume a vital function in the assessment, use, and evaluation of medication. 2. Placebo agents are known to have an effectiveness rate between 30% and 50%. Nurses and other health professionals severely underestimate the magnitude of this effect. 3. The patient's perception of the medication experience, beliefs, degree of trust, expectation, and the psychosocial context in which medications are used, contribute to agent effectiveness. 4. The nurse's personal beliefs, nonverbal cues, anticipation, and interpersonal style can influence effectiveness of agents in relieving symptoms; likewise, by understanding and increasing various interpersonal skills, professionals can enhance effectiveness of psychotropic agents.


Cost-effectiveness of switching to insulin degludec from other basal insulins in real-world clinical practice in Italy.
Aims: The costs associated with insulin therapy and diabetes-related complications represent a significant and growing economic burden for healthcare systems. The aim of this study was to evaluate the cost-effectiveness of switching to insulin degludec (degludec) vs continuing previous basal insulin, in Italian patients with type 1 (T1D) or type 2 (T2D) diabetes, using a long-term economic model.Materials and methods: Data were retrieved from a real-world population of patients from clinical practice in Italy. Clinical parameters included in the base-case model were change from baseline in HbA1c, rates of hypoglycemia, and basal and bolus insulin dose, at 6 months following switch to degludec. Costs of treatments were taken from official Italian pharmaceutical list prices and costs of hypoglycemia were based on the literature. The data were used to populate a long-term (lifetime) IQVIA CORE Diabetes Model to evaluate the incremental cost-effectiveness ratio (ICER) - cost per quality-adjusted life-year (QALY). The robustness of these results was tested with extensive sensitivity analyses by varying the time horizons and abolishing each of the treatment differences and previous basal insulins.Results: The total incremental cost for degludec vs previous basal insulin was €-6,310 and €-2,682 for patients with T1D and T2D, respectively; the switch to degludec resulted in a QALY gain of 0.781 and 0.628. The long-term ICER for degludec vs continuing the previous basal insulin regimen showed that degludec was dominant for both T1D and T2D, meaning that patient health was improved in terms of QALYs with lower healthcare costs. Sensitivity analyses showed that degludec remained dominant in most scenarios including after elimination of any benefit in non-severe hypoglycemia and insulin dose, in both T1D and T2D.Conclusions: Under routine care, switching to degludec is dominant, compared with continuing previous basal insulin, in Italian patients with T1D or T2D.


Cholera in the United States, 2001-2011: a reflection of patterns of global epidemiology and travel.
US cholera surveillance offers insight into global and domestic trends. Between 2001 and 2011, 111 cases were reported to the Centers for Disease Control and Prevention. Cholera was associated with international travel in 90 (81%) patients and was domestically acquired in 20 (18%) patients; for one patient, information was not available. From January 2001 to October 2010, the 42 (47%) travel-associated cases were associated with travel to Asia. In October 2010, a cholera epidemic started in Haiti, soon spreading to the Dominican Republic (Hispaniola). From then to December 2011, 40 (83%) of the 48 travel-associated cases were associated with travel to Hispaniola. Of 20 patients who acquired cholera domestically, 17 (85%) reported seafood consumption; 10 (59%) ate seafood from the US Gulf Coast. In summary, an increase in travel-associated US cholera cases was associated with epidemic cholera in Hispaniola in 2010-2011. Travel to Asia and consumption of Gulf Coast seafood remained important sources of US cholera cases.


Patient specific pre-treatment QA verification using an EPID approach.
A software program [MU-EPID], has been developed to perform patient specific pre-treatment quality assurance (QA) verification for intensity modulated radiation therapy (IMRT) using fluence maps measured with an electronic portal imaging device (EPID). The software converts the EPID acquired images of each IMRT beam, to fluence maps that are equivalent to those calculated by the treatment planning system (TPS). The software has the capability to process Varian, Elekta and Siemens EPID DICOM images. In the present investigation, several IMRT plans for different treatment sites were used to validate the software using the Varian a-Si 1000 EPID with the Pinnacle TPS. A total of 20 IMRT plans of different treatment sites were analyzed. Isodose distributions, dose profiles, dose volume histograms (DVH's) and gamma analysis comparisons were performed to evaluate the accuracy of our method. A gamma index analysis of the isocenter coronal plane was done for each plan and showed an average of 97.44% of gamma passing rate using a 3% and 3 mm gamma criterion. Isodose, DVH and dose profile comparisons were conducted between the original calculated plan and the measured reconstructed plan from the EPID images processed through the MU-EPID software. The results suggest that MU-EPID can be used clinically for patient specific IMRT QA, providing a comprehensive 3D dosimetric evaluation through DVH comparison as well as an option for a 2D gamma analysis.


Effects of calmodulin antagonists and cytochalasins on proliferation and differentiation of human promyelocytic leukemia cell line HL-60.
To identify the possible roles of Ca2+-related proteins, calmodulin and microfilaments in leukemic cells, we tested the effect of calmodulin antagonists and cytochalasins on proliferation and differentiation of human promyelocytic leukemic HL-60 cells. The growth of HL-60 was inhibited by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide, N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide, and trifluoperazine dihydrochloride. In contrast, the 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]-induced differentiation of HL-60, as judged by plasma-membrane antigenic changes detected by monoclonal antibodies (OKM1, OKT9), nitroblue tetrazolium reduction, and induction of phagocytotic capacity, was not inhibited by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide or N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide, although phagocytosis was depressed by N-(6-amino-hexyl)-5-chloro-1-naphthalenesulfonamide or N-(4-aminobutyl)-5-chloro-2-naphthalenesulfonamide. Trifluoperazine dihydrochloride also failed to inhibit the antigenic change induced by 1,25-(OH)2D3. Cytochalasins B and D, microfilament-disrupting agents, inhibited the cytoplasmic division and the growth of HL-60 but did not inhibit the 1,25-(OH)2D3-induced differentiation. These findings suggest that the calmodulin- and microfilament-dependent process may be involved in the proliferation of HL-60, but not in the differentiation induced by 1,25-(OH)2D3.


POLD1 Germline Mutations in Patients Initially Diagnosed with Werner Syndrome.
Segmental progeroid syndromes are rare, heterogeneous disorders characterized by signs of premature aging affecting more than one tissue or organ. A prototypic example is the Werner syndrome (WS), caused by biallelic germline mutations in the Werner helicase gene (WRN). While heterozygous lamin A/C (LMNA) mutations are found in a few nonclassical cases of WS, another 10%-15% of patients initially diagnosed with WS do not have mutations in WRN or LMNA. Germline POLD1 mutations were recently reported in five patients with another segmental progeroid disorder: mandibular hypoplasia, deafness, progeroid features syndrome. Here, we describe eight additional patients with heterozygous POLD1 mutations, thereby substantially expanding the characterization of this new example of segmental progeroid disorders. First, we identified POLD1 mutations in patients initially diagnosed with WS. Second, we describe POLD1 mutation carriers without clinically relevant hearing impairment or mandibular underdevelopment, both previously thought to represent obligate diagnostic features. These patients also exhibit a lower incidence of metabolic abnormalities and joint contractures. Third, we document postnatal short stature and premature greying/loss of hair in POLD1 mutation carriers. We conclude that POLD1 germline mutations can result in a variably expressed and probably underdiagnosed segmental progeroid syndrome.


Preferences regarding targeted education and risk assessment in people with a family history of major depressive disorder.
Genetic testing for susceptibility to major depressive disorder (MDD) is not available for clinical use at present. Given this, family history remains the best predictor for development of MDD, and family-history-based risk assessment and information about familial aspects of MDD may be useful to clients at increased risk for MDD attending for genetic counseling. This study uses a mixed-methods design to assess the information needs and preferences of people at increased familial risk for MDD. Telephone interviews were conducted with 23 individuals, who had at least one first-degree relative with MDD and were recruited through advertisements placed on depression education websites. The most preferred way to access depression information was via the internet (87 % of participants), although this preference may have been due to the internet-based recruitment method. The second most preferred dissemination strategy (56 %) was face-to-face delivery through a health professional, including genetic counselors. Individuals reported a need for information about etiology and development of MDD, reproductive decision-making, early detection of symptoms and risk-reducing strategies. Nearly all participants expressed an interest in risk assessment. The present study found evidence of a high level of interest for information targeted to people at increased familial risk for MDD. Genetic counselors are likely to be called upon increasingly to provide supportive counseling to assist clients at increased familial risk in interpreting and contextualizing such information once it becomes available.


A Preclinical Systematic Review of Ginsenoside-Rg1 in Experimental Parkinson's Disease.
To date, no drug has been proven to be neuroprotective or disease-modifying for Parkinson's disease (PD) in clinical trials. Here, we aimed to assess preclinical evidence of Ginsenosides-Rg1 (G-Rg1), a potential neuroprotectant, for experimental PD and its possible mechanisms. Eligible studies were identified by searching six electronic databases from their inception to August 2016. Twenty-five eligible studies involving 516 animals were identified. The quality score of these studies ranged from 3 to 7. Compared with the control group, two out of the 12 studies of MPTP-induced PD showed significant effects of G-Rg1 for improving the rotarod test (P < 0.01), two studies for improving the swim-score values (P < 0.01), six studies for improving the level of TH protein expression (P < 0.01), and two studies for increasing the expression of TH mRNA in the substantia nigra of mice (P < 0.01). The studies reported that G-Rg1 exerted potential neuroprotective effects on PD model through different mechanisms as antineuroinflammatory activities (n = 10), antioxidant stress (n = 3), and antiapoptosis (n = 11). In conclusion, G-Rg1 exerted potential neuroprotective functions against PD largely by antineuroinflammatory, antioxidative, and antiapoptotic effects. G-Rg1 as a promising neuroprotectant for PD needs further confirmation by clinical trials.


Selection and characterization of a breast cancer cell line resistant to the antiestrogen LY 117018.
We have selected and cloned a stable variant of the MCF-7 human breast cancer cell line (LY 2) that is resistant to LY 117018 (LY), a potent antiestrogen that inhibits cell growth at concentrations as low as 10(-10) M. The cell line was selected by increasing the concentration of LY in the growth medium in a stepwise manner from 10(-8) to 10(-6) M as the cells become resistant. LY2 has been cloned in soft agar and carried for over 50 passages with no change in resistance. Other antiestrogens, such as tamoxifen and 40-hydroxytamoxifen no longer inhibit cell proliferation of LY 2. The cell line is still responsive to estrogen in a cell proliferation assay, but contains somewhat less estrogen receptors than MCF-7. The cytosolic estrogen receptor sediments to a 4S position on high salt sucrose density gradient centrifugation and is completely shifted to a denser gradient region when the receptor is incubated with a monoclonal antiestrophilin. The nuclear estrogen receptor when covalently labeled with [3H]tamoxifen aziridine has the same mol wt (62,000) in both MCF-7 and LY2 cells, when determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. In a competitive binding assay, LY 117018 competes for [3H]estradiol binding to its cytosol receptor with the same Ki in both MCF-7 and LY2 cells. When the induction of estrogen-specific proteins was examined, no detectable progesterone receptor could be detected in either estrogen-induced or control LY2 cells, in contrast to MCF-7 cells. However, both 52,000- and 160,000-dalton proteins were estrogen inducible in the medium of LY2 and MCF-7 cells, as measured by labeling with [35S]methionine. The phenotypic stability of the antiestrogen resistance in LY2 cells coupled with the cross-resistance the antiestrogens of widely different structures make this cell line an ideal model system for the study of hormone resistance in human breast cancer. In addition, while the mechanism of resistance is currently not elucidated, the selective loss of estrogen-inducible functions in this cell line may provide powerful clues for future study.


Breast cancer, sickness absence, income and marital status. A study on life situation 1 year prior diagnosis compared to 3 and 5 years after diagnosis.
Improved cancer survival poses important questions about future life conditions of the survivor. We examined the possible influence of a breast cancer diagnosis on subsequent working and marital status, sickness absence and income. We conducted a matched cohort study including 4,761 women 40-59 years of age and registered with primary breast cancer in a Swedish population-based clinical register during 1993-2003, and 2,3805 women without breast cancer. Information on socioeconomic standing was obtained from a social database 1 year prior and 3 and 5 years following the diagnosis. In Conditional Poisson Regression models, risk ratios (RRs) and 95% confidence intervals (CIs) were estimated to assess the impact of a breast cancer diagnosis. Three years after diagnosis, women who had had breast cancer more often had received sickness benefits (RR = 1.49, 95% CI 1.40-1.58) or disability pension (RR = 1.47, 95% CI 1.37-1.58) than had women without breast cancer. We found no effect on income (RR = 0.99), welfare payments (RR = 0.98), or marital status (RR = 1.02). A higher use of sickness benefits and disability pension was evident in all stages of the disease, although the difference in use of sickness benefits decreased after 5 years, whereas the difference in disability pension increased. For woman with early stage breast cancer, the sickness absence was higher following diagnosis among those with low education, who had undergone mastectomy, and had received chemo- or hormonal therapy. Neither tumour size nor presence of lymph nodes metastasis was associated with sickness absence after adjustment for treatment. Even in early stage breast cancer, a diagnosis negatively influences working capacity both 3 and 5 years after diagnosis, and it seems that the type of treatment received had the largest impact. A greater focus needs to be put on rehabilitation of breast cancer patients, work-place adaptations and research on long-term sequelae of treatment.


Hypothalamic-pituitary-adrenal axis responsivity during adolescence in relation to psychopathic personality traits later in life.
Psychopathic personality traits have been linked to low physiological arousal, particularly among high risk and forensic samples. A core indicator of physiological arousal is the activity of the hypothalamic-pituitary-adrenal (HPA) axis; however, findings of a link between HPA axis functioning and psychopathic personality traits have been inconsistent. Furthermore, given sex differences in both HPA axis responsivity and psychopathic personality traits, the association may be expected to differ between men and women. The aim of this study was to investigate the association between HPA axis responsivity in mid-adolescence and psychopathic personality traits in early adulthood and determine whether the association was moderated by sex. We examined this link in a general population sample of twins (N = 556). Adolescents participated in a psychosocial stress task during which samples of salivary cortisol were collected (11-15 years) and reported psychopathic personality traits using the Triarchic Psychopathy Measure (19-20 years). Multilevel linear regression models were estimated in which psychopathic personality traits (boldness, meanness and disinhibition), and their interactions with sex, were regressed on HPA axis responsivity. The study was pre-registered on the Open Science Framework (osf.io/gs2a8). Preliminary analyses showed that cortisol levels did not increase significantly during the stressor task but decreased during recovery. Results showed that there was no association between HPA axis responsivity in mid-adolescence and psychopathic personality traits in early adulthood. The associations were not moderated by sex. Findings suggest that HPA axis responsivity in mid-adolescence did not serve as a biological marker for psychopathic personality traits among young adults from the general population.


Central nervous system involvement in human immunodeficiency virus disease. A prospective study including neurological examination, computerized tomography, and magnetic resonance imaging.
Sixty-seven patients with different stages of human immunodeficiency virus (HIV) infection (47 CDC group IV, 20 CDC groups II or III) were followed prospectively for a median of 18 months with neurological examination, magnetic resonance imaging (MRI), and computerized tomography (CT) to evaluate the incidence of the AIDS dementia complex (CDC definition) and other neurological complications. Ten patients developed CNS opportunistic infection or malignancy. Among the remaining 57 patients, 12 of 37 (32%) belonging to CDC group IV, and 1 of 20 (5%) belonging to CDC groups II/III developed the AIDS dementia complex (p = 0.03). MRI white matter lesions occurred in 32% of CDC group IV patients and 5% of CDC groups II/III patients (p = 0.03). The corresponding figures for brain atrophy at CT were 71% and 30% (p less than 0.01) and for neurologic signs 49% and 20% (p = 0.06). The development of the AIDS dementia complex was significantly associated with the occurrence of MRI white matter lesions and a CD4 cell count of less than 200 x 10(6)/l, whereas it was not statistical significantly associated with brain atrophy at baseline. It is concluded that the AIDS dementia complex is a common feature of late stage HIV infection. Brain atrophy occurs in a large percentage of HIV infected patients, but the clinical significance of this atrophy is not clear.


Estimation of Acutely Ill Medical Patients at Venous Thromboembolism Risk Eligible for Extended Thromboprophylaxis Using APEX Criteria in US Hospitals.
Major medical illnesses place patients at risk of venous thromboembolism (VTE). Some risk factors including age ≥75 years or history of cancer place them at increased risk of VTE that extends for at least 5 to 6 weeks following hospital admission. Betrixaban thromboprophylaxis is now approved in the United States for this indication. We estimated the annual number of acutely ill medical patients at extended risk of VTE discharged from US hospital. Major medical illnesses (stroke, respiratory failure/chronic obstructive pulmonary disease, heart failure, pneumonia, other infections, and rheumatologic disorders) and 2 common risk factors for extended VTE risk, namely, age ≥75 years and history of cancer (active or past) were examined in 2014 US hospital discharges using the first 3 discharge diagnosis codes in the National Inpatient Sample (database of acute-care hospital discharges from the US Agency for Health Care Quality and Research). In 2014, there were 20.8 million discharges with potentially at risk of nonsurgical-related VTE. Overall, 7.2 million (35%) discharges corresponded to major medical illness that warranted thromboprophylaxis according to 2012 American College of Chest Physicians (ACCP) guideline. Among them, 2.79 million were aged ≥75 years and 1.36 million had a history of cancer (aged 40-74 years). Overall, 3.48 million discharges were at extended risk of VTE. Many medical inpatients at risk of VTE according to 2012 ACCP guideline might benefit from the awareness of continuing risk and some of these patients might benefit from extended thromboprophylaxis, depending on the risk of bleeding and comorbidities.


Computationally approximated solution for the equation for Henssge's time of death estimation.
Time of death estimation in humans for the benefit of forensic medicine has been successfully approached by Henssge, who modelled body cooling based on measurements of Marshall and Hoare. Thereby, body and ambient temperatures are measured at the death scene to estimate a time of death based on a number of assumptions, such as initial body temperature and stable ambient temperature. While so far, practical use of the method resorted to paper print outs or copies of a nomogram using a ruler, increasingly, users are interested in computer or mobile device applications. We developed a computational solution that has been available online as a web accessible PHP program since 2005. From that, we have received numerous requests not so much to detail our code but to explain how to efficiently approximate the solution to the Henssge equation. To solve Henssge's double exponential equation that models physical cooling of a body, it is sufficient to determine a difference term of the equation that will be close to zero for the correct time of death using a discrete set of all sensible possible solutions given that the modelled time frame has practical upper limits. Best post-mortem interval approximation yields minimal difference between equation terms RESULTS: The solution is approximated by solving the equation term difference for a discrete set of all possible time of death intervals that are sensibly found, and by then determining the particular time of death where equation term difference is minimal. The advantage of a computational model over the nomogram is that the user is also able to model hypothermia and hyperthermia. While mathematically impossible to solve in a straightforward way, solutions to the Henssge equation can be approximated computationally.


Short-term intubation in children with acute epiglottitis.
Management of the airway in acute epiglottitis is still controversial. One argument against intubation as opposed to tracheostomy is the increased complications from prolonged intubation. We describe a study of 26 children treated for acute epiglottitis from 1971 to 1979. Included in this series are 16 consecutive patients who were treated by nasotracheal intubation and simultaneous medical therapy. Fifteen of the 16 patients extubated safely in less than 48 hours, significantly decreasing the possibility for complications.


Nanoporous gold film: fabrication and role as a catalytic reactor.
Nanoporous gold (NPG) is attractive due to its high catalytic activity. From an applied and economical point of view, fabricating thin NPG films is recognized to be an ideal approach. Herein, we report an interesting finding that a thin NPG film with a thickness of 90 nm can be prepared on various substrates conveniently by using seed-mediated growth. The film has a nanoporous character with 30-60 nm and 10-30 nm of ligament and pore size, respectively. The high cost-efficiency, adjustable substrates, easy and convenient operation make this film reactor a good candidate for catalyzing both oxidative and hydrogenation reactions.


Harbor porpoise losing its edge: Genetic time series suggests a rapid population decline in Iberian waters over the last 30 years.
Impact of climate change is expected to be especially noticeable at the edges of a species' distribution, where they meet suboptimal habitat conditions. In Mauritania and Iberia, two genetically differentiated populations of harbor porpoises (Phocoena phocoena) form an ecotype adapted to local upwelling conditions and distinct from other ecotypes further north on the NE Atlantic continental shelf and in the Black Sea. By analyzing the evolution of mitochondrial genetic variation in the Iberian population between two temporal cohorts (1990-2002 vs. 2012-2015), we report a substantial decrease in genetic diversity. Phylogenetic analyses including neighboring populations identified two porpoises in southern Iberia carrying a divergent haplotype closely related to those from the Mauritanian population, yet forming a distinct lineage. This suggests that Iberian porpoises may not be as isolated as previously thought, indicating possible dispersion from Mauritania or an unknown population in between, but none from the northern ecotype. Demo-genetic scenario testing by approximate Bayesian computation showed that the rapid decline in the Iberian mitochondrial diversity was not simply due to the genetic drift of a small population, but models support instead a substantial decline in effective population size, possibly resulting from environmental stochasticity, prey depletion, or acute fishery bycatches. These results illustrate the value of genetics time series to inform demographic trends and emphasize the urgent need for conservation measures to ensure the viability of this small harbor porpoise population in Iberian waters.


Improved Measurement of Blood Pressure by Extraction of Characteristic Features from the Cuff Oscillometric Waveform.
We present a novel approach to improve the estimation of systolic (SBP) and diastolic blood pressure (DBP) from oscillometric waveform data using variable characteristic ratios between SBP and DBP with mean arterial pressure (MAP). This was verified in 25 healthy subjects, aged 28 ± 5 years. The multiple linear regression (MLR) and support vector regression (SVR) models were used to examine the relationship between the SBP and the DBP ratio with ten features extracted from the oscillometric waveform envelope (OWE). An automatic algorithm based on relative changes in the cuff pressure and neighbouring oscillometric pulses was proposed to remove outlier points caused by movement artifacts. Substantial reduction in the mean and standard deviation of the blood pressure estimation errors were obtained upon artifact removal. Using the sequential forward floating selection (SFFS) approach, we were able to achieve a significant reduction in the mean and standard deviation of differences between the estimated SBP values and the reference scoring (MLR: mean ± SD = -0.3 ± 5.8 mmHg; SVR and -0.6 ± 5.4 mmHg) with only two features, i.e., Ratio2 and Area3, as compared to the conventional maximum amplitude algorithm (MAA) method (mean ± SD = -1.6 ± 8.6 mmHg). Comparing the performance of both MLR and SVR models, our results showed that the MLR model was able to achieve comparable performance to that of the SVR model despite its simplicity.


Confirming candidate genes for longevity by RT-qPCR using two different genetic backgrounds and selection methods.
Elucidating genes that affect life span or that can be used as biomarkers for ageing has received attention in diverse studies in recent years. Using model organisms and various approaches several genes have been linked to the longevity phenotype. For Drosophila melanogaster those studies have usually focussed on one sex and on flies originating from one genetic background, and results from different studies often do not overlap. Using D. melanogaster selected for increased longevity we aimed to find robust longevity related genes by examining gene expression in both sexes of flies originating from different genetic backgrounds. Further, we compared expression changes across three ages, when flies were young, middle aged or old, to examine how candidate gene expression changes with the onset of ageing. We selected 10 genes based on their expression differences in prior microarray studies. For about 50% of these we confirmed their potential as a candidate longevity gene. We found one robust candidate gene for longevity, CG32638. Three other genes, CG8934, mRpS10 and Spn43Ad, showed a tendency to be involved in life span determination in both backgrounds tested.


Are Tanner growth charts applicable to children at school entry in Leeds?
Analysis of the heights and weights of about 85% of school entrants in Leeds in 1982 and 1983 showed that the distribution at a mean of 5.3 years is similar to the accepted standard centiles and confirms the appropriateness of the use of these standards at this age.


Hormone effects on transport in cultured epithelia with high electrical resistance.
Three continuous lines of amphibian epithelial cells form epithelia with a high transepithelial resistance (greater than 4,000 omega . cm2) in culture. The cell lines are TB-M and TB-6c, derived from the urinary bladder of Bufo marinus, and A6, derived from the kidney of Xenopus laevis. Short-circuit current is equivalent to net mucosa-to-serosa sodium transport in two cell lines and slightly exceeds sodium transport in epithelia formed by TB-6c cells. None of the cell lines has an adenylate cyclase response or a transport or permeability response to vasopressin. Water permeability is low in all three cell lines and is not affected by adenosine 3',5'-cyclic monophosphate (cAMP). In the three lines of cells, cAMP and aldosterone each increases short-circuit current with a time course similar to that seen in naturally occurring epithelia. In contrast to the toad urinary bladder and epithelia of line TB-M in which the aldosterone stimulation of short-circuit current is associated with a fall in transepithelial resistance, there is no change in resistance across epithelia of lines TB-6c and A6. There is also a striking difference in the sensitivity of the three lines to inhibition of short-circuit current by amiloride.


Diverse Exopolysaccharide Producing Bacteria Isolated from Milled Sugarcane: Implications for Cane Spoilage and Sucrose Yield.
Bacterial deterioration of sugarcane during harvesting and processing is correlated with significant loss of sucrose yield and the accumulation of bacterial polysaccharides. Dextran, a homoglucan produced by Leuconostoc mesenteroides, has been cited as the primary polysaccharide associated with sugarcane deterioration. A culture-based approach was used to isolate extracellular polysaccharide (EPS) producing bacterial strains from milled sugarcane stalks. Ribosomal RNA sequencing analysis grouped 25 isolates into 4 genera. This study identified 2 bacterial genera not previously associated with EPS production or sucrose degradation. All isolates produced polysaccharide when grown in the presence of sucrose. Monosaccharide analysis of purified polymers by Gas Chromatography revealed 17 EPSs consisting solely of glucose (homoglucans), while the remainder contained traces of mannose or fructose. Dextranase treatment of polysaccharides yielded full digestion profiles for only 11 extracts. Incomplete hydrolysis profiles of the remaining polysaccharides suggest the release of longer oligosaccharides which may interfere with sucrose crystal formation.


Well-trained Endurance Runners' Foot Contact Patterns: Barefoot vs. Shod Condition.
We aimed to investigate the initial foot contact and contact time in experienced endurance runners at individualized speeds, in running shoes and barefoot. Forty-eight participants (33.71±7.49 y, 70.94±8.65 kg, 175.07±7.03 cm, maximum aerobic speed 18.41±1.54 km.h-1) were distributed into three groups according to athletic performance: highly-trained runners, middle-trained runners, and control group. An incremental running test until exhaustion was performed for assessing maximum aerobic speed. After≥24 h of recovery participants randomly walked and ran, barefoot and in running shoes, over a pressure plate at ~4.7 km.h-1 and 85% of the maximum aerobic speed, respectively. They wore the same model of running shoes with homogeneous lacing pattern. A rearfoot strike was performed by 68.8% and 77.1% of participants when running barefoot and in running shoes, respectively. Considering the tendency to develop a rearfoot strike was lower in the barefoot condition, runners with higher performance may benefit from training in minimalist running shoes because their foot contact pattern could tend towards a non-rearfoot strike. Our results suggest that initial foot contact and contact time are related to running performance and may also be influenced by running shoes.


Bacteremia in granulocytopenic patients in a tertiary-care general hospital.
Episodes of bacteremia in granulocytopenic patients during 1985 and 1986 at a tertiary-care general hospital were reviewed to assess the adequacy of current empiric antimicrobial therapy. The major pathogens in these cases were Pseudomonas aeruginosa, Enterobacteriaceae organisms, and Staphylococcus epidermidis. This combination of pathogens differed from that found at the same facility from 1975 to 1977, when Staphylococcus aureus and streptococci predominated. When apparent, the sources of infection were predominantly venous catheters, the lower respiratory tract, and the urinary tract; most frequently there was no identifiable focus. S. epidermidis and streptococci were isolated more frequently during initial episodes of febrile bacteremia, and P. aeruginosa was isolated more often during subsequent episodes. If a narrow definition for therapeutic outcome is used, only 38% of episodes had a favorable response; response rates were no different with appropriate or inappropriate therapy. The low response rate may have been related to the use of data from the previous review to guide empiric therapy and to the subsequent inadequate treatment of infections caused by Pseudomonas and Enterobacter organisms. The overall mortality per total bacteremic episodes was 19%, and the primary factor associated with mortality was pneumonia (P less than .0001). This study emphasizes the need for ongoing surveillance of local patterns of bacteremia to direct empiric therapy.


[Possibilities and limitations for use of the polymerase chain reaction (PCR) in the diagnosis of bovine leukemia virus (BLV) infection in cattle].
Enzootic bovine leukosis is caused by the bovine leukemia virus (BLV) and has a world wide distribution in cattle. Due to the program for eradication of BLV-infections in Germany the BLV incidence in cattle declined and only few new cases seem to occur per year. On the other hand, BLV-infected cattle with low, transient or without BLV-antibody titers are difficult to identify as BLV-infected. These animals may be sources for new infections. It was the aim of this study to compare the suitability of agargel-immunodiffusion (AGID), enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) for diagnosis of BLV-infected cattle. We investigated a herd with 10 cows, where after a long period when the herd was negative suddenly a positive serological reaction appeared. In addition 64 animals from 6 federal states of different herds with doubtful serological reactions found in previous tests were included. In the herd with 10 cows we were able to detect BLV-infection in one animal 8 weeks earlier with PCR than with ELISA. Investigation of 56 adult cattle and 3 calves from different herds with both PCR and ELISA showed that 51 animals were positive in ELISA and 55 in PCR. Seven animal were positive in PCR and negative in ELISA. Three calves yielded negative results in PCR and positive results in ELISA. One cow which was positive in previous serological tests was negative in ELISA, AGID and PCR. Restriction fragment length polymorphism analysis demonstrated that the majority of the cattle was infected with the same BLV provirus variant. The four PCR variants used in this study yielded a similar sensitivity for BLV provirus detection. In conclusion, compared to the serological tests, PCR detects BLV-infection earlier in naturally infected cattle. The method is also a useful tool to exclude or confirm BLV-infection in cattle with doubtful serological results. PCR may be used to complement the serological tests in the diagnosis of BLV-infection.


Regulation of hepatic monooxygenases by phenobarbital, 3-methylcholanthrene, and polychlorinated biphenyls in rapid and slow acetylator mice.
A/J and C57BL/6J inbred mouse strains have been previously used as models of slow and fast acetylators, respectively, of human acetylator polymorphism. Studies were carried out to characterize possible differences in basal activities of hepatic monooxygenases and the response of these mouse strains to microsomal enzyme inducers. No significant difference in cytochrome P-450 content and associated enzyme activities of ethylmorphine N-demethylase and benzo(a)pyrene hydroxylase were observed between the two strains. The administration of the inducers, phenobarbital or the polychlorinated biphenyl mixture Aroclor 1254, resulted in significant increases in cytochrome P-450 and ethylmorphine N-demethylase activity and minimal changes in benzo(a)pyrene hydroxylase activity in both strains. Pretreatment with 3-methylcholanthrene resulted in little or no increase in N-demethylase activity in both strains. The polycyclic hydrocarbon caused a CO difference spectral shift to a lower wavelength only in the C57BL/6J mice. Further, it increased benzo(a)pyrene hydroxylase activity in both strains, but to a greater extent in the C57BL/6J strain. Electrophoretic studies using solubilized microsomal preparations confirmed the findings that the fast acetylators were highly responsive to the inducing properties of the polycyclic aromatic hydrocarbon, whereas the slow acetylators were relatively much less responsive to its inducing properties. The latter strain appeared to be more responsive to the inducing properties of the phenobarbital class of inducers, as reflected in the inducibility of cytochrome P-450 and the associated enzymic activities in the liver.


Decompression sickness during construction of the Great Belt Tunnel, Denmark.
Thirteen cases of decompression sickness (DCS) occurred during the construction of the 8-km long railway tunnel under the Great Belt in Denmark between January 1992 and February 1996. 320 compressed air workers were subjected to 9018 pressure exposures in four tunnel boring machines. Overall DCS incidence was 0.14%. Working pressures ranged between 0.25 bar (1.25 atm abs or 126.3 kPa) and 2.95 bar (3.91 atm abs or 396.3 kPa) and working times ranged between 2 minutes and 339 minutes. During the first 1798 pressure exposures 7 DCS cases occurred using French air decompression tables from 1974. The following 7220 exposures were then decompressed in accordance with the newly issued French air decompression tables of 1992. After changing schedules 6 DCS cases occurred and DCS incidence was reduced to 0.08%. Two of the first seven DCS cases had permanent residual symptoms after recompression treatment. All DCS cases, except one, occurred among the 30% of exposures that imposed the greatest decompression stress. DCS incidence among these exposures was 0.42%.


Nomenclature for the Nameless: A Proposal for an Integrative Molecular Taxonomy of Cryptic Diversity Exemplified by Planktonic Foraminifera.
Investigations of biodiversity, biogeography, and ecological processes rely on the identification of "species" as biologically significant, natural units of evolution. In this context, morphotaxonomy only provides an adequate level of resolution if reproductive isolation matches morphological divergence. In many groups of organisms, morphologically defined species often disguise considerable genetic diversity, which may be indicative of the existence of cryptic species. The diversity hidden by morphological species can be disentangled through genetic surveys, which also provide access to data on the ecological distribution of genetically circumscribed units. These units can be identified by unique DNA sequence motifs and allow studies of evolutionary and ecological processes at different levels of divergence. However, the nomenclature of genetically circumscribed units within morphological species is not regulated and lacks stability. This represents a major obstacle to efforts to synthesize and communicate data on genetic diversity for multiple stakeholders. We have been confronted with such an obstacle in our work on planktonic foraminifera, where the stakeholder community is particularly diverse, involving geochemists, paleoceanographers, paleontologists, and biologists, and the lack of stable nomenclature beyond the level of formal morphospecies prevents effective transfer of knowledge. To circumvent this problem, we have designed a stable, reproducible, and flexible nomenclature system for genetically circumscribed units, analogous to the principles of a formal nomenclature system. Our system is based on the definition of unique DNA sequence motifs collocated within an individual, their typification (in analogy with holotypes), utilization of their hierarchical phylogenetic structure to define levels of divergence below that of the morphospecies, and a set of nomenclature rules assuring stability. The resulting molecular operational taxonomic units remain outside the domain of current nomenclature codes, but are linked to formal morphospecies as regulated by the codes. Subsequently, we show how this system can be applied to classify genetically defined units using the SSU rDNA marker in planktonic foraminifera and we highlight its potential use for other groups of organisms where similarly high levels of connectivity between molecular and formal taxonomies can be achieved.


Managing the complexity of nurse shortages: a case study of bank and agency staffing in an acute care Trust in Wales, UK.
Managing nurse shortages is a major challenge in Trusts today given the worldwide shortage of nurses. To fill the gap created by a lack of permanent staff UK government agencies have increasingly used bank and agency staff. Managing this type of staffing effectively and efficiently, in the context of shrinking healthcare funds, is a major challenge in providing safe and quality healthcare. To analyse bank and agency nursing staffing patterns and factors that impact on these patterns. Case study within the largest hospital in one Welsh Integrated Healthcare Trust. De-identified bank and agency staffing electronic and manual database records and focus group interview with bank and agency office staff. A predictable bank and agency staffing pattern was found, wherein bank and agency nursing staff were used with increasing frequency towards the end of the week. Demand for bank and agency nursing staff occurred because of: hospital practices that fund a fixed staff establishment for nursing units, while patient numbers and acuity are variable; poor forward planning; sickness, and absence due to professional development or staff training. There is a need for managers to reconsider management and recruitment policies, particularly in relation to using bank and agency staff. The complexity of staffing challenges managers to focus on predictability of workload needs and other factors that affect staffing requirements, such as: professional development, flexible working rosters to match the need and minimize sickness and turnover of staff.


Homozygous Resistance to Thyroid Hormone β: Can Combined Antithyroid Drug and Triiodothyroacetic Acid Treatment Prevent Cardiac Failure?
Resistance to thyroid hormone β (RTHβ) due to homozygous THRB defects is exceptionally rare, with only five kindreds reported worldwide. Cardiac dysfunction, which can be life-threatening, is recognized in the disorder. Here we describe the clinical, metabolic, ophthalmic, and cardiac findings in a 9-year-old boy harboring a biallelic THRB mutation (R243Q), along with biochemical, physiologic, and cardiac responses to carbimazole and triiodothyroacetic acid (TRIAC) therapy. The patient exhibits recognized features (goiter, nonsuppressed thyroid-stimulating hormone levels, upper respiratory tract infections, hyperactivity, low body mass index) of heterozygous RTHβ, with additional characteristics (dysmorphic facies, winging of scapulae) and more markedly elevated thyroid hormone levels, associated with the homozygous form of the disorder. Notably, an older sibling with similar clinical features and probable homozygous RTHβ had died of cardiac failure at age 13 years. Features of early dilated cardiomyopathy in our patient prompted combination treatment with carbimazole and TRIAC. Careful titration of therapy limited elevation in TSH levels and associated increase in thyroid volume. Subsequently, sustained reduction in thyroid hormones with normal TSH levels was reflected in lower basal metabolic rate, gain of lean body mass, and improved growth and cardiac function. A combination of antithyroid drug and TRIAC therapy may prevent thyrotoxic cardiomyopathy and its decompensation in homozygous or even heterozygous RTHβ in which life-threatening hyperthyroid features predominate.


Growth hormone and bone.
It is well known that GH is important in the regulation of longitudinal bone growth. Its role in the regulation of bone metabolism in man has not been understood until recently. Several in vivo and in vitro studies have demonstrated that GH is important in the regulation of both bone formation and bone resorption. In Figure 9 a simplified model for the cellular effects of GH in the regulation of bone remodeling is presented (Fig. 9). GH increases bone formation in two ways: via a direct interaction with GHRs on osteoblasts and via an induction of endocrine and autocrine/paracrine IGF-I. It is difficult to say how much of the GH effect is mediated by IGFs and how much is IGF-independent. GH treatment also results in increased bone resorption. It is still unknown whether osteoclasts express functional GHRs, but recent in vitro studies indicate that GH regulates osteoclast formation in bone marrow cultures. Possible modulations of the GH/IGF axis by glucocorticoids and estrogens are also included in Fig. 9. GH deficiency results in a decreased bone mass in both man and experimental animals. Long-term treatment (> 18 months) of GHD patients with GH results in an increased bone mass. GH treatment also increases bone mass and the total mechanical strength of bones in rats with a normal GH secretion. Recent clinical studies demonstrate that GH treatment of patients with normal GH secretion increases biochemical markers for both bone formation and bone resorption. Because of the short duration of GH treatment in man with normal GH secretion, the effect on bone mass is still inconclusive. Interestingly, GH treatment to GHD adults initially results in increased bone resorption with an increased number of bone-remodeling units and more newly produced unmineralized bone, resulting in an apparent low or unchanged bone mass. However, GH treatment for more than 18 months gives increased bone formation and bone mineralization of newly produced bone and a concomitant increase in bone mass as determined with DEXA. Thus, the action of GH on bone metabolism in GHD adults is 2-fold: it stimulates both bone resorption and bone formation. We therefore propose "the biphasic model" of GH action in bone remodeling (Fig. 10). According to this model, GH initially increases bone resorption with a concomitant bone loss that is followed by a phase of increased bone formation. After the moment when bone formation is stimulated more than bone resorption (transition point), bone mass is increased. However, a net gain of bone mass caused by GH may take some time as the initial decrease in bone mass must first be replaced (Fig. 10). When all clinical studies of GH treatment of GHD adults are taken into account, it appears that the "transition point" occurs after approximately 6 months and that a net increase of bone mass will be seen after 12-18 months of GH treatment. It should be emphasized that the biphasic model of GH action in bone remodeling is based on findings in GHD adults. It remains to be clarified whether or not it is valid for subjects with normal GH secretion. A treatment intended to increase the effects of GH/IGF-I axis on bone metabolism might include: 1) GH, 2) IGF, 3) other hormones/factors increasing the local IGF-I production in bone, and 4) GH-releasing factors. Other hormones/growth factors increasing local IGF may be important but are not discussed in this article. IGF-I has been shown to increase bone mass in animal models and biochemical markers in humans. However, no effect on bone mass has yet been presented in humans. Because the financial cost for GH treatment is high it has been suggested that GH-releasing factors might be used to stimulate the GH/IGF-I axis. The advantage of GH-releasing factors over GH is that some of them can be administered orally and that they may induce a more physiological GH secretion. (ABSTRACT TRUNCATED)


Demonstration of cytomegalovirus nucleic acids in the coronary arteries of transplanted hearts.
Cytomegalovirus (CMV) infection has been associated with the development of accelerated arteriosclerosis in heart transplant recipients. This association prompted the authors to examine, using in situ hybridization techniques, the coronary arteries of 19 patients who had received heart transplants for the presence of CMV nucleic acids. Two probes were employed on formalin-fixed paraffin-embedded tissues. The first was an S35-labeled nick translated probe derived from CMV DNA. CMV nucleic acids were identified in the arterial intima of 5 (45%) of 11 transplanted hearts examined with this probe. Hybridization to cells morphologically consistent with endothelial cells, lymphocytes, and smooth muscle cells was identified. Hybridization was not detected in any of the hearts when a control probe, a vector without CMV DNA, was employed. The second probe that was used was a tritium-labeled strand-specific ribo-probe derived from the immediate early (IE1) gene of CMV. Using this second probe, hybridization was detected in the coronary arteries of three of five hearts that were positive with the DNA probe, in one of the hearts that was negative with the DNA probe, and in three (38%) of eight additional transplanted hearts. The pattern of hybridization was the same as that seen with the DNA probe, and no hybridization was detected when a control sense probe for the IE1 gene of CMV was employed. These results suggest that CMV nucleic acids are present in the coronary arteries of heart transplant recipients.


Matricellular protein SPARC/osteonectin expression is regulated by DNA methylation in its core promoter region.
SPARC/osteonectin is an evolutionarily conserved matricellular protein that modulates cell-matrix interaction and cell function. In all vertebrates, SPARC is dynamically expressed during embryogenesis. However, the precise function of SPARC and the regulatory elements required for its expression in particular during early embryogenesis are largely unknown. The present study was undertaken to explore the molecular mechanisms that regulate sparc gene expression by in vivo functional characterization of the sparc promoter and identification of possible putative regulatory elements that govern basal promoter activity. We report here transient expression analyses of eGFP expression from transgenic zebrafish containing a Sparc-iTol2-eGFP-BAC and/or 7.25 kb-sparc-Tol2-eGFP constructs. eGFP expression was specifically found in the notochord, otic vesicle, fin fold, intermediate cell mass, and olfactory placode of BAC and Tol2 transposon vectors injected embryos. Deletion analysis revealed that promoter activity resides in the unique 5'-untranslated intronic region. Computer-based analysis revealed a putative CpG island immediately proximal to the translation start site within the intron sequence. Global inhibition of methylation with 5-Aza-2-deoxycytidine promoted sparc expression in association with decreasing CpG methylation. Taken together, these data identify a contributory role for DNA methylation in regulating sparc expression in zebrafish embryogenesis.


Association between body mass index and blood pressure levels across socio-demographic groups and geographical settings: analysis of pooled data in Peru.
Understanding the relationship between BMI and blood pressure requires assessing whether this association is similar or differs across population groups. This study aimed to assess the association between body mass index (BMI) and blood pressure levels, and how these associations vary between socioeconomic groups and geographical settings. Data from the National Demographic Health Survey of Peru from 2014 to 2019 was analyzed considering the complex survey design. The outcomes were levels of systolic (SBP) and diastolic blood pressure (DBP), and the exposure was BMI. Exposure and outcomes were fitted as continuous variables in a non-linear quadratic regression model. We explored effect modification by six socioeconomic and geographical variables (sex, age, education level, socioeconomic position, study area, and altitude), fitting an interaction term between each of these variables and BMI. Data from 159, 940 subjects, mean age 44.4 (SD: 17.1), 54.6% females, was analyzed. A third (34.0%) of individuals had ≥12 years of education, 24.7% were from rural areas, and 23.7% lived in areas located over 2,500 m above sea level. In the overall sample mean BMI was 27.1 (SD: 4.6) kg/m2, and mean SBP and DBP were 122.5 (SD: 17.2) and 72.3 (SD: 9.8) mmHg, respectively. In the multivariable models, greater BMI levels were associated with higher SBP (p-value < 0.001) and DBP (p-value < 0.001). There was strong evidence that sex, age, education level, and altitude were effect modifiers of the association between BMI and both SBP and DBP. In addition to these socio-demographic variables, socioeconomic position and study area were also effect modifiers of the association between BMI and DBP, but not SBP. The association between BMI and levels of blood pressure is not uniform on a range of socio-demographic and geographical population groups. This characterization can inform the understanding of the epidemiology and rise of blood pressure in a diversity of low-resource settings.


Modeling rates of life form cover change in burned and unburned alpine heathland subject to experimental warming.
Elevated global temperatures are expected to alter vegetation dynamics by interacting with physiological processes, biotic relationships and disturbance regimes. However, few studies have explicitly modeled the effects of these interactions on rates of vegetation change, despite such information being critical to forecasting temporal patterns in vegetation dynamics. In this study, we build and parameterize rate-change models for three dominant alpine life forms using data from a 7-year warming experiment. These models allowed us to examine how the interactions between experimental warming, the abundance of bare ground (a measure of past disturbance) and neighboring life forms (a measure of life form interaction) affect rates of cover change in alpine shrubs, graminoids and forbs. We show that experimental warming altered rates of life form cover change by reducing the negative effects of neighboring life forms and positive effects of bare ground. Furthermore, we show that our models can predict the observed direction and rate of life form cover change at burned and unburned long-term monitoring sites. Model simulations revealed that warming in unburned vegetation is expected to result in increased forb and shrub cover and decreased graminoid cover. In contrast, in burned vegetation, warming is predicted to slow post-fire regeneration in both graminoids and forbs and facilitate rapid expansion in shrub cover. These findings illustrate the applicability of modeling rates of vegetation change using experimental data. Our results also highlight the need to account for both disturbance and the abundance of other life forms when examining and forecasting vegetation dynamics under climatic change.


Application of treatment fidelity in tailored caregiver interventions.
Demonstrations of the effectiveness of interventions requires evidence that the model can be implemented with fidelity. Caregiving interventions that are tailored to the individual or family require flexibility, which adds some challenges to the assessment of fidelity. This paper outlines the components necessary for examining treatment fidelity and common barriers to implementing fidelity studies, offers considerations for designing fidelity studies with tailored caregiver interventions, and aims to provide a set of procedures that can be used to guide future fidelity studies. Case study methods are used to illustrate the processes and findings, drawing on two research studies of fidelity in tailored caregiver interventions. Fidelity studies consist of core components (i.e. training on intervention delivery, adherence to the intervention, therapist competence, acceptability and outcomes) that should be maintained and monitored throughout the study to elucidate the relationship between the intervention and outcomes. These components are applicable to tailored caregiver interventions and can be implemented with the consideration of some key issues that are addressed prior to the evaluation. The two cases presented utilized similar methods to evaluate fidelity of two different tailored caregiver interventions. Treatment fidelity can be assessed for tailored caregiving interventions, which increases confidence about the potency of the active ingredients in the interventions. Standard fidelity guidelines can be implemented with minor additional considerations.


Need for certainty and interest in genetic testing.
The relation among need for certainty, type of information presented about a genetic test, and level of interest in predictive genetic testing was examined. Participants were randomly assigned to receive 1 of 2 descriptions of the test. The only difference between the descriptions was that one included a paragraph that emphasized the cancer risk remaining for those who test negative for gene mutations. As predicted, a significant interaction between need for certainty and type of information presented was observed. Whereas women high in need for certainty were more interested in genetic testing when provided with the standard description and less interested when provided with the more complete one, women low in need for certainty showed the opposite pattern. The results suggest that interest in genetic testing is determined by the correspondence between an individual's personal goals and her perception of the kind of information provided by the test.


The effect of cyclic anaerobic-aerobic conditions on biodegradation of azo dyes.
The effect of cyclic anaerobic-aerobic conditions on the biodegradative capability of the mixed microbial culture for the azo dye Remazol Brilliant Violet 5R (RBV-5R) was investigated in the sequencing batch reactor (SBR) fed with a synthetic textile wastewater. The SBR had a 12-h cycle time with anaerobic-aerobic periods of 3/9, 6/6 and 9/3 h. General SBR performance was assessed by measurement of catabolic enzymes (catechol 2,3-dioxygenase, azo reductase), chemical oxygen demand (COD), color and amount of aromatic amines. In this study, under steady-state conditions, the anaerobic period of the cyclic SBR was found to allow the reductive decolorization of azo dye. Longer anaerobic periods resulted in higher color removal efficiencies, approximately 71% for the 3-h, 87% for 6-h and 92% for the 9-h duration. Total COD removal efficiencies were over 84% under each of the cyclic conditions and increased as the length of the anaerobic period was increased; however, the highest color removal rate was attained for the cycle with the shortest anaerobic period of 3 h. During the decolorization of RBV-5R, two sulfonated aromatic amines (benzene based and naphthalene based) were formed. Additionally, anaerobic azo reductase enzyme was found to be positively affected with the increasing duration of the anaerobic period; however; it was vice versa for the aerobic catechol 2,3-dioxygenase (C23DO) enzyme.


Increasing leaf vein density by mutagenesis: laying the foundations for C4 rice.
A high leaf vein density is both an essential feature of C4 photosynthesis and a foundation trait to C4 evolution, ensuring the optimal proportion and proximity of mesophyll and bundle sheath cells for permitting the rapid exchange of photosynthates. Two rice mutant populations, a deletion mutant library with a cv. IR64 background (12,470 lines) and a T-DNA insertion mutant library with a cv. Tainung 67 background (10,830 lines), were screened for increases in vein density. A high throughput method with handheld microscopes was developed and its accuracy was supported by more rigorous microscopy analysis. Eight lines with significantly increased leaf vein densities were identified to be used as genetic stock for the global C4 Rice Consortium. The candidate population was shown to include both shared and independent mutations and so more than one gene controlled the high vein density phenotype. The high vein density trait was found to be linked to a narrow leaf width trait but the linkage was incomplete. The more genetically robust narrow leaf width trait was proposed to be used as a reliable phenotypic marker for finding high vein density variants in rice in future screens.


CPRD GOLD and linked ONS mortality records: Reconciling guidelines.
The Clinical Practice Research Datalink (CPRD) GOLD is an extremely influential U.K. primary care dataset for epidemiological research having a number of published papers based on its data much bigger than any other U.K. primary care dataset. The Office for National Statistics (ONS) death data for England can be linked to GOLD at the patient level and are considered the gold standard on mortality. GOLD, which also holds death data, has been recently assessed against ONS linked dataset and the accuracy of its dates of death has been deemed sufficient for the majority of observational studies. However, there is a lack of guidance on how to manage the challenges existing when ONS mortality and GOLD datasets are linked, including linkage coverage period, linkage correctness likelihood, linkage regional limitations and data discrepancy. Provide reconciling guidelines on how to make maximum and at the same time trustworthy use of mortality information coming from both GOLD and ONS linked datasets with the aim of improving the quality, reproducibility, transparency and comparison of clinical research. We have developed recommendations on how to manage mortality data coming from both GOLD and linked ONS, taking into account linkage coverage period, linkage correctness likelihood, linkage regional limitations and data discrepancies between these two datasets. We have also implemented these guidelines in an SQL algorithm for researchers to use. We have provided detailed guidelines on the reconciliation of mortality data between GOLD and ONS linked death datasets, taking into account both their strengths and limitations. The consistent application of these guidelines made practical by an SQL algorithm, has the potential to improve clinical research quality, reproducibility, transparency and comparison.


Light induced intraspecific variability in response to thermal stress in the hard coral Stylophora pistillata.
Recent research suggests that prior exposure of several months to elevated irradiance induces enhanced thermal tolerance in scleractinian corals. While this tolerance has been reported at the species level, individual coral colonies may react differently due to individual variability in thermal tolerance. As thermal anomalies are predicted to become common in the upcoming future, intraspecific variation may be key to the survival of coral populations. In order to study light-history based thermal stress responses on individual colonies, we developed a preliminary microcosm experiment where three randomly chosen, aquacultured colonies of the model coral Stylophora pistillata were exposed to two irradiance treatments (200 and 400 μmol photons m-2 s-1) for 31 days, followed by artificially induced heat stress (∼33.4 °C). We found different responses to occur at both the intraspecific and the intracolonial levels, as indicated by either equal, less severe, delayed, and/or even non-necrotic responses of corals previously exposed to the irradiance of 400 compared to 200 μmol photons m-2 s-1. In addition, all individual colonies revealed light-enhanced calcification. Finally, elevated irradiance resulted in a lower chlorophyll a concentration in one colony compared to the control treatment, and the same colony displayed more rapid bleaching compared to the other ones. Taken together, this study highlights the potential importance of intra-individual variability in physiological responses of scleractinian corals and provides recommendations for improving methodological designs for future studies.


In situ mass spectrometry monitoring of fungal cultures led to the identification of four peptaibols with a rare threonine residue.
Peptaibols are an intriguing class of fungal metabolites due both to their wide range of reported bioactivities and to the structural variability that can be generated by the exchange of variable amino acid building blocks. In an effort to streamline the discovery of structurally diverse peptaibols, a mass spectrometry surface sampling technique was applied to screen the chemistry of fungal cultures in situ. Four previously undescribed peptaibols, all containing a rare threonine residue, were identified from a fungal culture (MSX53554), which was identified as Nectriopsis Maire (Bionectriaceae, Hypocreales, Ascomycota). These compounds not only increased the known threonine-containing peptaibols by nearly 20%, but also, the threonine residue was situated in a unique place compared to the other reported threonine-containing peptaibols. After the initial in situ detection and characterization, a large-scale solid fermentation culture was grown. The four peptaibols were isolated and characterized by mass spectrometry. In addition, one of the peptaibols was fully characterized by NMR and amino acid analysis using Marfey's reagent and exhibited moderate in vitro anticancer activity.


Initiation of an intestinal transplant program: the Indiana experience.
Establishment of a new intestinal transplant (Itx) program in the United States entails significant programmatic costs and a steep learning curve. We report results of the first 4 years of the program at Indiana University. Forty-six intestinal and multivisceral transplants (MVtx) were performed between 2003 and 2007. All organ procurements were performed by our team. Immunosuppression included an induction protocol combined with maintenance tacrolimus monotherapy. Scheduled rejection surveillance was with magnification endoscopy. Forty-three patients (13 children and 30 adults) received 10 Itx (22%), 5 modified MVtxs (11%), and 31 (MVtx, 67%). Recipient ages ranged from 3 months to 66 years, with median follow-up time of 15 months. Thirty-five patients are currently alive (81%). Patient and graft survival at 30 days was 85%/86% in pediatric and 93%/91% in adult; overall survival was 69%/64% in pediatric and 87%/75% in adult. Thirty patients (69%) experienced episodes of rejection. Multivisceral transplanted patients experienced less episodes of severe rejection (2/31, 6%) when compared with patients with isolated Itx and modified MVtxs. Retransplantation was performed in three patients with nonresponsive severe acute rejection. The Indiana University Intestinal and Multivisceral Transplant program experienced significant early graft loss and mortality among pediatric patients, but not among adults. This discrepancy resolved within 2 years of program initiation. After 4 years, adult and pediatric graft and patient survival statistics are similar to those at other programs.


IMAGING DIAGNOSIS-SCLEROSING ENCAPSULATING PERITONITIS IN A DOG.
An approximately 5-month-old American Staffordshire terrier was presented with a history of recurrent peritoneal effusion. Abdominal radiographs and ultrasound showed a loculated effusion in the ventral abdomen with dorsal displacement of abdominal organs, hepatomegaly and rounding of liver and splenic margins. Computed tomography demonstrated centrally located gastrointestinal segments surrounded by a thin soft tissue band and a thickened peritoneal lining. At necropsy a fibrous membrane continuous with liver and splenic capsules encapsulated all abdominal organs. Microscopically the abdominal wall and fibrous capsule consisted of an irregular thick layer of hypocellular connective tissue. The final diagnosis was sclerosing encapsulating peritonitis.


Dose-response relationship of propranolol in the treatment of essential tremor.
The effect of doses of propranolol hydrochloride, 80 to 800 mg/day, was investigated in 15 patients with essential tremor. The dose was increased by 80 mg weekly. Tremor was recorded by an accelerometer and its amplitude and frequency was determined by spectral analysis. Serum propranolol level was measured by radioreceptor assay. Tremor control varied greatly from complete suppression at 80 mg/day to no reduction at 800 mg/day. Mean serum propranolol levels increased with increasing dosage, but they did not correlate with tremor suppression. Five patients did not tolerate doses higher than 640 mg/day. Maximum tremor suppression occurred within a dose range between 160 and 320 mg/day. Higher doses did not cause additional tremor reduction.


The food metabolome: a window over dietary exposure.
The food metabolome is defined as the part of the human metabolome directly derived from the digestion and biotransformation of foods and their constituents. With >25,000 compounds known in various foods, the food metabolome is extremely complex, with a composition varying widely according to the diet. By its very nature it represents a considerable and still largely unexploited source of novel dietary biomarkers that could be used to measure dietary exposures with a high level of detail and precision. Most dietary biomarkers currently have been identified on the basis of our knowledge of food compositions by using hypothesis-driven approaches. However, the rapid development of metabolomics resulting from the development of highly sensitive modern analytic instruments, the availability of metabolite databases, and progress in (bio)informatics has made agnostic approaches more attractive as shown by the recent identification of novel biomarkers of intakes for fruit, vegetables, beverages, meats, or complex diets. Moreover, examples also show how the scrutiny of the food metabolome can lead to the discovery of bioactive molecules and dietary factors associated with diseases. However, researchers still face hurdles, which slow progress and need to be resolved to bring this emerging field of research to maturity. These limits were discussed during the First International Workshop on the Food Metabolome held in Glasgow. Key recommendations made during the workshop included more coordination of efforts; development of new databases, software tools, and chemical libraries for the food metabolome; and shared repositories of metabolomic data. Once achieved, major progress can be expected toward a better understanding of the complex interactions between diet and human health.


Interleukin-7 inhibits apoptosis of mouse malignant T-lymphoma cells by both suppressing the CPP32-like protease activation and inducing the Bcl-2 expression.
Mouse malignant T-lymphoma CS-21 cells grow in vitro in the presence of CA-12 lymph node stromal cells, but they undergo apoptotic cell death when separated from CA-12 stromal cells. In the course of examining the nursing effects of CA-12 stromal cells, we found that these cells provided some soluble factors that suppressed CS-21 cell apoptosis. We recently found that cysteine was an antiapoptotic soluble factor. In this report, we identify interleukin-7 (IL-7) as another antiapoptotic soluble factor secreted by CA-12 stromal cells. Although the activity of CPP32-like protease was increased in induction of CS-21 cell apoptosis, the addition of IL-7 suppressed the activity. The expression of Bcl-2 protein was down-regulated when CS-21 cells were cultured alone, but the addition of IL-7 recovered the expression of Bcl-2. These results indicate that CA-12 stromal cells inhibit CS-21 cell apoptosis by producing IL-7, which leads to the suppression of CPP32-like protease activation and the expression of Bcl-2 protein.