Differential modulation of motor cortical plasticity and excitability in early and late phases of human motor learning.
Different phases of motor skill learning appear to involve different physiological processes, with long-term potentiation (LTP) occurring at existing synapses in early and cortical reorganization involving synaptogenesis in later phases. Here, we test the evolution of skill learning-dependent changes in motor plasticity and excitability in six subjects trained to perform rapid thumb abductions over 5 d. Plasticity was examined using paired-associative stimulation (PAS) of the median nerve and motor cortex to induce LTP-like "PAS given with an interstimulus interval of 25 ms (PAS25)" or long-term depression (LTD)-like "PAS given with an interstimulus interval of 10 ms (PAS10)" plasticity. Excitability was tested by measuring recruitment of motor-evoked-potentials "input-output (IO) curve" and of short-latency intracortical inhibition (SICI curve), and sensorimotor organization (SMO). Task performance improved continuously over 5 d. After practice on day 1, the PAS25 effect reversed from facilitation to inhibition whereas the slope of the IO curve increased and the level of SICI decreased. These effects on IO curve and SICI were still present or even enhanced before the last practice on day 5, and were not changed by it. The effect of proprioceptive input from the trained muscle on SMO was also strengthened before practice on day 5. In contrast, PAS-induced plasticity was not influenced by motor practice on day 5, and had returned to prepractice values. The interference with PAS-induced plasticity suggests that the initial performance improvement relies on increasing the efficacy of existing synaptic connections. However, the long-lasting changes in the IO curve, SICI curve, and SMO suggest that continued practice enhances performance by changing Motor cortical organization. We hypothesize that new synaptic connections might have formed that allow LTP/LTD-susceptibility to be restored without reducing synaptic strength and performance skill.


C3b receptor activity on transfected cells expressing glycoprotein C of herpes simplex virus types 1 and 2.
Glycoprotein C from herpes simplex virus type 1 (gC-1 from HSV-1) acts as a receptor for the C3b fragment of the third component of complement on HSV-1-infected cell surfaces. Direct binding assays with purified gC-1 and C3b demonstrate that other viral and cellular proteins are not required for this interaction. Although C3b receptor activity is not expressed on HSV-2-infected cell surfaces, purified gC-2 specifically binds C3b in direct binding assays, suggesting that gC-1 and gC-2 are functionally similar. Here, we used a transient transfection system to further characterize the role of gC-1 and gC-2 as C3b receptors and to localize the site(s) on gC involved in C3b binding. The genes for gC-1 and gC-2 were each cloned into a eucaryotic expression vector containing the Rous sarcoma virus long terminal repeat as the promoter and transfected into NIH 3T3 cells. The expressed proteins were similar in molecular size, extent of carbohydrate processing, and antigenic properties to gC-1 and gC-2 purified from infected cells. Using a double-label immunofluorescence assay, we found that both gC-1 and gC-2 were expressed on the surfaces of transfected cells and bound C3b. These results suggest that other proteins expressed during HSV-2 infection prevent receptor activity. We constructed three in-frame deletion mutants of gC-2 to identify domains on the protein important for C3b receptor activity. These mutants lacked amino acids 26 to 73, 219 to 244, or 318 to 346. The mutant protein lacking residues 26 to 73 was reactive with two monoclonal antibodies recognizing distinct epitopes, showed a wild-type pattern of carbohydrate processing, and bound C3b on the transfected cell surface. These results suggest that residues 26 to 73 are not involved in C3b binding. The other two mutant proteins were present on the cell surface, but did not bind C3b. In addition, these mutant proteins showed altered patterns of carbohydrate processing, formed aggregates, and were no longer recognized by the monoclonal antibodies. These properties indicate that removal of residues 219 to 244 or 318 to 346 disrupted the native conformation of gC-2, possibly owing to an alteration in the spacing between critical cysteine residues.


Experimental glaucoma induced by ocular injection of magnetic microspheres.
Progress in understanding the pathophysiology, and providing novel treatments for glaucoma is dependent on good animal models of the disease. We present here a protocol for elevating intraocular pressure (IOP) in the rat, by injecting magnetic microspheres into the anterior chamber of the eye. The use of magnetic particles allows the user to manipulate the beads into the iridocorneal angle, thus providing a very effective blockade of fluid outflow from the trabecular meshwork. This leads to long-lasting IOP rises, and eventually neuronal death in the ganglion cell layer (GCL) as well as optic nerve pathology, as seen in patients with the disease. This method is simple to perform, as it does not require machinery, specialist surgical skills, or many hours of practice to perfect. Furthermore, the pressure elevations are very robust, and reinjection of the magnetic microspheres is not usually required unlike in some other models using plastic beads. Additionally, we believe this method is suitable for adaptation for the mouse eye.


From numbers to a biological sense: How the strategy chosen for metabolomics data treatment may affect final results. A practical example based on urine fingerprints obtained by LC-MS.
Application of high-throughput technologies in metabolomics studies increases the quantity of data obtained, which in turn imposes several problems during data analysis. Correctly and clearly addressed biological question and comprehensive knowledge about data structure and properties are definitely necessary to select proper chemometric tools. However, there is a broad range of chemometric tools available for use with metabolomics data, which makes this choice challenging. Precisely performed data treatment enables valuable extraction of information and its proper interpretation. The effect of an error made at an early stage will be enhanced throughout the later stages, which in combination with other errors made at each step can accumulate and significantly affect the data interpretation. Moreover, adequate application of these tools may help not only to detect, but sometimes also to correct, biological, analytical, or methodological errors, which may affect truthfulness of obtained results. This report presents steps and tools used for LC-MS based metabolomics data extraction, reduction, and visualization. Following such steps as data reprocessing, data pretreatment, data treatment, and data revision, authors want to show how to extract valuable information and how to avoid misinterpretation of results obtained. The purpose of this work was to emphasize problematic characteristics of metabolomics data and the necessity for their attentive and precise treatment. The dataset used to illustrate metabolomics data properties and to illustrate major data treatment challenges was obtained utilizing an animal model of control and diabetic rats, both with and without rosemary treatment. Urine samples were fingerprinted employing LC-QTOF-MS.


Estimated dietary acid load is not associated with blood pressure or hypertension incidence in men who are approximately 70 years old.
Dietary acid load affects acid-base homeostasis, which may be associated with blood pressure (BP). Previous research on dietary acid load and BP in the community has provided conflicting results, which may be confounded by underlying kidney function with inability to eliminate acid excess. The objective of this study was to determine whether dietary acid load is associated with blood pressure or the incidence of hypertension in older men taking into account each individual's kidney function. We included 673 men aged 70-71 y and not receiving antihypertensive medication from the Uppsala Longitudinal Study of Adult Men. Of those, 378 men were re-examined after 7 y. Dietary acid load was estimated at baseline by potential renal acid load (PRAL) and net endogenous acid production (NEAP), based on nutrient intake assessed by 7-d food records at baseline. Ambulatory blood pressure monitoring (ABPM) was performed at both visits. Cystatin C-estimated kidney function allowed identification of underlying chronic kidney disease. Median estimated PRAL and NEAP were 3.3 and 40.7 mEq/d, respectively. In cross-section, PRAL was in general not associated with ABPM measurements (all P > 0.05, except for the 24-h diastolic BP). During follow-up, PRAL did not predict ABPM changes (all P > 0.05). When individuals with baseline hypertension (ABPM ≥ 130/80 mm Hg) or nondippers (with nighttime-to-daytime systolic BP ratio > 0.9) were excluded, PRAL was not a predictor of incident cases (P > 0.30). Kidney function did not modify these null relations. Similar findings were obtained with the use of NEAP as the exposure. Our analyses linking estimated dietary acid load with BP outcome measurements both cross-sectionally and after 7 y in community-based older Swedish men of similar age did not reveal an association between dietary acid load and BP.


Effects of sodium oxybate on sleep physiology and sleep/wake-related symptoms in patients with fibromyalgia syndrome: a double-blind, randomized, placebo-controlled study.
To determine the effects of sodium oxybate (SXB) on sleep physiology and sleep/wake-related symptoms in patients with fibromyalgia syndrome (FM). Of 304 patients with FM (American College of Rheumatology tender point criteria) in the screened study population, 209 underwent polysomnography, 195 were randomized, and 151 completed this 8-week, double-blind, placebo-controlled study of SXB 4.5 g and 6 g/night. We evaluated changes in objective sleep measures and subjective symptoms, including daytime sleepiness [Epworth Sleepiness Scale (ESS)], fatigue visual analog scale (FVAS), sleep [Jenkins Scale for Sleep (JSS)], and daytime functioning [Functional Outcome of Sleep Questionnaire (FOSQ), SF-36 Vitality domain, and Fibromyalgia Impact Questionnaire (FIQ) general and morning tiredness]. Pretreatment screening revealed an elevated incidence of maximum alpha EEG-intrusion > 24 min/hour of sleep (66%), periodic limb movements of sleep (20.1% ≥ 5/hour), and moderate to severe obstructive sleep apnea disorder (15.3% apnea-hypopnea index ≥ 15/hour). Compared with placebo, both doses of SXB achieved statistically significant improvements in ESS, morning FVAS, JSS, FOSQ, SF-36 Vitality, and FIQ general and morning tiredness; both doses also demonstrated decreased rapid eye movement (REM) sleep (all p ≤ 0.040). SXB 6 g/night improved afternoon, evening and overall FVAS, reduced wakefulness after sleep onset, and increased Stage 2, slow-wave, and total non-REM sleep (all p ≤ 0.032) versus placebo. Moderate correlations (≥ 0.40) were noted between changes in subjective sleep and pain measures. Adverse events occurring significantly more frequently with SXB than placebo were nausea, pain in extremity, nervous system disorders, dizziness, restlessness, and renal/urinary disorders (including urinary incontinence). This large cohort of patients with FM demonstrated that SXB treatment improved EEG sleep physiology and sleep-related FM symptoms.


Sequence-based classification scheme for the genus Legionella targeting the mip gene.
The identification and speciation of strains of Legionella is often difficult, and even the more successful chromatographic classification techniques have struggled to discriminate newly described species. A sequence-based genotypic classification scheme is reported, targeting approximately 700 nucleotide bases of the mip gene and utilizing gene amplification and direct amplicon sequencing. With the exception of Legionella geestiana, for which an amplicon was not produced, the scheme clearly and unambiguously discriminated among the remaining 39 Legionella species and correctly grouped 26 additional serogroup and reference strains within those species. Additionally, the genotypic classification of approximately 150 wild strains from several continents was consistent with their phenotypic classification, with the exception of a few strains where serological cross-reactivity was complex, potentially confusing the latter classification. Strains thought to represent currently uncharacterized species were also found to be genotypically unique. The scheme is technically simple for a laboratory with even basic molecular capabilities and equipment, if access to a sequencing laboratory is available.


Retrieval barriers in individual participant data reviews with network meta-analysis.
Individual participant data (IPD) from randomised controlled trials (RCTs) can be used in network meta-analysis (NMA) to underpin patient care and are the best analyses to support the development of guidelines about the use of healthcare interventions for a specific condition. However, barriers to IPD retrieval pose a major threat. The aim of this study was to present barriers we encountered during retrieval of IPD from RCTs in two published systematic reviews with IPD-NMA. We evaluated retrieval of IPD from RCTs for IPD-NMA in Alzheimer's dementia and type 1 diabetes. We requested IPD from authors, industry sponsors and data repositories, and recorded IPD retrieval, reasons for IPD unavailability, and retrieval challenges. In total, we identified 108 RCTs: 78 industry sponsored, 11 publicly sponsored and 19 with no funding information. After failing to obtain IPD from any trial authors, we requested it from industry sponsors. Seven of the 17 industry sponsors shared IPD for 12 950 participants (59%) through proprietary-specific data sharing platforms from 26 RCTs (33%). We found that lack of RCT identifiers (eg, National Clinical Trial number) and unclear data ownership were major challenges in IPD retrieval. Incomplete information in retrieved datasets was another important problem that led to exclusion of RCTs from the NMA. There were also practical challenges in obtaining IPD from or analysing it within platforms, and additional costs were incurred in accessing IPD this way. We found no clear evidence of retrieval bias (where IPD availability was linked to trial findings) in either IPD-NMA, but because retrieval bias could impact NMA findings, subsequent decision-making and guideline development, this should be considered when assessing risk of bias in IPD syntheses.


[Atypical osteodystrophy of visceral origin (author's transl)].
The authors report a case of atypical osteodystrophy of visceral origin (uretero-sigmoid by-pass for bladder exstrophy) which was characterized by the association of osteocondensation and looser-Milkman lines. They emphasize the rareness of osteodystrophy after uro-digestive by-pass and the exceptional character of the osteocondensation.


Anaesthetic management of a pregnant patient with intracranial space occupying lesion for craniotomy.
Intracranial space occupying lesion [SOL] during pregnancy presents several challenges to the neurosurgeons, obstetricians and anaesthesiologists in not only establishing the diagnosis, but also in the perioperative management as it requires a careful plan to balance both maternal and foetal well-being. It requires modification of neuroanaesthetic and obstetric practices which often have competing clinical goals to achieve the optimal safety of both mother and foetus. Intracranial tuberculoma should be considered in the differential diagnosis of intracranial SOL in pregnant women with signs and symptoms of raised intracranial pressure with or without neurological deficits, especially when they are from high incidence areas. We report a 28-week pregnant patient with intracranial SOL who underwent craniotomy and excision of the lesion, subsequently diagnosed as cranial tuberculoma.


Increased apoptosis of motoneurons and altered somatotopic maps in the brachial spinal cord of Hoxc-8-deficient mice.
Mice deficient for the homeotic gene Hoxc-8 suffer from a congenital prehension deficiency of the forepaw. During embryogenesis, Hoxc-8 is highly expressed in motoneurons within spinal cord segments C7 to T1. These motoneurons innervate forelimb distal muscles that move the forepaw. In Hoxc-8 mutant embryos, formation of these muscles is normal, but their innervation is perturbed. From E13.5 onwards, distal muscles normally supplied by C(7-8) MNs also receive ectopic projections from C(5-6) and T1 motoneurons. Coordinates of motor pools are altered along the rostrocaudal and also the mediolateral axes. Following this aberrant connectivity pattern and during the time of naturally occurring cell death, apoptosis is specifically enhanced in C7-T1 motoneurons. Loss of Hox-encoded regional specifications subsequently leads to a numerical deficit of motoneurons and an irreversible disorganization of motor pools. In Hoxc-8 null mutants, C(7-8) motoneurons lose their selective advantage in growth cone pathfinding behavior and/or target recognition, two essential steps in the establishment and maintenance of a functional nervous system.


Characterization of deoxyribonucleic acid (DNA) obtained from teeth subjected to various environmental conditions.
This study was designed to determine the effects of various environmental factors on the deoxyribonucleic acid (DNA) obtained from dental pulp. Extracted teeth were subjected to the following conditions: varying pH (3,7,10); temperature (4 degrees C, 25 degrees C, 37 degrees C, incineration); humidity (20%, 66%, 98%); various types of soil (sand, potting soil, garden soil); seawater; burying the teeth outdoors, and aging (one week to six months). In addition, teeth that had been extracted and held at room temperature for 16 and 19 years were also examined. Following isolation of DNA, the samples were analyzed on yield gels to determine the concentration and integrity of the recovered DNA. Restriction digestion with Pst I was followed by electrophoresis of the generated fragments, Southern transfer to nylon membranes, and hybridization to both human and bacterial probes. It was determined that, aside from soil, the environmental conditions examined did not affect the ability to obtain high-molecular-weight human DNA from dental pulp. Restriction fragment length polymorphic (RFLP) analysis of selected samples was performed. Dental pulp patterns were compared with bloodstain exemplars, revealing matching patterns, although an increase in band-shifting was observed with extended exposure to elevated temperatures.


Antioxidants in treatment of idiopathic sudden hearing loss.
Assuming that superoxide anion radicals (O(2)-) may play a role in damage to the inner ear, the authors investigated the possible benefit of vitamin E as an antioxidant in the treatment of idiopathic sudden hearing loss. Prospective, double-blind study. The Department of Otolaryngology of Rambam Medical Center serves as a tertiary referral center for a population of 1.2 million people. A total of 66 patients, aged 15 to 70 years, with diagnoses of idiopathic sudden hearing loss of less than 7 days' duration during 1998 to 2001, were included in the study. All were treated with bed rest, steroids, magnesium, and carbogen inhalation. The study group received vitamin E in addition. The recovery rate, calculated as hearing gain divided by the difference in hearing level between the affected and unaffected ear, was better than 75% in 41 of 66 (62.12%) patients. This rate was achieved in 26 (78.78%) patients in the study group treated with vitamin E, compared with 15 (45.45%) patients in the control group. Patients treated with the addition of vitamin E achieved better recovery than did the control patients. Further studies should be directed toward a better understanding of the role of antioxidants in idiopathic sudden hearing loss.


Natural Green coating inhibits adhesion of clinically important bacteria.
Despite many advances, biomaterial-associated infections continue to be a major clinical problem. In order to minimize bacterial adhesion, material surface modifications are currently being investigated and natural products possess large potential for the design of innovative surface coatings. We report the bioguided phytochemical investigation of Pityrocarpa moniliformis and the characterization of tannins by mass spectrometry. It was demonstrated that B-type linked proanthocyanidins-coated surfaces, here termed Green coatings, reduced Gram-positive bacterial adhesion and supported mammalian cell spreading. The proposed mechanism of bacterial attachment inhibition is based on electrostatic repulsion, high hydrophilicity and the steric hindrance provided by the coating that blocks bacterium-substratum interactions. This work shows the applicability of a prototype Green-coated surface that aims to promote necessary mammalian tissue compatibility, while reducing bacterial colonization.


Oral erythromycin is ineffective in the treatment of pityriasis rosea.
Despite the availability of various medical treatments for pityriasis rosea, a large percentage of patients fail to achieve satisfactory results. Erythromycin is reported to be effective in the treatment of pityriasis rosea. We designed a placebo-controlled study on 184 patients with pityriasis rosea attending the outpatient dermatology department at Hazrat-e-Rasul Hospital in Tehran, Iran. Adult patients were treated with 200 mg of erythromycin 4 times daily and children were treated with 20 to 40 mg/kg daily in 4 divided doses. Controls were given a placebo (an emollient cream) that was not identical in appearance. Subjects were seen at follow-up visits 2, 4, 6, and 8 weeks after starting treatment. Both groups were comparable with regard to sex, age, and mean duration of disease at the time of attending the clinic. We found no significant difference between the 2 treatment groups at weeks 4, 6, and 8 after beginning of treatment. (p > .05 Chi2).


ZD1839, a selective oral epidermal growth factor receptor-tyrosine kinase inhibitor, is well tolerated and active in patients with solid, malignant tumors: results of a phase I trial.
To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-tyrosine kinase inhibitor ZD1839 in patients with solid malignant tumors. This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non-small-cell lung cancer (NSCLC) had objective partial responses observed from ZD1839 300 to 700 mg/d. Overall, 16 patients remained on study for > or = 3 months, with seven of these patients (five with NSCLC, including three of the patients with partial response) remaining on study for > or = 6 months. ZD1839 was well tolerated, with DLT observed at a dose well above that at which antitumor activity was seen. Pharmacokinetic analysis confirmed that ZD1839 was suitable for administration as a once-daily oral tablet formulation. Phase II monotherapy and phase III combination trials in NSCLC are being conducted to investigate further the efficacy, tolerability, and optimal daily dose of ZD1839.


Adherence to exercise in later life: how can exercise on prescription programmes be made more effective?
A broad consensus has emerged in relation to the desirability of promoting exercise among a variety of 'at risk' groups via 'exercise on prescription' (EoP) schemes, as an alternative to orthodox, biomedical approaches to the management of health problems. Underpinning the rationale for such schemes is the notion that they can act as vehicles for encouraging long-term adherence to exercise. Whilst there is a common sense appeal to using EoP schemes to promote exercise, research to date suggests that evidence of their impact is limited. This paper attempts to make sense of these findings in the light of recent debates about adult lifestyles and exercise. More specifically, it brings work in the sociology of leisure to bear on the topic, on the premise that any study of adults' propensity towards sustainable physical activity needs to be viewed as an aspect of their lives 'in the round'. Such an analysis points up the value of synthesizing perspectives from across the disciplinary divide in order to shed light on particular 'problems', which obviate the necessity for further empirical work. The paper concludes by identifying a number of implications for public health policy and practice with respect to the matter of encouraging lifelong participation in sport and exercise in general, and via EoP schemes in particular. One such implication is the development of a model for understanding participation that shifts the emphasis away from a focus on motivation and behaviour change per se towards satisfaction and enjoyment through the development of skills and relationships. Reconceptualizing the matter of participation in this way is likely to lead not only to a more realistic appreciation of what can be expected from EoP schemes, but also a more adequate understanding of adherence to exercise in later life.


Physical Visualization of Geospatial Datasets.
Geospatial datasets are too complex to easily visualize and understand on a computer screen. Combining digital fabrication with a discrete global grid system (DGGS) can produce physical models of the Earth for visualizing multiresolution geospatial datasets. This proposed approach includes a mechanism for attaching a set of 3D printed segments to produce a scalable model of the Earth. The authors have produced two models that support the attachment of different datasets both in 2D and 3D format.


Differences among major taxa in the extent of ecological knowledge across four major ecosystems.
Existing knowledge shapes our understanding of ecosystems and is critical for ecosystem-based management of the world's natural resources. Typically this knowledge is biased among taxa, with some taxa far better studied than others, but the extent of this bias is poorly known. In conjunction with the publically available World Registry of Marine Species database (WoRMS) and one of the world's premier electronic scientific literature databases (Web of Science®), a text mining approach is used to examine the distribution of existing ecological knowledge among taxa in coral reef, mangrove, seagrass and kelp bed ecosystems. We found that for each of these ecosystems, most research has been limited to a few groups of organisms. While this bias clearly reflects the perceived importance of some taxa as commercially or ecologically valuable, the relative lack of research of other taxonomic groups highlights the problem that some key taxa and associated ecosystem processes they affect may be poorly understood or completely ignored. The approach outlined here could be applied to any type of ecosystem for analyzing previous research effort and identifying knowledge gaps in order to improve ecosystem-based conservation and management.


Calorimetric analysis of lisinopril binding to angiotensin I-converting enzyme.
Isothermal titration microcalorimetry has been used to measure changes in enthalpy and heat capacity for binding of lisinopril to the angiotensin I-converting enzyme (ACE; EC 188.8.131.52) and to its apoenzyme at pH 7.5 over a temperature range of 15-30 degrees C. Calorimetric measurements indicate that lisinopril binds to two sites in the monomer of both holo- and apo-ACE. Binding of lisinopril to both systems is enthalpically unfavorable and, thus, is dominated by a large positive entropy change. The enthalpy change of binding is strongly temperature-dependent for both holo- and apo-ACE, arising from a large heat capacity change of binding equal to -2.4 +/- 0.2 kJ/K/mol of monomeric holo-ACE) and to -1.9 +/- 0.2 kJ/K/mol of monomeric apo-ACE), respectively. The negative values of deltaCp for both systems are consistent with burial of a large non-polar surface area upon binding. Although the binding of lisinopril to holo- and apo-ACE is favored by entropy changes, this is more positive for the holoenzyme. Thus, the interaction between Zn2+ and lisinopril results in a higher affinity of the holoenzyme for this drug due to a more favorable entropic contribution.


Circadian dysfunction in response to in vivo treatment with the mitochondrial toxin 3-nitropropionic acid.
Sleep disorders are common in neurodegenerative diseases including Huntington's disease (HD) and develop early in the disease process. Mitochondrial alterations are believed to play a critical role in the pathophysiology of neurodegenerative diseases. In the present study, we evaluated the circadian system of mice after inhibiting mitochondrial complex II of the respiratory chain with the toxin 3-nitropropionic acid (3-NP). We found that a subset of mice treated with low doses of 3-NP exhibited severe circadian deficit in behavior. The temporal patterning of sleep behavior is also disrupted in some mice with evidence of difficulty in the initiation of sleep behavior. Using the open field test during the normal sleep phase, we found that the 3-NP-treated mice were hyperactive. The molecular clockwork responsible for the generation of circadian rhythms as measured by PER2::LUCIFERASE was disrupted in a subset of mice. Within the SCN, the 3-NP treatment resulted in a reduction in daytime firing rate in the subset of mice which had a behavioral deficit. Anatomically, we confirmed that all of the treated mice showed evidence for cell loss within the striatum but we did not see evidence for gross SCN pathology. Together, the data demonstrates that chronic treatment with low doses of the mitochondrial toxin 3-NP produced circadian deficits in a subset of treated mice. This work does raise the possibility that the neural damage produced by mitochondrial dysfunction can contribute to the sleep/circadian dysfunction seen so commonly in neurodegenerative diseases.


Long-term outcomes of artificial chordal replacement with tourniquet technique in mitral valve repair: a single-center experience of 700 cases.
Artificial chordal replacement has been shown to be effective and durable, with numerous techniques reported. However, the outcomes of each technique have remained poorly defined. We report the long-term outcomes of the tourniquet technique. We reviewed the data from 700 patients who had undergone mitral valve repair with the tourniquet technique from 1992 to 2010. We analyzed the operative outcomes, long-term survival rate, freedom from reoperation, and freedom from recurrent moderate or severe mitral regurgitation (MR). We also performed Cox regression analysis to explore the predictors of recurrent MR after mitral valve repair using the tourniquet technique. The mean age was 54.7±14.9 years; 212 patients (30.3%) had anterior leaflet prolapse, 142 (20.3%) had posterior leaflet prolapse, and 346 (49.4%) had bileaflet prolapse. Operative mortality was 1.3%. In 26 cases (3.7%), mitral valve repair was unsuccessful and was converted to replacement. Of those successfully repaired, the 12-year survival rate, freedom from mitral reoperation, freedom from recurrent moderate or severe MR, and freedom from recurrent leaflet prolapse was 85.9%, 88.7%, 72.3%, and 89.0%, respectively. The significant predictors of recurrent MR were anterior leaflet prolapse, age, New York Heart Association class III or IV, left ventricular end-systolic dimension, no annuloplasty ring or band, and postoperative residual mild or greater MR. The tourniquet technique is a simple and effective method to repair leaflet prolapse, with a low incidence of recurrent prolapse. The incidence of recurrent MR was high in the anterior leaflet prolapse group. Age, no annuloplasty ring or band, and residual MR were strong predictors of recurrent MR.


[Primary pulmonary NUT carcinoma: a clinicopathological analysis of seven cases].
Objective: To investigate the clinicopathological characteristics of primary pulmonary NUT carcinoma. Methods: A total of 7 cases of primary pulmonary NUT carcinoma were collected from Fujian Provincial Hospital (n=5), Fuzhou Taijiang Hospital (n=1) and Binzhou City People's Hospital of Shandong Province (n=1) from January 2021 to April 2023. The clinical, histopathological, and immunohistochemical features were analyzed, and NUT rearrangement were detected by fluorescence in situ hybridization (FISH) with break-apart probes. Results: Seven cases were all male with age ranging from 32 to 73 years. The main clinical manifestations were cough, expectoration and chest tightness. Microscopically, NUT carcinoma was composed of monotonous proliferation of primitive-appearing small-to-medium round cells, with few eosinophilic cytoplasm, arranged in solid sheets, nests or clusters. Abrupt keratinization was typically observed in 4 cases (4/7), with high mitotic activities and necrosis. Immunohistochemistry (IHC) showed that the tumors were positive for NUT (7/7), CK7 (4/4), CK5/6 (5/6), p40 (6/7). Ki-67 index were 30%-80%. NUT gene segregation (7/7) was detected by FISH break probes. Conclusions: Primary pulmonary NUT carcinoma is rare and highly malignant. Diagnosis depends on histopathology and IHC, with molecular detection as an adjunct for diagnosis. Pathologists should be aware of the clinicopathological characteristics to avoid misdiagnosis.


[Ultrastructural aspects of the process of Salmonella typhi bacterial interaction with L929-line cells].
The study of the use of scanning electron microscopy and the analysis of the initial stages of interaction between S. typhi and eukaryotic cells by the method of three-dimensional reconstruction has revealed that the infective agent penetrates into the cytoplasm on the principle of internalization. The internalization of S. typhi occurs with the active participation of the eukaryotic cells which, at the beginning, envelopes the bacteria with its processes, and the infective agents firmly adhere to the glycocalyx of the host cell by means of special fimbria-like formations differing from fimbriae by their lesser rigidity and thickness; then the microbes fixed to the membrane penetrate inside the cell without destroying its cytoplasmic membrane. Differences in the processes of the interaction of eukaryotic cells with S. typhi initial strain 238 and its variant free from the plasmid with a molecular weight of 6 Md, characterized by its lower capacity for association with cells of continuous cell culture L929, have been revealed. The factors stimulating the ingestion of S. typhi by eukaryotic cells are under study at present.


The key to long-term success in liposuction: a guide for plastic surgeons and patients.
Patients need to have realistic expectations for a long-term successful body contour result. There are four key elements for long-term successful improvement in body contour, and the patient is responsible for the first three: exercise, a proper diet, and other positive lifestyle changes; and successful body contouring. An extensive survey requesting information about the procedures, areas of liposuction, lifestyle habits, and satisfaction was mailed to 600 patients who had liposuction surgery performed between 1999 and 2003. One hundred and eight surveys were undeliverable and 209 completed surveys were returned (34.8 percent of 600 mailed surveys and 42.5 percent of 492 delivered surveys). Data were analyzed by a binary logistic regression with backward elimination. Weight gain (versus no weight gain) was used as the dependent variable. The results showed that regardless of whether the patient did or did not gain weight, both groups reported being very satisfied (30 percent and 48 percent, respectively) or satisfied (43 percent and 34 percent, respectively) with their procedure. Among the weight gain patients, 72 percent would still have the procedure again, compared with 82 percent of responders who did not gain weight. When asked if they would recommend the procedure to family or friends, 90 percent of responders who did not gain weight would recommend the procedure whereas only 74 percent of responders who did gain weight would recommend the procedure (p < 0.001). Among those patients who gained weight, only 29 percent thought their appearance was excellent or good (compared with 79 percent of those who did not gain weight). Among the 57 percent of patients who did not gain weight, 35 percent report exercising more postoperatively (compared with only 10 percent in the weight gain group, p = 0.002) and 50 percent report eating a healthier diet (22 percent in the weight gain group report eating a healthier diet, p = 0.002). In the weight gain group, 67 percent report no change in their diet regimen and only 17 percent thought their productivity increased (compared with 25 percent among the no weight gain group, p = 0.002). Successful body contouring surgery requires a patient to embrace positive lifestyle habits. The results of this survey have been used to create a quantitative decision-making framework or a "road map" for patients and plastic surgeons to use for navigating toward successful long-term results.


Elder Abuse and Depressive Symptoms: Which is Cause and Effect? Bidirectional Longitudinal Studies From the JAGES.
Elder abuse is a serious public health concern that increases the risks of negative health outcomes globally. It is well known that abuse in older adults is associated with depression; however, longitudinal studies investigating the causal relationship between these events are scarce. Because the cause precedes the result over time, the temporal relationships between abuse and depression should be verified from each direction. This longitudinal study, therefore, investigated and clarified whether depression causes or results from elder abuse among older Japanese adults. Two longitudinal analyses were conducted using data derived from the Japan Gerontological Evaluation Study. The data were collected in 2010 and 2013 through a mail survey of 1,737 people (983 females, 754 males) across Japan. Of those who did not experience abuse in 2010, 38 (5.0%) males and 53 (5.4%) females newly experienced abuse in 2013. Among respondents who did not have depressive symptoms in 2010, 60 (8.0%) males and 61 (6.2%) females newly reported depressive symptoms in 2013. After adjusting for demographic factors in Analysis 1, people who experienced abuse were 2.28-fold (95% confidence interval [CI] = 1.68-3.09) more likely to have depressive symptoms three years later than those who were not abused. In Analysis 2, respondents who had mild or severe depression in 2010 were 2.23-fold (95% CI = 1.61-3.10) more likely to have experienced abuse after three years than those who did not have depression. After adjusting for several demographic factors, the results showed that abuse can lead to depression and that depression can be a cause of abuse. Therefore, preventing abuse should be considered from both directions.


Now you Bayes, now you don't: effects of set-problem and frequency-format mental representations on statistical reasoning.
People appear to be Bayesian when statistical information is presented in terms of natural frequencies and non-Bayesian when presented in terms of single-event probabilities, unless the probabilities resemble natural frequencies, for example, as chances. The isomorphic format of chances, however, does not always facilitate performance to the extent that the format of natural frequencies does. Prior research has not addressed the underlying mechanism that accounts for this gap despite its theoretical significance. The mechanism explaining this external format gap could lie in the interpretation of the problem as a set-problem, which cues relevant problem model and arithmetic operations (the problem interpretation hypothesis) and/or in the interpretation of the format as frequencies, which may be easier to process (the format interpretation hypothesis). In two parallel experiments, we found support for the problem interpretation hypothesis only: set representations mediated solely the isomorphic format gap (Experiment 1: part A) and accounted for the transfer effect to natural frequencies (Experiment 1: part B); priming set representations improved performance with chances (Experiment 2). We discuss how the supported explanation corroborates the nested-sets rather than the ecological rationality account of statistical reasoning and how it helps explain individual differences in Bayesian reasoning.


Medical nutrition therapy administered by a dietitian yields favourable diabetes outcomes in individual with type 2 diabetes mellitus.
This prospective, single-group, pre-post design trial was conducted to evaluate the effect of individualised Medical Nutrition Therapy intervention administered by a dietitian in individuals with type 2 diabetes mellitus on glycaemic control, metabolic parameters and dietary intake. Subjects (n=104; age=56.4 ±9.9 years; 37% male; years of diagnosis = 6.3 ±4.9 years) treated with diet and on a stabile dose of oral anti-diabetic agents were given dietary advice by a dietitian for a 12 week period. Individualised dietary advice was based on Malaysian Medical Nutrition Therapy for adults with type 2 diabetes mellitus. The primary outcome measure was glycaemic control (fructosamine and HbA1c level) and the secondary outcome included measures of anthropometry, blood pressure, lipid profile, insulin levels dietary intake and knowledge on nutrition. At week 12, 100 subjects completed the study with a dropout rate of 3.8%. The post-Medical Nutrition Therapy results showed a significant reduction of fructosamine (311.5 ±50 to 297 ±44 umol/L; P< 0.001) and HbA1c (7.6 ±1.2 to 7.2 +1.1%, p<0.001) with pronounced reduction for subjects who had very high HbA1c levels of >9.3% at baseline. Waist circumference (90.7 ±10.2 to 89.1 ±9.8 cm, p<0.05), HDL-cholesterol (1.1 ±0.3 to 1.2 ±0.3 mmol/L, p<0.05), dietary intake and nutrition knowledge score (42 ±19 vs. 75 ±17%; p< 0.001) were significantly improved from the baseline. Individualised Medical Nutrition Therapy administered by a dietitian resulted in favourable diabetes outcomes, which were more apparent for individuals with higher than optimal HbA1c levels at the start of the study.


[An update on unconjugated neonatal hyperbilirubinaemia in Denmark].
Approximately 60% of term newborn infants are jaundiced during the first week of life, which is caused by unconjugated bilirubin. Bilirubin encephalopathy is seen with severe hyperbilirubinaemia, when unbound bilirubin crosses the blood-brain barrier. The chronic form is called kernicterus spectrum disorder. To avoid this devastating condition, the treatment of choice for neonatal hyperbilirubinaemia is phototherapy, which is most efficient with LED light of 478-nm wavelength. In this review, we argue, that a systematic approach to hyperbilirubinaemic infants as well as surveillance of extreme neonatal hyperbilirubinaemia is highly important.


Change in multimodal MRI markers predicts dementia risk in cerebral small vessel disease.
To determine whether MRI markers, including diffusion tensor imaging (DTI), can predict cognitive decline and dementia in patients with cerebral small vessel disease (SVD). In the prospective St George's Cognition and Neuroimaging in Stroke study, multimodal MRI was performed annually for 3 years and cognitive assessments annually for 5 years in a cohort of 99 patients with SVD, defined as symptomatic lacunar stroke and confluent white matter hyperintensities (WMH). Progression to dementia was determined in all patients. Progression of WMH, brain volume, lacunes, cerebral microbleeds, and a DTI measure (the normalized peak height of the mean diffusivity histogram distribution) as a marker of white matter microstructural damage were determined. Over 5 years of follow-up, 18 patients (18.2%) progressed to dementia. A significant change in all MRI markers, representing deterioration, was observed. The presence of new lacunes, and rate of increase in white matter microstructural damage on DTI, correlated with both decline in executive function and global functioning. Growth of WMH and deterioration of white matter microstructure on DTI predicted progression to dementia. A model including change in MRI variables together with their baseline values correctly classified progression to dementia with a C statistic of 0.85. This longitudinal prospective study provides evidence that change in MRI measures including DTI, over time durations during which cognitive change is not detectable, predicts cognitive decline and progression to dementia. It supports the use of MRI measures, including DTI, as useful surrogate biomarkers to monitor disease and assess therapeutic interventions.


Heat shock protein synthesis is induced by diethyl phthalate but not by di(2-ethylhexyl) phthalate in radish (Raphanus sativus).
The toxicity and effects on protein synthesis of the phthalate esters diethyl phthalate (DEP) and di(2-ethylhexyl) phthalate (DEHP) was studied in radish seedings (Raphanus sativus cv. Kööpenhaminan tori). Phthalate esters are a class of commercially important compounds used mainly as plasticizers in high molecular-weight polymers such as many plastics. They can enter soil through various routes and can affect plant growth and development. First the effect of DEP and DEHP on the growth of radish seedings was determined in an aqueous medium. It was found that DEP, but not DEHP, caused retardation of growth in radish. A further investigation on protein synthesis during DEP-stress was executed by in vivo protein labeling combined with two-dimensional gel electrophoresis (2D-PAGE). For comparisons with known stress-induced proteins a similar experiment was done with heat shock, and the induced heat shock proteins (HSPs) were compared with those of DEP-stress. The results showed that certain HSPs can be used as an indicator of DEP-stress, although the synthesis of most HSPs was not affected by DEP. DEP also elicited the synthesis of numerous proteins found only in DEP-treated roots. The toxic effect of phthalate esters and the roles of the induced proteins are discussed.


The IFCC recommendation on estimation of reference intervals. The RefVal program.
The International Federation of Clinical Chemistry (IFCC) published between 1987--91 a series of six recommendations on reference values in laboratory medicine. This paper reviews the history and scope of the fifth part of these recommendations. This fifth recommendation deals with statistical methods used for analysis of reference values and estimation of reference intervals. The RefVal program, which implements the recommended method, is also described.


The information content of phase-known matings for ordering genetic loci.
This analysis evaluates the amount of linkage information that can be obtained for for ordering three loci. The information contents of data collected on three independent pairwise samples of two loci, and data obtained jointly from three loci in a single set of individuals are compared. The level of support of the maximum likelihood order and the interpretation of that support are also examined.


Cutaneous superficial myiasis: report of a rare nosocomial parasitic disease caused by Sarcophaga spp. (diptera, sarcophagidae).
Flies of the genus Sarcophaga are known to cause myiasis in necrotic wounds and in anatomical cavities where fluids have collected. We present here the first case of external cutaneous myiasis by Sarcophaga larvae in the absence of skin ulcerations or necrosis. The host in this case was a geriatric patient with limited motor and neurological capacity who lives in a nursing home. Of particular importance is that Sarcophaga is capable of causing myiasis even in the absence of cutaneous infections or significant stasis of fluids or secretions and that the larvae can cause damage in otherwise healthy tissue.


A randomized controlled trial of a decision aid for women considering genetic testing for breast and ovarian cancer risk.
To measure the effectiveness of a tailored decision aid (DA) designed to help women make informed decisions about genetic testing for breast/ovarian cancer risk. A total of 145 women were randomized to receive the DA or a control pamphlet at the end of their first genetic counseling consultation. Of these, 120 (82.8%) completed two questionnaires, 1 week and 6 months post-consultation. While the DA had no effect on informed choice, post-decisional regret or actual genetic testing decision, the trial showed that women who received the DA had higher knowledge levels and felt more informed about genetic testing than women who received the control pamphlet (chi(2)(2) = 6.82; P = 0.033; chi(2)(1) = 4.86; P = 0.028 respectively). The DA also helped women who did not have blood drawn at their first consultation to clarify their values with regards to genetic testing (chi(2)(1) = 5.27; P = 0.022). Women who received the DA were less likely to share the information with other family members than women in the control condition (chi(2)(1) = 8.78; P = 0.003). Decision aids are an effective decision-support strategy for women considering genetic testing for breast/ovarian cancer risk, and are most effective before the patient has made a decision, which is generally at the point of having blood drawn.


Determination of dynamic variations in the optical properties of graphene oxide in response to gas exposure based on thin-film interference.
We present an effective yet simple approach to study the dynamic variations in optical properties (such as the refractive index (RI)) of graphene oxide (GO) when exposed to gases in the visible spectral region, using the thin-film interference method. The dynamic variations in the complex refractive index of GO in response to exposure to a gas is an important factor affecting the performance of GO-based gas sensors. In contrast to the conventional ellipsometry, this method alleviates the need of selecting a dispersion model from among a list of model choices, which is limiting if an applicable model is not known a priori. In addition, the method used is computationally simpler, and does not need to employ any functional approximations. Further advantage over ellipsometry is that no bulky optics is required, and as a result it can be easily integrated into the sensing system, thereby allowing the reliable, simple, and dynamic evaluation of the optical performance of any GO-based gas sensor. In addition, the derived values of the dynamically changing RI values of the GO layer obtained from the method we have employed are corroborated by comparing with the values obtained from ellipsometry.


[Experimental investigation of cardiac lymph vascular system (author's transl)].
Ligatures of the supracardiac lymph vessels and the cardiac lymph nodes have been performed in fifty mongrel dogs. Comparative electrocardiographical, light microscopical, scanning and transmission electron microscopical investigations were done one day to three months after surgery. The demonstrated findings confirmed former results concerning the topography and the microstructure of the cardiac lymph vascular drainage system. In addition, the comparative functional and morphological examinations made evident the pathogenetic importance of cardiac lymphostasis. Lymphostatic oedema has been discussed as a pathogenetic co-factor for human heart diseases. Therapeutic attempts on experimental cardiac lymphostasis with i.v. - application of Coumarin-Troxerutin were without effect.


Intensive Home Hemodialysis Results in Regression of Left Ventricular Hypertrophy and Better Clinical Outcomes.
Left ventricular hypertrophy (LVH) is an independent risk factor for mortality and cardiovascular events in patients with end-stage renal disease. Studies have shown that frequent hemodialysis leads to LVH regression, but the impact of left ventricular mass (LVM) regression on clinical outcomes remains unknown. This observational cohort study assessed the impact of LVH regression on the composite outcome of time to all-cause mortality, technique failure or cardiovascular hospitalization in patients on home hemodialysis. LVH regression was defined as either a reduction of more than 10% in LVM in patients with LVH at baseline or prevention of LVH in those without LVH at baseline. Risk factors associated with progression of LVM were also examined. We studied 144 intensive hemodialysis patients between 1999 and 2012 with a mean follow-up of 4.7 years. Eighty-seven patients (60.4%) had LVH regression or prevention and 57 patients (39.6%) had LVH progression. In a multivariate analysis, smoking (OR 2.78, 95% CI 1.06-7.36) and presence of LVH at baseline (OR 2.21, 95% CI 1.06-4.59) were significant predictors for LVM progression. Sixteen patients (18.4%) in the regressor group and 19 patients (33.3%) in the progressor group developed the composite end point. When adjusted for age and diabetes, regression was significantly associated with a decreased risk (hazards ratio (HR) 0.42, 95% CI 0.21-0.84) for the composite end point. Regression was also significantly associated with a decreased risk of death in the adjusted analysis (HR 0.20, 95% CI 0.06-0.67). Regression of LVH with intensive hemodialysis is associated with favorable clinical outcomes.


Cutaneous malignant melanoma in Hawaii--an update.
In an examination of the descriptive epidemiology of cutaneous malignant melanoma in Hawaii for the period of 1960 through 1980, we identified 589 cases of invasive disease. On analysis, we found that the incidence of cutaneous malignant melanoma increased substantially among all age groups, both sexes and all anatomic sites in whites during the study period. In contrast, little change in incidence was found for nonwhites. Our findings are in agreement with the hypothesis that solar ultraviolet radiation is a causal factor for the occurrence of this condition among whites.


[Application of four variants of the diagnostic disc test (CD01, CD02, CD03, CD04) for detection of ESBL-positive strains of gram-negative rods].
The aim of this study was to evaluate the usefulness of four variants of the diagnostic disc test (DD) to detect extended-spectrum beta-lactamases (ESBLs) in nosocomial strains of gram-negative rods. Also, the diagnostic disc test (DD) was compared with the double-disc synergy test (DDST) for the effectivity of ESBLs identification. A total number of 111 ESBL-positive (DDST-positive) strains of gram-negative rods isolated from hospitalized patients in 2004 was examined. Ninety nine strains belonged to enteric rods (89.2%) and twelve strains--to nonfermentative rods (10.8%). Two reference strains: E. coli ATCC 25922 (ESBL-negative one) and K. pneumoniae ATCC 700603 (ESBL-positive one) were included in the study. Four variants of the diagnostic disc test (DD, Oxoid Ltd, UK) were applied for ESBLs detection: CPD/CD01, CAZ/CD02, CTX/CD03 and CPO/CD04. All examined strains (111) were DDST-positive. Positive results in the DD test (Oxoid Ltd) were as follows: CPD/CD01--59 strains (53.2%), CAZ/CD02--80 strains (72.1%), CTX/CD03--92 strains (82.9%) and CPO/CD04--110 strains (99.1%). Discs containing cefpirome (CPO) and cefpirome with clavulanic acid (CD04) were the best set for detection of ESBLs in our collection of clinical gram-negative rods. Results of this variant of the DD test were the most consistent with the results of the DDST. Application of several disc diffusion methods to detect ESBL producers increases the probability of proper identification of these strains.


Assessment and Impact of Intravenous Medication Fluid Administration in Critically Ill Patients With Acute Respiratory Failure.
Positive fluid balance early in critical illness is associated with poor outcomes. Reducing intravenous medication volume may mitigate volume overload. Objective: Assessment of fluid and medication administration and clinical outcomes in acute respiratory failure. Single-center, prospective observational study of hemodynamically stable adult patients in a medical intensive care unit (MICU) with acute respiratory failure. Median cumulative total intake volume was 12 890 (interquartile range [IQR] = 8654-22 221) mL (n = 27), and median cumulative intravenous medication volume was 3563 (IQR = 2371-9412) mL over the first 7 days. Medication volume accounted for 27.6% of aggregate fluid volume. Median daily intravenous medication volume administered was 591 (IQR = 339-1082) mL. Cumulative fluid volume was associated with reduced ventilator-free days (r2 = -0.393; P = 0.043), and cumulative fluid volumes during the first 3 and 7 days were associated with increased MICU length of stay (LOS ± standard error 0.73 ± 0.35 d/L, P = 0.047, and 0.38 ± 0.16 d/L, P = 0.021, respectively). Cumulative medication volume administered significantly reduced the likelihood of mechanical ventilator liberation (hazard ratio [HR] = 0.917; 95% CI: 0.854, 0.984; P = 0.016) and MICU discharge (HR = 0.911; 95% CI: 0.843, 0.985; P = 0.019). Small-volume infusion may decrease cumulative intravenous medication volume by 38%. Intravenous medication diluent contributes substantially to total fluid intake in patients with acute respiratory failure and is associated with poor outcomes. Reduction of intravenous medication fluid volume to improve clinical outcomes should be further investigated.


A Mobile Health Platform for Self-Management of Pediatric Cystic Fibrosis: Qualitative Study of Adaptation to Stakeholder Needs and Integration in Clinical Settings.
Cystic fibrosis (CF) is an inherited chronic condition that requires extensive daily care and quarterly clinic visits with a multidisciplinary care team. The limited exchange of information outside of the quarterly clinic visits impedes optimal disease self-management, patient engagement, and shared decision making. The aim of this study is to adapt a mobile health (mHealth) app originally developed in Sweden to the needs of patients, families, and health care providers in a CF center in the United States and to test it as a platform for sharing patient-generated health data with the CF health care team. Focus groups with health care providers of patients with CF, adolescents with CF, and caregivers of children with CF were conducted to determine what modifications were necessary. Focus group data were analyzed using a thematic analysis, and emergent themes were ranked according to desirability and technical feasibility. The mHealth platform was then modified to meet the identified needs and preferences, and the flow of patient-generated health data to a secure Research Electronic Data Capture database was tested. Protocols for data management and clinical follow-up were also developed. A total of 5 focus groups with 21 participants were conducted. Recommended modifications pertained to all functionalities of the mHealth platform, including tracking of symptoms, treatments, and activities of daily care; creating and organizing medication lists and setting up reminders; generating reports for the health care team; language and presentation; sharing and privacy; and settings and accounts. Overall, health care providers recommended changes to align the mHealth platform with US standards of care, people with CF and their caregivers requested more tracking functionalities, and both groups suggested the inclusion of a mental health tracker as well as more detailed response options and precise language. Beta testers of the modified platform reported issues related to translatability to US environment and various bugs. This study demonstrated the importance of identifying the needs and preferences of target users and stakeholders before adopting existing mHealth solutions. All relevant perspectives, including those of clinicians, patients, and caregivers, should be thoroughly considered to meet both end users' needs and evidence-based practice recommendations.


A synergetic stabilization and strengthening strategy for two-dimensional ordered hybrid transition metal carbides.
Two-dimensional (2D) transition metal carbides (MXenes) exhibit excellent thermodynamic stability and remarkable mechanical strength and flexibility, as well as rich functionality, which attract considerable interest due to their potential application for high-performance flexible and stretchable devices. However, premature phonon instability of some non-hybrid MXenes was recently found to intrinsically limit their strength and flexibility, evoking passionate curiosity in pursuing an effective solution for more impressive mechanical properties. In this work, on the basis of an alloying strengthening mechanism, a combinational strategy is proposed to build ordered hybrid M2''M'C2O2 (M'' = Mo, W; M' = Ti, Zr, Hf) with remarkable dynamic stability and superior mechanical properties by hindering the premature phonon instability originating from the outer transition metals. By means of comprehensive screening, symmetrical-Mo2TiC2O2 is interestingly found to possess excellent stability at equilibrium and outstanding tolerance to phonon instability during straining compared to its Ti counterpart, being attributed to the character of the robust Mo-dz2 and O-pz hybridization. Although similar optical phonon soft modes appear in Ti3C2O2 and Mo2TiC2O2 under multiple loadings, the latter is much stiffer during straining. An in-depth analysis of deformed electronic structures reveals that a strain-induced increasing density of states in the vicinity of the Fermi level mainly composed of Mo-dz2 states facilitates the fatal phonon softening in Mo2TiC2O2 under biaxial tension, while differing from the mechanical instability in Ti3C2O2 triggered by a Peierls transition. Our findings provide a novel stabilization and strengthening strategy for 2D materials, and pave a new way for searching for 2D material candidates in designing flexible devices.


The effects of graded levels of concentrate supplementation on colour and lipid stability of beef from pasture finished late-maturing bulls.
Finishing late-maturing bulls on grass may alter the antioxidant/prooxidant balance leading to beef with higher susceptibility to lipid oxidation and a lower colour stability compared to bulls finished on cereal concentrates. In this context, lipid oxidation and colour stability of beef from late-maturing bulls finished on pasture, with or without concentrate supplements, or indoors on concentrate was assessed. Charolais or Limousin sired bulls (n = 48) were assigned to four production systems: (1) pasture only (P), (2) pasture plus 25% dietary DM intake as barley-based concentrate (PC25), (3) pasture plus 50% dietary DM intake as barley-based concentrate (PC50) or (4) a barley-based concentrate ration (C). Following slaughter and postmortem ageing, M. Longissimus thoracis et lumborum was subjected to simulated retail display (4°C, 1000 lux for 12 h out of 24 h) for 3, 7, 10 and 14 days in modified atmosphere packs (O2 : CO2; 80 : 20). Lipid oxidation was determined using the 2-thiobarbituric acid-reactive substances assay; α-tocopherol was determined by HPLC; fatty acid methyl esters were determined using Gas Chromatography. Using a randomised complete block design, treatment means were compared by either ANOVA or repeated measures ANOVA using the MIXED procedure of SAS. Total polyunsaturated fatty acid (PUFA) concentrations were not affected by treatment, n-3 PUFAs were higher (P < 0.001) and the ratio of n-6 to n-3 PUFAs was lower (P < 0.001) in muscle from P, PC25 and PC50 compared to C. α-Tocopherol concentration was higher in muscle from P compared to PC50 and C bulls (P = 0.001) and decreased (P < 0.001) in all samples by day 14. Lipid oxidation was higher in muscle from C compared to P bulls on day 10 and day 14 of storage (P < 0.01). Finishing on pasture without supplementation did not affect beef colour stability and led to lower lipid oxidation, possibly due to the higher α-tocopherol concentration compared to concentrate finished beef.


Hybrid resistive tactile sensing.
The paper describes a novel design of a robot tactile sensor, called hybrid tactile sensor, based on analog resistive technology. The design employs a set of parallel analog resistive sensing strips, rather than a two-dimensional (2D) grid of sensing elements, to sample the sensor surface. It is therefore analog in one dimension and discrete in the other. As a result, the number of samples that need to be obtained is significantly reduced, as is the number of connectors in the sensor circuitry. In addition, the sensor design scales easily to a large sensing surface area, and offers flexibility in sensor geometry. However, only the contact location and shape can be sensed, but not the contact force. The paper provides the theoretical model of the sensor, and presents simulation and experimental results.


Hypoglycemia, polycythemia and hyponatremia in a newborn exposed to nebivolol during pregnancy.
Nebivolol is a third-generation beta blocker that exerts selective antagonistic activity on β1 receptors. It has vasodilating properties that result from direct stimulation of endothelial nitric oxide synthase. Nebivolol is indicated for the treatment of hypertension and heart failure, and is generally well tolerated. In this article, we report a case of an infant who was admitted to the Pediatrics and Neonatology Unit of the Moscati Hospital (Aversa, Italy) about 24 hours after birth. The reason for hospitalization was persistent severe hypoglycemia (blood glucose = 30 mg/dL) and jaundice (total bilirubin = 12.5 mg/dL, indirect bilirubin 11.75 mg/dL). He was born by spontaneous delivery after a normal term pregnancy. Birth weight was 3040 g and the Apgar score was 6-9. The mother reported taking nebivolol 5 mg/day for unspecified tachycardia in the last 4 months of pregnancy. Clinical and instrumental investigations carried out during hospitalization did not reveal any congenital or perinatal abnormalities. After treatment for metabolic and electrolyte imbalance, he was discharged on the 10(th) day of hospitalization, in good clinical condition and with normalization of clinical and laboratory parameters. Currently, there are no specific studies on nebivolol tolerability during pregnancy. Our data suggest that the risk profile of nebivolol during pregnancy is the same as that of other β-blockers. Therefore, further studies are required to determine the safety of β-blockers during pregnancy and the risks to the unborn child.


Molecular nature of Spemann's organizer: the role of the Xenopus homeobox gene goosecoid.
This study analyzes the function of the homeobox gene goosecoid in Xenopus development. First, we find that goosecoid mRNA distribution closely mimics the expected localization of organizer tissue in normal embryos as well as in those treated with LiCl and UV light. Second, goosecoid mRNA accumulation is induced by activin, even in the absence of protein synthesis. It is not affected by bFGF and is repressed by retinoic acid. Lastly, microinjection of goosecoid mRNA into the ventral side of Xenopus embryos, where goosecoid is normally absent, leads to the formation of an additional complete body axis, including head structures and abundant notochordal tissue. The results suggest that the goosecoid homeodomain protein plays a central role in executing Spemann's organizer phenomenon.


Li(+) solvation in glyme-Li salt solvate ionic liquids.
Certain molten complexes of Li salts and solvents can be regarded as ionic liquids. In this study, the local structure of Li(+) ions in equimolar mixtures ([Li(glyme)]X) of glymes (G3: triglyme and G4: tetraglyme) and Li salts (LiX: lithium bis(trifluoromethanesulfonyl)amide (Li[TFSA]), lithium bis(pentafluoroethanesulfonyl)amide (Li[BETI]), lithium trifluoromethanesulfonate (Li[OTf]), LiBF4, LiClO4, LiNO3, and lithium trifluoroacetate (Li[TFA])) was investigated to discriminate between solvate ionic liquids and concentrated solutions. Raman spectra and ab initio molecular orbital calculations have shown that the glyme molecules adopt a crown-ether like conformation to form a monomeric [Li(glyme)](+) in the molten state. Further, Raman spectroscopic analysis allowed us to estimate the fraction of the free glyme in [Li(glyme)]X. The amount of free glyme was estimated to be a few percent in [Li(glyme)]X with perfluorosulfonylamide type anions, and thereby could be regarded as solvate ionic liquids. Other equimolar mixtures of [Li(glyme)]X were found to contain a considerable amount of free glyme, and they were categorized as traditional concentrated solutions. The activity of Li(+) in the glyme-Li salt mixtures was also evaluated by measuring the electrode potential of Li/Li(+) as a function of concentration, by using concentration cells against a reference electrode. At a higher concentration of Li salt, the amount of free glyme diminishes and affects the electrode reaction, leading to a drastic increase in the electrode potential. Unlike conventional electrolytes (dilute and concentrated solutions), the significantly high electrode potential found in the solvate ILs indicates that the solvation of Li(+) by the glyme forms stable and discrete solvate ions ([Li(glyme)](+)) in the molten state. This anomalous Li(+) solvation may have a great impact on the electrode reactions in Li batteries.


C2CD6 regulates targeting and organization of the CatSper calcium channel complex in sperm flagella.
The CatSper cation channel is essential for sperm capacitation and male fertility. The multi-subunit CatSper complexes form highly organized calcium signaling nanodomains on flagellar membranes. Here, we report identification of an uncharacterized protein, C2CD6, as a subunit of the mouse CatSper complex. C2CD6 contains a calcium-dependent, membrane-targeting C2 domain. C2CD6 associates with the CatSper calcium-selective, core-forming subunits. Deficiency of C2CD6 depletes the CatSper nanodomains from the flagellum and results in male sterility. C2CD6-deficient sperm are defective in hyperactivation and fail to fertilize oocytes both in vitro and in vivo. CatSper currents are present but at a significantly lower level in C2CD6-deficient sperm. Transient treatments with either Ca2+ ionophore, starvation, or a combination of both restore the fertilization capacity of C2CD6-deficient sperm. C2CD6 interacts with EFCAB9, a pH-dependent calcium sensor in the CatSper complex. We postulate that C2CD6 facilitates incorporation of the CatSper complex into the flagellar plasma membrane and may function as a calcium sensor. The identification of C2CD6 may enable the long-sought reconstitution of the CatSper ion channel complex in a heterologous system for male contraceptive development.


[Formation of systems of unilateral conditioned reflexes following section of the rostral portion of the corpus callosum].
Unilateral conditioned reflexes and two-link reflex systems with regular rhythmic alternation of positive and inhibitory reflexes were elaborated by Abuladze method in four dogs with a preliminarily dissected rostral part of the callosal body. Whereas the rate of formation of simple unilateral positive reflexes did not differ from that of reflex formation in intact animals, the formation of two-link unilateral systems proved to be disturbed. In spite of considerable stabilization of positive and inhibitory reflexes, ultraparadoxical relations were revealed when the same stimuli were applied in the system which testified to the disturbance of the after-effect dynamics. It has been assumed that rostral parts of the callosal body take part in the fixation of traces as the first component of the memory mechanism.


Results of percutaneous closure of patent foramen ovale with the GORE(®) septal occluder.
The aim of this study was to evaluate the safety and efficacy of the GORE(®) Septal Occluder (GSO) at 1-, 6-, and 12-month follow-up in patients with a clinical indication for patent foramen ovale (PFO) closure. Limited data are available regarding the safety and efficacy of the GSO for PFO closure. Sixty consecutive patients with an embolic event, migraine, or risk of decompression sickness were enrolled. Transesophageal or transthoracic echocardiography and clinical follow-up were performed at 1, 6 and 12 months after implantation. All patients received 100 mg aspirin and 75 mg clopidogrel for 6 months. Procedures were technically successful in 98.3% (59/60). In one case, the anterior interatrial septal rim proved too short to allow safe GSO implantation and, instead, a different occluder was implanted. One patient developed transient neurological symptoms during the procedure without evidence for a stroke by magnetic resonance imaging. At 6-month follow-up, the closure rate was 86.6% (52/60). The complete closure rate after 1 year was 93.3% (56/60). Stroke, thrombus formation and atrial fibrillation (AF)/flutter occurred in 1 (1.7%), 1 (1.7%), and 5 (8.3%) patients, respectively. PFO closure with the GSO is accompanied by a high technical success rate and closure rates similar to other currently used devices. The incidence of AF was higher than reported with most other devices. This may be a chance finding but warrants further investigation in larger trials.


Evaluation of an ultrasonic method applied to the measurement of blood coagulation time.
Clinical assessment of the blood clotting mechanism is usually made by measuring the time necessary for a sample of plasma to clot. In this work a semi-automatic method for measuring coagulation time is evaluated. It employs ultrasound, at 2.7 MHz, for monitoring variations of the viscosity in a plasma sample undergoing coagulation. The evaluation is performed by comparing measurements obtained by two well-known methods, the manual tilt tube and the fibrometer, with those obtained using the ultrasonic method. A total of 330 plasma samples from individuals with normal and altered homeostatic process were analysed. The experimental protocol follows two standard tests: the prothrombin time (141 samples) and the activated partial thromboplastin time (189 samples). The agreement between the three different methods is estimated statistically and it is shown that all the three can be used interchangeably for clinical purposes.


Fast discrimination of traditional Chinese medicine according to geographical origins with FTIR spectroscopy and advanced pattern recognition techniques.
Combined with Fourier transform infrared (FTIR) spectroscopy and three kinds of pattern recognition techniques, 53 traditional Chinese medicine danshen samples were rapidly discriminated according to geographical origins. The results showed that it was feasible to discriminate using FTIR spectroscopy ascertained by principal component analysis (PCA). An effective model was built by employing the Soft Independent Modeling of Class Analogy (SIMCA) and PCA, and 82% of the samples were discriminated correctly. Through use of the artificial neural network (ANN)-based back propagation (BP) network, the origins of danshen were completely classified.


Pseudomonas aeruginosa nosocomial pneumonia: impact of pneumonia classification.
To describe and compare the mortality associated with nosocomial pneumonia due to Pseudomonas aeruginosa (Pa-NP) according to pneumonia classification (community-onset pneumonia [COP], hospital-acquired pneumonia [(HAP], and ventilator-associated pneumonia [VAP]). We conducted a retrospective cohort study of adults with Pa-NP. We compared mortality for Pa-NP among patients with COP, HAP, and VAP and used logistic regression to identify risk factors for hospital mortality and inappropriate initial antibiotic therapy (IIAT). Twelve acute care hospitals in 5 countries (United States, 3; France, 2; Germany, 2; Italy, 2; and Spain, 3). A total of 742 patients with Pa-NP. Hospital mortality was greater for those with VAP (41.9%) and HAP (40.1%) compared with COP (24.5%) (P<.001). In multivariate analyses, independent predictors of hospital mortality differed by pneumonia classification (COP: need for mechanical ventilation and intensive care; HAP: multidrug-resistant isolate; VAP: IIAT, increasing age, increasing Charlson comorbidity score, bacteremia, and use of vasopressors). Presence of multidrug resistance was identified as an independent predictor of IIAT for patients with COP and HAP, whereas recent antibiotic administration was protective in patients with VAP. Among patients with Pa-NP, pneumonia classification identified patients with different risks for hospital mortality. Specific risk factors for hospital mortality also differed by pneumonia classification and multidrug resistance appeared to be an important risk factor for IIAT. These findings suggest that pneumonia classification for P. aeruginosa identifies patients with different mortality risks and specific risk factors for outcome and IIAT.


Homogeneous Glycoconjugate Produced by Combined Unnatural Amino Acid Incorporation and Click-Chemistry for Vaccine Purposes.
Genetic code expansion is a powerful tool to introduce unnatural amino acids (UAAs) into proteins to modify their characteristics, to study or create new protein functions or to have access to protein conjugates. Stop codon suppression, in particular amber codon suppression, has emerged as the most popular method to genetically introduce UAAs at defined positions. This methodology is herein applied to the preparation of a carrier protein containing an UAA harboring a bioorthogonal functional group. This reactive handle can next be used to specifically and efficiently graft a synthetic oligosaccharide hapten to provide a homogeneous glycoconjugate vaccine. The protocol is limited to the synthesis of glycoconjugates in a 1:1 carbohydrate hapten/carrier protein ratio but amenable to numerous pairs of biorthogonal functional groups. Glycococonjugate vaccine homogeneity is an important criterion to ensure complete physico-chemical characterization, thereby, satisfying more and more demanding drug regulatory agency recommendations, a criterion which is unmet by classical conjugation strategies. Moreover, this protocol makes it possible to finely tune the structure of the actual conjugate vaccine, giving rise to tools to address structure-immunogenicity relationships.


Incidence, predictors and outcomes of valve-in-valve TAVI: A systematic review and meta-analysis.
Surgical aortic valve replacement has been the treatment of choice for patients with aortic valve disease before the arrival of transcatheter aortic valve replacement (TAVI), although limited by degeneration of the bioprosthesis. "Redo" intervention itself is burdened by high risk of complications and valve-in-valve (ViV) TAVI could be a valid strategy of redo for patients with comorbidities. Two independent reviewers screened all studies investigating patients undergoing ViV TAVI. Mortality at 30 days and at 1 year was the primary end point. Of 286 studies identified, 26 articles were included in this review with a total of 1448 patients. Median age was 78.8 years, 57.7% male. Median STS score and Logistic EuroSCORE were 9.4% and 31.3% respectively. Stenosis (45%) was the leading cause of prosthesis failure. Transfemoral approach was preferred (76%), with a prevalence of balloon expandable valves (73.3%). Mean follow up was 376 days. Overall and cardiovascular mortality at 30 days was 6.5% and 5.5% respectively, while at 1 year it was 14.5% and 8.9% respectively. At meta-regression analysis study year (p < .001), Logistic EuroSCORE (p < .01) and valve diameter ≤ 21 mm (p < .05) at 30 days, and stenosis as reason for failure (p = .05) at 1 year were identified as possible predictors of survival. ViV TAVI offers a valid strategy to treat high risk patients with a failure of bioprosthesis with satisfying results in terms of short and mid-term mortality. Future studies are needed to find predictors of long term survival and outcomes in lower risk patients.


Significant, quantifiable differences exist between IgG subclass standards WHO67/97 and ERM-DA470k and can result in different interpretation of results.
Accurate measurement of IgG subclass (IgGSc) levels are essential to aid in the diagnosis of disease states such as primary immunodeficiencies. However, there is no single standardisation of nephelometric and turbidimetric assays for these analytes and two reference materials have been utilised. We expand on previous reports and present data from a multi-site analysis that both identifies and quantitatively defines the differences in calibration resulting from the use of different reference materials. IgGSc antibodies in the serum specimens and reference materials were measured according to the manufacturers' instructions using commercially available IgGSc assays or components. Data from four independent sites showed that in spite of the different commercial suppliers of IgGSc assays calibrating to different reference materials, ERM-DA470k and WHO67 /97, the resulting calibrations were comparable for IgG1 and IgG2. However, for IgG3 and IgG4 the calibrations were significantly different. The use of assay specific normal ranges should compensate for these calibration differences, however, the two manufacturers' assays can give differing clinical classifications. The agreement between the different manufacturers' IgGSc assays was between 85.1% and 95.8% for all IgGSc assays, the discordance of sample classification for IgG1 and IgG2 assays was approximately 12% and 15% respectively, whilst that for IgG3 and IgG4 was 4% and 13% respectively. We discuss the similarities and differences between assays that utilise the different reference materials.


Expression and regulation of excitation-contraction coupling proteins in aging skeletal muscle.
Functional and structural decline of the neuromuscular system is a recognized cause of decreased strength, impaired performance of daily living activities, and loss of independence in the elderly. However, in mammals, including humans, age-related loss of strength is greater than loss of muscle mass, so the underlying mechanisms remain only partially understood. This review focuses on the mechanisms underlying impaired skeletal muscle function with aging, including external calcium-dependent skeletal muscle contraction; increased voltage-sensitive calcium channel Cav1.1 β1asubunit and junctional face protein JP-45 and decreased Cav1.1 (α1) expression, and the potential role of these and other recently discovered molecules of the muscle T-tubule/sarcoplasmic reticulum junction in excitation-contraction uncoupling. We also examined neural influences and trophic factors, particularly insulin-like growth factor-I (IGF-1). Better insight into the triad proteins' involvement in muscle ECC and nerve/muscle interactions and regulation will lead to more rational interventions to delay or prevent muscle weakness with aging. The focus of this review is on the proteins mediating excitation-contraction coupling (ECC) and their expression and regulation in humans and rodent models of skeletal muscle functional decline with aging. Age-dependent changes in proteins other than those related to ECC, muscle composition, clinical assessment and interventions, have been extensively reviewed recently [1-3].


Simulation of ultrafast excited-state dynamics and elastic x-ray scattering by quantum wavepacket dynamics.
Simulation of the ultrafast excited-state dynamics and elastic X-ray scattering of the [Fe(bmip)2]2+ [bmip = 2,6-bis(3-methyl-imidazole-1-ylidine)-4-pyridine] complex is presented and analyzed. We employ quantum wavepacket dynamics simulations on a 5-dimensional potential energy surface (PES) calculated by time-dependent density functional theory with 26 coupled diabatic states. The simulations are initiated by explicit inclusion of a time-dependent electromagnetic field. In the case of resonant excitation into singlet metal-to-ligand charge transfer (1MLCT) states, kinetic (exponential) population dynamics are observed with small nuclear motion. In agreement with transient optical absorption spectroscopy experiments, we observe a subpicosecond 1MLCT → 3MLCT intersystem crossing and a subsequent decay into triplet metal-centered (3MC) states on a picosecond time scale. The simulated time-resolved difference scattering signal is dominated by the 3MC component, for which the structural distortions are significant. On the other hand, excitation into 1MC states leads to ballistic (nonexponential) population dynamics with strong nuclear motion. The reason for these ballistic dynamics is that in this case, the excitation occurs into a nonequilibrium region, i.e., far from the minimum of the 1MC PES. This results in wavepacket dynamics along the principal breathing mode, which is clearly visible in both the population dynamics and difference scattering. Finally, the importance of decomposing the difference scattering into components by electronic states is highlighted, information which is not accessible from elastic X-ray scattering experiments.


HKT1;5-like cation transporters linked to Na+ exclusion loci in wheat, Nax2 and Kna1.
Bread wheat (Triticum aestivum) has a greater ability to exclude Na+ from its leaves and is more salt tolerant than durum wheat (Triticum turgidum L. subsp. durum [Desf.]). A novel durum wheat, Line 149, was found to contain a major gene for Na+ exclusion, Nax2, which removes Na+ from the xylem in the roots and leads to a high K+-to-Na+ ratio in the leaves. Nax2 was mapped to the distal region on chromosome 5AL based on linkage to microsatellite markers. The Nax2 locus on 5AL coincides with the locus for a putative Na+ transporter, HKT1;5 (HKT8). The Nax2 region on 5AL is homoeologous to the region on chromosome 4DL containing the major Na+ exclusion locus in bread wheat, Kna1. A gene member of the HKT1;5 family colocates to the deletion bin containing Kna1 on chromosome 4DL. This work provides evidence that Nax2 and Kna1 are strongly associated with HKT1;5 genes.


Anticoagulation and the elderly head trauma patient.
We sought to determine the effect of anticoagulation therapy on outcomes in elderly patients with closed head injury. We retrospectively reviewed elderly closed head injury patients (> or = 65 years) comparing 52 patients on warfarin (AC) with 439 patients not on warfarin (NAC) with subsequent 1:3 propensity matching used to analyze comparable groups. The overall AC group had a higher head abbreviated injury score (AIS) (4.0 +/- 0.7 vs 3.8 +/- 0.7, P = 0.04) compared with the NAC group. After propensity matching, 49 AC patients were compared with 147 NAC patients who were similar for age, gender, injury severity score, and head AIS. Admission INR was higher in the AC group compared to the NAC group (2.5 +/- 1.3 vs 1.1 +/- 0.3, P < 0.0001) and the AC group had a higher mortality rate (38.8% AC (19/49) vs 23.1% NAC (34/147), P = 0.04). In the AC group, survivors and nonsurvivors had similar repeat International Normalized Ratio (INR) values (1.57 +/- 0.65 survivors vs 1.8 +/- 0.72 nonsurvivors, P = 0.31). The AC group experienced greater morbidity after trauma and had higher mortality rates than their NAC counterparts. Prevention of injury and more selective use of warfarin in this patient population are essential to decrease mortality.


Pseudopolycythemia, pseudothrombocytopenia, and pseudoleukopenia due to overfilling of blood collection vacuum tubes.
A patient blood sample with an unexpectedly high hemoglobin level, high hematocrit, low white blood cell count, and low platelet count was recognized as being spurious based on previously available data. Repeated testing of the original sample showed a gradual return of all parameters to expected levels. We provide evidence that the overfilling of blood collection vacuum tubes can lead to inadequate sample mixing and that, in combination with the settling of the cellular contents in the collection tubes, can result in spuriously abnormal hematological parameters as estimated by an automated method.


Lack of association between risk of biliary tract cancer and circulating IGF (Insulin-like Growth Factor) -I, IGF-II or IGFBP-3 (IGF-binding Protein-3): A nested case-control study in a large scale cohort study in Japan.
Biliary tract cancer, encompassing gallbladder and bile duct cancers, has a poor prognosis, but little is known of the etiology. A nested case-control study was here conducted to evaluate the association between serum levels of IGF-I, IGF-II and IGFBP-3 and death from biliary tract cancer. In a large scale cohort study, 35 gallbladder and 42 bile duct cancers were observed during the follow-up. For each subject in the case group, 1-3 control subjects (228 in total) were selected randomly, matched for sex, age (as near as possible) and residential area. The subjects were divided into tertiles by circulating levels of IGF-I, IGF-II or IGFBP-3. Using conditional logistic regression, risks among the tertiles were compared adjusted for defecation, smoking and drinking habits. No remarkable differences in risks of gallbladder or bile duct cancer were observed among tertiles of IGF-I or IGF-II, and no remarkable trend was observed. Circulating IGFBP-3 showed an inverse U-shape association with gallbladder cancer and a U-shaped one with bile duct cancer. Associations between IGF-I or IGF-II and gallbladder or bile duct cancer thus were lacking or very weak. The observed U- and inverse U-shaped association of IGFBP-3 with the cancers is not suggestive of any meaningful relationships.


Effects of gonadotrophin releasing hormone analogues on human endometrial stromal cells and embryo invasion in vitro.
Gonadotrophin releasing hormone (GnRH) analogues are widely used in IVF programmes as a method of suppressing the luteinizing hormone (LH) surge prior to ovarian stimulation, but their roles outside the pituitary remain relatively unknown. A 2002 Cochrane review (Al-Inany et al. Gonadotrophin-releasing hormone antagonists for assisted conception. Cochrane Database Syst Rev 2006;3:CD001750) described lower pregnancy rates in women administered with GnRH antagonist, compared with those using an agonist, as part of an IVF programme, despite the fact that GnRH antagonist is a more effective repressor of LH. This study aimed to analyse the in-vitro effects of GnRH analogues on the decidualizing endometrium, blastocyst invasion and GnRH receptor expression in fertile women. We analysed the in-vitro decidualization capacity of endometrial stromal cells, derived from fertile women during the implantation window, in the presence of GnRH analogues. The influence of GnRH analogues on GnRH receptor expression and blastocyst invasion was assessed by in-vitro assays of biomedical marker secretion, immunoblots and blastocyst attachment to the stromal extracellular matrix. We demonstrate that, at the concentrations and time periods used, GnRH analogues did not significantly influence the extent of decidualization of endometrial stromal cells. In addition, no adverse effect of GnRH analogues was seen on human blastocyst invasion. We suggest that GnRH analogues affect neither the capacity of the endometrium to support invasion nor the invasive potential of the blastocyst in the early stages of implantation.


Antemortem diagnosis of external iliac arterial thromboembolism in a calf using contrast-enhanced computed tomography: a case report.
A 28-day-old Holstein calf with astasia (i.e., right hind limb flaccid paralysis) was referred to Large Animal Veterinary Educational Center. Thoracic radiographs showed an alveolar pattern and air bronchograms indicating pneumonia, whereas skeletal radiography showed muscle atrophy of the right hind limb but no abnormalities in the coxofemoral and stifle joints. Contrast-enhanced computed tomography revealed the pulmonary abscess in the right cranial pulmonary lobe and a thrombus (5 × 5 × 20 mm) in the right external iliac artery distal to the bifurcation of the abdominal aorta. These findings were confirmed via pathological examination. Streptococcus bovis/equinus complex colonies were isolated from the thrombus and pulmonary abscess. Thus, the pulmonary abscess was considered the infectious source of the thromboembolism in the right external iliac artery. Arterial thromboembolism should be included in the differential diagnoses in calves with astasia but without radiographic skeletal abnormalities.


Density-dependent survival of Ehrlich ascites tumour cells in the presence of various substrates for energy metabolism.
We have found that Ehrlich ascites tumour (EAT) cells, deprived of any carbon source, and suspended at a density of 2 X 10(5) cells/cm3, begin to die only after 12 h of starvation, though it is known that under these conditions they lose over 80% of their ATP within 30 min. Moreover, we have found that the viability of the cells incubated in the absence of any substrate for energy metabolism is strongly dependent on the density of the cell suspension, and can be significantly improved simply by increasing the suspension density. This prompted us to investigate the density dependence of the maintenance of EAT cell viability in the presence of various substrates for energy metabolism and metabolic intermediates. It was found that: Glucose ensures 48 h viability of EAT cells irrespective of suspension density. Fatty acids and pyruvate as sole carbon source do not improve EAT cell survival. In the presence of glutamine as sole carbon source the EAT cell survival shows dependence on cell-suspension density. At densities of 1.6 X 10(6) to 3.2 X 10(6) cells/cm3 the cell viability is maintained at least as well as in the presence of glucose, but at low cell-suspension densities glutamine does not support cell viability. In the presence of glutamine, addition of 1 mM-inosine and 1 mM-uridine ensures high cell survival irrespective of the cell-suspension density. In the presence of inosine or uridine (10 mM) as sole carbon source, the EAT cell survival is the same as in the presence of glucose and does not depend upon cell-suspension density. Guanosine is less effective, whereas adenosine has no effect at all on the maintenance of EAT cell viability for 48 h. There is no correlation at all between EAT cell survival and the rate of lactic acid production. At a cell-suspension density of 1.6 X 10(6) cells/cm3 the cell survival is of the same order in the presence of glutamine as in the presence of glucose, in spite of the fact that in the first case the rate of lactic acid production is more than 20 times lower. There is no correlation between the capacity of particular nucleosides to support EAT cell survival and their effects on glycolysis and oxygen consumption.


Quantitative genetics and the persistence of environmental effects in clonally propagated organisms.
Phenotype is often viewed as a product of genes and the environment in which these genes are expressed. However, numerous studies have shown that environment can cause lasting changes in phenotype that can be passed from one generation to the next, much as genes are transmitted. In clonally propagated organisms, persistence of environmental effects has been observed in a range of plant and animal species, but has rarely been the object of study. We measured the persistence and magnitude of environmental effects on phenotype over three clonal generations in the arctic sedge Eriophorum vaginatum. We found that the environment in which tillers developed had large effects on their later performance (parental effects) and that these effects were in part independent of the size of tillers. The magnitude and persistence of environmental effects did not differ between environmental treatments or among genotypes. However, after 52 weeks of growth and two rounds of clonal propagation, grandparental treatment effects were not significant. We describe methods that can be used in quantitative genetics studies of clonal organisms to reduce bias in estimates of genotypic and environmental variance and argue that the persistence of environmental effects in clonal plant material has ecological and evolutionary consequences similar to those described for maternal environmental effects in sexual organisms.


Investigator profile. An interview with Zhiyuan Gong, Ph.D. Interview by Vicki Glaser.
Dr. Zhiyuan Gong is Associate Professor in the Department of Biological Sciences, National University of Singapore. He graduated with a B.Sc. degree in marine biology from Ocean University of China and received his Ph.D. degree in developmental biology from McGill University in Canada. He spent many years at the University of Toronto and Hospital for Sick Children in Toronto for postdoctoral research in marine biotechnology and transgenic technology before he joined his current university.


Analysis of translocatory balance in durian (Durio zibethinus) fruit.
We estimated translocatory balance in fruit of the tropical tree Durio zibethinus Murray on the basis of a compartment model. Rates of fruit respiration, dry weight growth and translocation increased with time. Over the 8.2 weeks of fruit development, the relative distribution of translocation was 80% to dry weight growth and 20% to respiration. The ratio of respiration rate to translocation rate, which ranged from 14 to 32%, tended to decrease with time, whereas the ratio of dry weight growth rate to translocation rate, which ranged from 68 to 86%, tended to increase with time. The relationship between dry weight growth rate and translocation rate was fitted by a power function, where dry weight growth rate was statistically proportional to translocation rate. The relationship between respiration rate and translocation rate was formulated by a smooth curve, where respiration rate increased as translocation rate increased. Examination of these ratios with respect to the translocation rate indicated that the dry weight growth rate/translocation rate ratio increased slightly with increasing translocation rate, whereas the respiration rate/translocation rate ratio decreased with increasing translocation rate. A comparative analysis of these results with those obtained for Cinnamomum camphora (L.) J. Presl revealed a lower ratio of translocation to dry weight growth in D. zibethinus than in C. camphora, indicating that D. zibethinus fruits have a low translocatory efficiency.