Building a research model for human genetic variation knowledge management.
Organizational knowledge management (KM) research studies the nature of knowledge, the scope of KM, the factors and mechanisms that affect KM outcomes, as well as theoretical KM frameworks. This paper discusses the implications of past studies for the KM efforts in the human genetic variation (HGV) research domain and presents a HGV-KM research model. This model identifies the context of HGV KM studies, the predispositions and factors that may impact KM outcomes, and important KM processes. It also represents the relationships among these issues. Applying the model, further studies will point the way for improved capture and dissemination of HGV knowledge from routine HGV research activities to contribute to the global genetics knowledge base.


Usefulness of the right parasternal view and non-imaging continuous-wave Doppler transducer for the evaluation of the severity of aortic stenosis in the modern area.
Evaluation of the severity of the aortic stenosis (AS) is based on echocardiographic assessment of peak velocity/mean transaortic pressure gradient (MPG) by continuous-wave Doppler and calculation of the aortic valve area (AVA) using the continuity equation. Pioneering echocardiographic studies have shown that MPG should be measured from the apical and right parasternal views using non-imaging continuous-wave Doppler transducer (NI-CWD). Nowadays, ultrasound systems are often sold without NI-CWD due, at least partially, to the improvement of two-dimensional continuous-wave Doppler transducers (2D-CWD). Whether this evolution translated into misevaluation of AS severity was uncertain. Our aim was to evaluate the additional diagnostic value of the use of NI-CWD and the right parasternal view for the evaluation of AS severity in the modern area. We prospectively evaluated MPG and AVA using the 2D-CWD (apical view) and the NI-CWD (right parasternal view) in 100 patients (78 +/- 5 years, 65% male) consecutively enrolled in an ongoing prospective study. Aortic stenosis severity was graded as mild (AVA > or = 1.5 cm(2)), moderate (1-1.5 cm(2)), or severe (AVA < 1 cm(2)). Misclassification was defined as at least a one grade difference and DeltaAVA > 0.15 cm(2) (twice the intra-observer variability). Feasibility of the 2D-CWD was 100%, MPG 20 +/- 13 mmHg, and AVA 1.52 +/- 0.45 cm(2). Fifty-three per cent had a mild AS, 34% a moderate AS, and 13% a severe AS. Using the NI-CWD, feasibility was 85%, MPG 25 +/- 16 mmHg, AVA 1.33 +/- 0.41 cm(2) (both P < 0.005 compared with 2D-CWD). Thirty-five per cent (n = 30) had a mild AS, 46% (n = 39) a moderate AS, and 19% (n = 16) a severe AS. Using only the 2D-CWD and the apical view, 21 patients (21%) would have been misclassified: 17 as mild instead of moderate AS and 4 as moderate instead of severe AS. In those misclassified patients, MPG was 9 +/- 6 mmHg higher with the NI-CWD and 33% had an MPG difference >10 mmHg. The use of the NI-CWD and the right parasternal view must be performed to evaluate AS severity, especially in case of discrepancy between symptoms and AS severity or for precise evaluation of AS progression.


Artificial intelligence framework for modeling and predicting crop yield to enhance food security in Saudi Arabia.
Predicting crop yields is a critical issue in agricultural production optimization and intensification research. Accurate foresights of natural circumstances a year in advance can have a considerable impact on management decisions regarding crop selection, rotational location in crop rotations, agrotechnical methods employed, and long-term land use planning. One of the most important aspects of precision farming is sustainability. The novelty of this study is to evidence the effective of the temperature, pesticides, and rainfall environment parameters in the influence sustainable agriculture and economic efficiency at the farm level in Saudi Arabia. Furthermore, predicting the future values of main crop yield in Saudi Arabia. The use of artificial intelligence (AI) to estimate the impact of environment factors and agrotechnical parameters on agricultural crop yields and to anticipate yields is examined in this study. Using artificial neural networks (ANNs), a highly effective multilayer perceptron (MLP) model was built to accurately predict the crop yield, temperature, insecticides, and rainfall based on environmental data. The dataset is collected from different Saudi Arabia regions from 1994 to 2016, including the temperature, insecticides, rainfall, and crop yields for potatoes, rice, sorghum, and wheat. For this study, we relied on five different statistical evaluation metrics: the mean square error (MSE), the root-mean-square error (RMSE), normalized root mean square error (NRMSE), Pearson's correlation coefficient (R%), and the determination coefficient (R 2). Analyses of datasets for crop yields, temperature, and insecticides led to the development of the MLP models. The datasets are randomly divided into separate samples, 70% for training and 30% for testing. The best-performing MLP model is characterized by values of (R = 100%) and (R 2 = 96.33) for predicting insecticides in the testing process. The temperature, insecticides, and rainfall were examined with different crop yields to confirm the effectiveness of these parameters for increasing product crop yields in Saudi Arabia; we found that these items had highest relationships. The average values are R = 98.20%, 96.50, and 99.14% with for the temperature, insecticides, and rainfall, respectively. Based on these findings, it appeared that each of the parameter categories that are considered (temperature, pesticides, and rainfall) had a similar contribution to the accuracy of anticipated yield projection.


Highly functional ipsilateral motor control after extensive left hemispheric damage during gestation.
In large early cortical lesions, one of the most devastating consequences is the impaired motor dexterity of the contralateral limb. We present the case of an 8-year-old girl with a large left hemispherical porencephaly. Unlike previous reports, the girl exhibited high dexterity of the contralateral hand with preserved independent finger movements. We performed functional MRI of hand motor functions and diffusion tensor imaging, which revealed activation of the ipsilateral motor cortex and absence of a contralateral corticospinal tract. These observations suggest that by intensive training in early life, a complete transhemispheric shift of motor control with high skills can be achieved.


Factors Associated With Discharge Destination in Community-Dwelling Adults Admitted to Acute General Medical Units.
General medical patients often present to the hospital with medical, social, cognitive, and functional issues that may impact discharge destination. The aim of this study was to investigate the association between patient factors at hospital admission and discharge destination in general medical patients. This was a prospective, single-site observational study conducted on the general medical wards at a tertiary hospital. Inpatients admitted to the general medical unit and referred to physical therapy were included. Patients admitted from residential care were excluded. Data were collected a median of 2 days (interquartile range: 1-3) from hospital admission and included demographics, comorbidities (Charlson Comorbidity Index), premorbid physical function (Blaylock Risk Assessment Screening Score, BRASS), current function (de Morton Mobility Index, DEMMI and Alpha Functional Independence Measure, AlphaFIM), and cognition (Rowland Universal Dementia Assessment Scale, RUDAS). Between July 2016 and August 2017, 417 patients were recruited (53% female, median age: 81 years (interquartile range: 76-86). Of these, 245 patients were discharged directly home; 172 were not discharged home of whom 140 were discharged to a subacute temporary facility providing further opportunity for therapy and discharge planning. Patients discharged directly home had higher functional, mobility, and cognitive scores. Data were partitioned into training, validation, and test sets to provide unbiased estimates of sensitivity, specificity, receiver operating characteristic curve, and area under the curve. Models best associated with discharge were "DEMMI and toilet transfers" (sensitivity 82.1%, specificity 66.2%, area under the curve 83.8%, 95% confidence interval: 76.4-91.2) and "AlphaFIM and walking independence" (sensitivity: 66.7%, specificity: 83.1%, area under the curve: 81.5, 95% confidence interval: 73.2-89.7). Two models were created that differentiated between discharge home and not home and had similar statistical measures of validity. Although the models require further validation, clinicians should consider whether identification of patients likely to be discharged home or not home is of greater relevance for their clinical setting.


Our experience with surgical treatment of tympanojugular pragangliomas.
Tympanojugular paragangliomas are benign and slow growing lesions of the lateral skull base. Due to their localization and vascularity, they represent a surgical challenge. Treatment modalities include preoperative embolization of feeding vessels and tumour itself, surgical removal and irradiation. In our group, 16 patients with large tympanojugular paragangliomas have been operated in the period of 10 years. Surgical radicality has been achieved in 62.5%, in the rest of patients the tumour remnants were either irradiated with a Leksell gamma knife, or left without treatment in a wait-end-rescan approach. According to the benign character of the tumour, radicality is not always the highest goal, since a radical removal may be compromised by a high postoperative morbidity.


Expert performance in sport and the dynamics of talent development.
Research on expertise, talent identification and development has tended to be mono-disciplinary, typically adopting genocentric or environmentalist positions, with an overriding focus on operational issues. In this paper, the validity of dualist positions on sport expertise is evaluated. It is argued that, to advance understanding of expertise and talent development, a shift towards a multidisciplinary and integrative science focus is necessary, along with the development of a comprehensive multidisciplinary theoretical rationale. Here we elucidate dynamical systems theory as a multidisciplinary theoretical rationale for capturing how multiple interacting constraints can shape the development of expert performers. This approach suggests that talent development programmes should eschew the notion of common optimal performance models, emphasize the individual nature of pathways to expertise, and identify the range of interacting constraints that impinge on performance potential of individual athletes, rather than evaluating current performance on physical tests referenced to group norms.


[Identification of palliative care patients :issues and screening tools].
From a health care perspective, and in order to improve the quality of care, early identification of palliative patients is a necessary step for the development of palliative care. Unfortunately, this early identification is still sub-optimal, resulting in a delayed introduction of palliative care in the patients' health care pathway. Although several tools exist to support health care professionals in this endeavour, their level of validity is incomplete, and they do not distinguish between patients in need of general versus specialised palliative care. A new tool which strives to better answer these criteria is presently being developed and validated at the CHUV.


Genetic variation in plant CYP51s confers resistance against voriconazole, a novel inhibitor of brassinosteroid-dependent sterol biosynthesis.
Brassinosteroids (BRs) are plant steroid hormones with structural similarity to mammalian sex steroids and ecdysteroids from insects. The BRs are synthesized from sterols and are essential regulators of cell division, cell elongation and cell differentiation. In this work we show that voriconazole, an antifungal therapeutic drug used in human and veterinary medicine, severely impairs plant growth by inhibiting sterol-14α-demethylation and thereby interfering with BR production. The plant growth regulatory properties of voriconazole and related triazoles were identified in a screen for compounds with the ability to alter BR homeostasis. Voriconazole suppressed growth of the model plant Arabidopsis thaliana and of a wide range of both monocotyledonous and dicotyledonous plants. We uncover that voriconazole toxicity in plants is a result of a deficiency in BRs that stems from an inhibition of the cytochrome P450 CYP51, which catalyzes a step of BR-dependent sterol biosynthesis. Interestingly, we found that the woodland strawberry Fragaria vesca, a member of the Rosaceae, is naturally voriconazole resistant and that this resistance is conferred by the specific CYP51 variant of F. vesca. The potential of voriconazole as a novel tool for plant research is discussed.


Thionation toward High-Contrast ACQ-DIE Probes by Reprogramming the Aqueous Segregation Behavior: Enlightenment from a Sulfur-Substituted G-Quadruplex Ligand.
Small-molecule-based fluorescent chemosensors provide powerful tools for analytical chemistry. However, their organic essence often "cursed" them for aggregation-caused quenching (ACQ) in an aqueous context. Albeit the praxis of the disaggregation-induced emission (DIE) strategy as a potential solution, it still awaited improvement due to the uncontrollability of the aggregation/segregation process. To address this issue, herein, we supposed that sulfur substitution on a molecule could serve as a promising strategy to achieve an evolved ACQ-DIE probe. To prove this concept, a precursor G-quadruplex (G4) ligand CQ was modified to get its thionation version CTQ. Strikingly, CTQ exhibited more arranged aqueous segregation behavior, as compared with CQ, and therefore enhanced fluorescence performance. Our research, in the meantime, manifested that CTQ remained to possess favorable G4 selectivity, whereby it could function as an evolved probe for more accurate in vitro G4-related assays, specifically, a classification assay for distinguishing virus variants.


Vascularised bone graft and osteotomy of the radius in Kienböck's disease.
Treatment of stage IIIA and III B avascular necrosis of the lunate bone remains controversial. We present a series of 5 cases in young patients treated with a vascularised bone graft from the second metacarpal, combined with a lateral shortening and closing wedge osteotomy of the radius. Good clinical and radiographic results were obtained and disease progression was halted with the combination of these two surgical procedures.


Nonlocal effects in high-energy charged-particle beams.
Within the framework of the thermal wave model, an investigation is made of the longitudinal dynamics of high-energy charged-particle beams. The model includes the nonlinear self-consistent interaction between the beam and its surroundings in terms of a coupling impedance, and when resistive as well as reactive parts are included, the evolution equation becomes a generalized nonlinear Schrödinger equation including a nonlocal nonlinear term. The consequences of the resistive part on the propagation of particle bunches are examined using analytical as well as numerical methods.


Ellagitannin-rich cloudberry inhibits hepatocyte growth factor induced cell migration and phosphatidylinositol 3-kinase/AKT activation in colon carcinoma cells and tumors in Min mice.
Berries have been found to inhibit colon carcinogenesis in animal models, and thus represent a potential source of compounds for prevention and treatment of colorectal cancer. The mechanistic basis for their effects is not well understood. We used human colon carcinoma cells and Min mice to investigate the effects of ellagitannin-rich cloudberry (Rubus chamaemorus) extract on cancer cell migration and underlying cell signaling. Intrinsic and hepatocyte growth factor (HGF) -induced cell motility in human HT29 and HCA7 colon carcinoma cells was assessed carrying out cell scattering and scratch wound healing assays using time-lapse microscopy. Activation of Met, AKT, and ERK in cell lines and tumors of cloudberry-fed Min mice were determined using immunoprecipitation, Western blot and immunohistochemical analyses. Cloudberry extract significantly inhibited particularly HGF-induced cancer cell migration in both cell lines. Cloudberry extract inhibited the Met receptor tyrosine phosphorylation by HGF and strongly suppressed HGF-induced AKT and ERK activation in both HT29 and HCA7 cells. Consistently, cloudberry feeding (10% w/w freeze-dried berries in diet for 10 weeks) reduced the level of active AKT and prevented phosphoMet localization at the edges in tumors of Min mice. These results indicate that cloudberry reduces tumor growth and cancer cell motility by inhibiting Met signaling and consequent activation of phosphatidylinositol 3-kinase/AKT in vitro and in tumors in vivo. As the Met receptor is recognized to be a major target in cancer treatment, our results suggest that dietary phytochemicals may have therapeutic value in reducing cancer progression and metastasis.


A large deletion in the succinate dehydrogenase B gene (SDHB) in a Japanese patient with abdominal paraganglioma and concomitant metastasis.
Recently, mutations in nuclear genes encoding two mitochondrial complex II subunit proteins, Succinate dehydrogenase D (SDHD) and SDHB, have been found to be associated with the development of familial pheochromocytomas and paragangliomas (hereditary pheochromocytoma/paraganglioma syndrome: HPPS). Growing evidence suggests that the mutation of SDHB is highly associated with abdominal paraganglioma and the following distant metastasis (malignant paraganglioma). In the present study, we used multiplex ligation dependent probe amplification (MLPA) analysis to identify a large heterozygous SDHB gene deletion encompassing sequences corresponding to the promoter region, in addition to exon 1 and exon 2 malignant paraganglioma patient in whom previously characterized SDHB mutations were undetectable. This is the first Japanese case report of malignant paraganglioma, with a large SDHB deletions. Our present findings strongly support the notion that large deletions in the SDHB gene should be considered in patients lacking characterized SDHB mutations.


ACTINOMYCIN D: ITS EFFECT ON ANTIBODY FORMATION IN VITRO.
The formation of antibodies to bacteriophage T(2) in vitro was inhibited by 5 X 10(-8)M actinomycin D. This result is consistent with the concept that antibody formation depends upon DNA-dependent RNA synthesis.


Optimisation of prescription in patients with long-term treatment-resistant schizophrenia.
The aim of this clinical review was to investigate the effectiveness and safety of the practice of antipsychotic poly-pharmacy (AP) in the long-term management of hospitalised patients with insufficient response to antipsychotic monotherapy. The databases Medline, PsycINFO, Embase and Scopus were searched. Studies were required to include inpatients with long-term, treatment-resistant schizophrenia on maintenance AP. The search was restricted to systematic review studies. The review yielded four studies of interest that showed no categorical advantage for maintenance AP for the population of interest. However, clozapine combination faired marginally well. Particular weaknesses of the present literature are low number of participants, and inadequate monitoring of potential adverse effects. The evidence on the risks and benefits of maintenance AP is not generally considered adequate to warrant a recommendation for its use in routine clinical practice in psychiatry. This review provides a synthesis of the evidence on the maintenance use of AP for hospitalised patients with long-term, treatment-resistant schizophrenia. The results show both no support for AP with some marginal benefit for clozapine combination therapy, and methodological weaknesses of the included studies. These findings have clinical implications for treatment decisions and suggest that sufficiently powered studies are needed.


Vital staining of blood vessels and bile ducts with carboxyfluorescein diacetate succinimidyl ester: a novel tool for isolation of cholangiocytes.
Current methods for visualization of the blood vasculature, biliary tree and for isolation of vital cholangiocytes are afflicted with a plethora of technical difficulties, especially in mice. In this project, we propose a novel, reliable and straightforward alternative technique for histological demonstration of blood- and biliary systems and derivation of vital cholangiocytes. Intravital retrograde perfusion of bile ducts was performed in twenty wild type mice. Liver and gallbladder were exposed by median laparotomy. Using a venous catheter, the gallbladder was cannulated, a few millimeters of the liver edge were cropped to allow free outflow of the perfusate, and carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) solution was retrogradely infused. Thereafter, formaldehyde solution was either injected through the same catheter, or the liver was immediately dissociated into a single-cell suspension for FACS-analysis. Intravital perfusion of the vascular system was performed in ten Lewis rats by direct intra-arterial injection of CFDA-SE into the abdominal aorta. The specificity and sensitivity of CFDA-SE labeling was controlled using Indian ink or cytokeratin 19 immunohistochemistry respectively. Upon histomorphological analysis of cryo- and paraffin sections, strong fluorescence was noted in large and small bile ducts throughout the entire liver and in the vascular system after infusion of the CFDA-SE solution. In preliminary FACS-experiments, we succeeded in separating cholangiocytes based on combined CFDA-SE-staining and cell size. Visualization of liver architecture and the isolation of cholangiocytes is feasible using a fast and cost-effective method of retrograde perfusion and vital fluorescent labeling of mouse bile duct epithelium and vascular endothelium with CFDA-SE.


Musculoskeletal Pain in Patients with Psoriasis and its Influence on Health-related Quality of Life: Results from a Danish Population-based Survey.
This study used a nationwide e-based survey of patients with psoriasis to assess the pattern of musculoskeletal pain and its influence on patient-reported outcomes, including health-related quality of life and disability. A total of 561 respondents (56% of the screened psoriasis patients) reported physician-diagnosed psoriasis and completed the questionnaire. Respondents were grouped based on the presence of musculoskeletal pain and/or diagnosed psoriatic arthritis: 81% had psoriasis without arthritis (29% pain now, 23% pain previously, 39% no pain ever), and 19% had psoriatic arthritis. Patients with psoriasis with pain now had poorer quality of life compared with patients without pain and, importantly, similar to that of patients with arthritis. Furthermore, patients with pain now/previously reported higher self-assessed severity of psoriasis and lower satisfaction with current treatment than patients without pain. Two-thirds of patients with psoriasis with pain now/previously and one-third of patients with arthritis had never been examined by a rheumatologist, demonstrating an unmet need for adequate evaluation of such patients. A nationwide e-based survey of patients with psoriasis was preformed to assess the pattern of musculoskeletal pain and its influence on patient-reported outcomes, including health-related quality of life and disability. A total of 561 respondents (56% of the screened psoriasis patients) reported physician- diagnosed psoriasis and completed the questionnaire. Respondents were grouped based on the presence of musculoskeletal pain and/or diagnosed psoriatic arthritis: 81% had psoriasis without arthritis (29% pain now, 23% pain previously, 39% no pain ever), and 19% had psoriatic arthritis. Patients with psoriasis with pain now had poorer quality of life compared with patients without pain and, importantly, similar to that of patients with arthritis. Furthermore, patients with pain now/previously reported higher self-assessed severity of psoriasis and lower satisfaction with current treatment than patients without pain. Two-thirds of patients with psoriasis with pain now/previously and one-third of patients with arthritis had never been examined by a rheumatologist, demonstrating an unmet need for adequate evaluation of such patients.


Biostable scaffolds of polyacrylate polymers implanted in the articular cartilage induce hyaline-like cartilage regeneration in rabbits.
To study the influence of scaffold properties on the organization of in vivo cartilage regeneration. Our hypothesis was that stress transmission to the cells seeded inside the pores of the scaffold or surrounding it, which is highly dependent on the scaffold properties, determines the differentiation of both mesenchymal cells and dedifferentiated autologous chondrocytes. 4 series of porous scaffolds made of different polyacrylate polymers, previously seeded with cultured rabbit chondrocytes or without cells, were implanted in cartilage defects in rabbits. Subchondral bone was injured during the surgery to allow blood to reach the implantation site and fill the scaffold pores. At 3 months after implantation, excellent tissue regeneration was obtained, with a well-organized layer of hyaline-like cartilage at the condylar surface in most cases of the hydrophobic or slightly hydrophilic series. The most hydrophilic material induced the poorest regeneration. However, no statistically significant difference was observed between preseeded and non-preseeded scaffolds. All of the materials used were biocompatible, biostable polymers, so, in contrast to some other studies, our results were not perturbed by possible effects attributable to material degradation products or to the loss of scaffold mechanical properties over time due to degradation. Cartilage regeneration depends mainly on the properties of the scaffold, such as stiffness and hydrophilicity, whereas little difference was observed between preseeded and non-preseeded scaffolds.


Amino-acid sequences of two basic chymotrypsin inhibitors from silkworm larval hemolymph.
Amino-acid sequences of two basic chymotrypsin inhibitors from silkworm hemolymph (SCI-I and SCI-II) are determined. They are composed of each 62 amino-acid residues with differences in only two positions to each other. They both contain six half cystines in a similar arrangement as that of Kunitz-type proteinase inhibitor, except for the one amino-acid insertion in the first cysteine frame. The inhibitory activity of SCI-II against trypsin should be attributed to Lys44 displacing Gln44 in SCI-I which has no antitryptic activity.


Conducting umbrella reviews.
In this article, Lazaros Belbasis and colleagues explain the rationale for umbrella reviews and the key steps involved in conducting an umbrella review, using a working example.


Teaching Chinese characters to students in grades 1 to 3 through emergency remote instruction during the COVID-19 pandemic.
The current study examined how Chinese characters were taught by primary grade teachers in Macao during online instruction resulting from the COVID-19 pandemic (i.e., emergency remote instruction). A random sample of 313 first to third grade teachers in public and private schools were surveyed about their instructional practices. Most teachers surveyed (72%) reported they taught a lesson about Chinese characters once every 3-4 weeks during emergency remote instruction, and 83% and 81% of teachers indicated they assigned homework for writing and reading characters, respectively, at the same rate. On average, they reportedly spent 97 min per week teaching students to write, read, and understand the meaning of new characters, devoting equal time to each of these skills. They also indicated students practiced writing and reading characters in class for 40 min per week. They further noted students were expected to spend 35 min a day practicing writing and reading characters for homework. While teachers reportedly used a variety of instructional practices for teaching characters (M = 30.38), the typical teacher applied less than one-half (N = 64) of practices assessed. Teachers reported use of asynchronous (online learning activities which can be completed at other times) and synchronous (real-time videos and audio/text) teaching methods and perceptions of adequacy of technical support predicted reported teaching practices. The findings from this study raise questions about the teaching of Chinese characters in Macao during emergency remote instruction.


Open data set of live cyanobacterial cells imaged using an X-ray laser.
Structural studies on living cells by conventional methods are limited to low resolution because radiation damage kills cells long before the necessary dose for high resolution can be delivered. X-ray free-electron lasers circumvent this problem by outrunning key damage processes with an ultra-short and extremely bright coherent X-ray pulse. Diffraction-before-destruction experiments provide high-resolution data from cells that are alive when the femtosecond X-ray pulse traverses the sample. This paper presents two data sets from micron-sized cyanobacteria obtained at the Linac Coherent Light Source, containing a total of 199,000 diffraction patterns. Utilizing this type of diffraction data will require the development of new analysis methods and algorithms for studying structure and structural variability in large populations of cells and to create abstract models. Such studies will allow us to understand living cells and populations of cells in new ways. New X-ray lasers, like the European XFEL, will produce billions of pulses per day, and could open new areas in structural sciences.


Southern Rural Access Program: an overview.
Rural residents experience significant disparities in health status and access to care. These disparities and access barriers are particularly prevalent in rural communities in the South. The Southern Rural Access Program, a national program of the Robert Wood Johnson Foundation, was designed as a long-term effort to improve access to basic health care in 8 of the most underserved states in the country. The program was launched in 1998 with 3 goals: (1) to increase the supply of providers in underserved areas, (2) to strengthen the health care infrastructure, and (3) to build capacity at the state and community level to solve problems. The first 3-year phase of the program made $13.8 million available to communities in the 8 target states, and a January 2002 reauthorization of the program will make an additional $18.9 million available in the next 4 years. This article will provide an overview of the Southern Rural Access Program, focusing on the development and evolution of the program during its first 3-year phase. The article will also highlight some of the refinements that the foundation has made during the 2002-2006 second phase of the program.


Osteochondritis dissecans of the elbow: histopathological assessment of the articular cartilage and subchondral bone with emphasis on their damage and repair.
Osteochondritis dissecans (OCD) of the elbow is a localized injury of the articular cartilage and subchondral bone that is commonly seen in the young athlete. In the present study, the extent of damage and repair on the articular cartilage and subchondral bone was examined histologically using specimens of 25 osteochondral cylinders and seven loose bodies obtained from 25 young athletes who had undergone osteochondral autograft surgery. Terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) assays for detecting apoptotic cells and immunohistochemistry of matrix metalloproteinases (MMP) were performed on the osteochondral cylinder specimens. The histological findings of the OCD of the elbow showed that the articular cartilage exhibited degenerative change, mimicking osteoarthritis, and was markedly damaged as the lesion progressed. TUNEL-positive cells and MMP-3- and -13-expressing cells were distributed in the degenerative articular cartilage and reparative fibrocartilage tissue. Separation occurred at either the deep articular cartilage or the subchondral bone, with the former being dominant in the early OCD lesions. The present results suggest that the primary pathological changes in OCD of the elbow were due to damage of articular cartilage induced by repeated stress following degenerative and reparative process of articular cartilage and subchondral fracturing, and separation subsequently occurred on the cartilage and developed onto the subchondral bone in its advanced stages.


Outbreak of varicella in a newborn intensive care nursery.
An outbreak of nosocomial varicella occurred in the neonatal intensive care unit of a west Texas hospital in 1982. Two health care workers and two infants were infected. The two infants acquired varicella following intimate exposures, although their mothers were shown to be seropositive. One of these infants had varicella-zoster antibody when exposed, received varicella-zoster immune globulin, and still had chickenpox develop. Thus, the presence of varicella-zoster antibody may not prevent infection in infants.


CT-guided percutaneous radiofrequency ablation of osteoid osteoma: Our experience in 87 patients.
To evaluate the technical and clinical success of radiofrequency ablation of osteoid osteoma and analyze the factors responsible for clinical success. We also tried to investigate the role of follow-up computed tomography (CT) imaging. This is a prospective study approved by the institute's ethics committee involving 87 patients with appendicular osteoid osteoma. CT-guided radio frequency ablation was performed using a bipolar ablation system. Patients were followed up over 15.4 (4-24) months for pain, and clinical success/failure was determined using established criteria. Patients with clinical failure were taken for repeat ablation. Follow-up CT was obtained at 6 months and correlated with clinical success. Procedural scans were later reviewed for technical success in a blinded manner and correlated with clinical success along with other imaging and patient characteristics. Mean pre-procedure visual analog scale (VAS) score was 7.0 ± 0.8. Primary success rate after single session was 86.2%(75/87 patients), and overall success rate after one/two sessions was 96.6%(84/87). No major complications were noted. Technical success rate was 89.7%(78/87). All 9 patients who had a suboptimal needle positioning had recurrence where as three patients had recurrence despite technical success. None of the imaging characteristics or history of prior intervention was significantly associated with clinical success. Follow-up CT showed advanced bone healing in 48 lesions, and was confined to the treatment success group. Alternately, minimal/absent bone healing was seen in all (12) patients of primary treatment failure and 27 patients with treatment success. CT-guided percutaneous radio frequency ablation is a safe and highly effective treatment for osteoid osteomas even in recurrent and residual cases. Technical success is the most important parameter affecting the outcome. Post radio frequency ablation CT findings have a good positive but a poor negative predictive value in prognostication.


Diagnostic criteria for retained products of conception-A scoping review.
Numerous studies have been performed assessing optimal treatment regimens for evacuating (retained) products of conception from the uterus, but standardized criteria for diagnosing retained products of conception (RPOC) are still lacking. We aim to provide an overview of diagnostic criteria in current literature, used to diagnose RPOC after induced first-trimester abortion or early pregnancy loss. Pubmed, EMBASE, and the Cochrane library were searched systematically up until March 2020 for English articles reporting on induced abortion or early pregnancy loss. Articles not specifying diagnostic criteria used to assess completeness of treatment were excluded, as were conference abstracts, expert opinions, reviews, and case reports. Four elements of diagnostic criteria were described: diagnostic tools, parameters used within these tools, applied cut-off values, and timing of follow up. Additionally, a meta-analysis was performed assessing diagnostic qualities of the most often applied diagnostic tool and parameter. The search strategy yielded 1233 unique articles, of which 248 were included, with a total of 339 517 participants. In the 79 included randomized controlled trials, six diagnostic tools to assess RPOC were identified, combined in 14 ways, with 55 different cut-off values. In 169 observational studies, seven diagnostic tools were identified, used in 28 combinations, applying 89 different cut-off values. Transvaginal ultrasonographic measurement of endometrial thickness with a cut-off value of at least 15 mm indicating RPOC, was used most frequently. In the timing of follow-up there was great variation, with 55 and 107 different combinations in randomized controlled trials and observational studies, respectively. Assessment of treatment success was scheduled most often around 2 weeks after treatment. Diagnostic qualities of endometrial thickness of 15 mm or more was not adequately assessed. There is wide variation in the way RPOC are assessed, and the criteria used to define RPOC following induced abortion and early pregnancy loss; ultrasonographic measurement of endometrial thickness, with a cut-off of 15 mm or more 2 weeks after primary treatment is the most widely used diagnostic approach. A meta-analysis on diagnostic accuracy of endometrial thickness of 15 mm or more did not lead to solid results. These findings can be a first step to develop a workable standard of establishing RPOC after induced abortion or early pregnancy loss.


New mechanical disruption method for extraction of whole cell protein from Candida albicans.
Cell disruption or lysis is a crucial step to obtain cellular components for various biological studies. We subjected different concentrations of Candida albicans to 5, 10, 15 and 20 cycles of disruption. The degree of cell lysis was observed using light microscopy and the yields obtained were measured and analysed. The optimum extraction with 1 x 10(10) yeast cells/ml was achieved after 5 cycles of disruption with 1.0 mm diameter glass beads at 5,000 rpm. Approximately 80% of the cells were lysed and the protein yield was 6,000 microg/ml. SDS-PAGE analysis revealed approximately 25 distinct protein bands with molecular weights ranging from 8 kDa to 220 kDa. We conclude that this mechanical disruption of fungal cells is a rapid, efficient and inexpensive technique for extracting whole cell proteins from yeast cells.


How to build your own coronary anastomosis simulator from scratch.
Gaining cardiac surgical competence is a complex, multifactorial process that may take years of experience and on-the-job training. It is critical to provide suitable educational opportunities to gain the necessary knowledge, judgment and skills. In response to the multitude of factors (e.g. European Working Time Directive) currently influencing cardiac surgical training, there have been concerted efforts to reform training practices. Simulation plays an increasingly important role in the educational process and serves to fill the most important gap in the current training model, i.e. operative exposure. Therefore, a contest has been written out for cardiac surgical trainees to construct their own coronary anastomosis simulator using everyday materials. Cardiac surgical trainees were invited to construct their own coronary anastomosis simulator. An international jury of cardiac surgeons assessed the simulator and its presentation according to preset developmental criteria (low fidelity concept, innovative character, general presentation and description, general attractiveness to the scholar, ergonomical issues, perceived haptics, number of applicable components, transportability, ease of construction, repeatability and overall costs of the simulator). Six prototypes of simulators built by cardiac surgical trainees were generated. A general evaluation of each simulator prototype is provided according to the preset developmental criteria. All simulator prototypes have provided a considerable contribution to the field of surgical simulation. By designing simulator prototypes, the trainees have demonstrated their 'out of the box' thinking capability, which is of paramount importance for the development of future innovative surgical techniques and procedures. The Valladolid cardiac team coronary anastomosis simulator box was selected for the EACTS Ethicon Simulation Award 2011. This project will be mass produced and distributed to the participants of structured simulation sessions for coronary anastomoses.


Optimizing gene transfer to conventional outflow cells in living mouse eyes.
The mouse eye has physiological and genetic advantages to study conventional outflow function. However, its small size and shallow anterior chamber presents technical challenges to efficient intracameral delivery of genetic material to conventional outflow cells. The goal of this study was to optimize methods to overcome this technical hurdle, without damaging ocular structures or compromising outflow function. Gene targeting was monitored by immunofluorescence microscopy after transduction of adenovirus encoding green fluorescent protein driven by a CMV promoter. Guided by a micromanipulator and stereomicroscope, virus was delivered intracamerally to anesthetized mice by bolus injection using a 33 gauge needle attached to Hamilton syringe or infusion with glass micropipette connected to syringe pump. The total number of particles introduced remained constant, while volume of injected virus solution (3-10 μl) was varied for each method and time of infusion (3-40 min) tested. Outflow facility and intraocular pressure were monitored invasively using established techniques. Unlike bolus injections or slow infusions, introduction of virus intracamerally during rapid infusions (3 min) at any volume tested preferentially targeted trabecular meshwork and Schlemm's canal cells, with minimal transduction of neighboring cells. While infusions resulted in transient intraocular pressure spikes (commensurate with volume infused, Δ40-70 mmHg), eyes typically recovered within 60 min. Transduced eyes displayed normal outflow facility and tissue morphology 3-6 days after infusions. Taken together, fast infusion of virus solution in small volumes intracamerally is a novel and effective method to selectively deliver agents to conventional outflow cells in living mice.


A novel prophylaxis with C1-inhibitor concentrate in hereditary angioedema during erythema marginatum.
Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is a rare, autosomal dominant disorder. The characteristic episodes of subcutaneous/submucosal edema formation may be preceded by erythema marginatum (EM) - the occurrence of a 'map-like' pattern on the skin. EM can occur as an isolated finding or accompanying a hereditary angiooedema (HAE) attack as well. Nevertheless, it is unknown whether a HAE attack can be prevented by the proper prophylactic treatment during EM. Our aim was to assess the prevalence of EM in the Hungarian C1-INH-HAE population and to introduce a safe and effective novel prophylactic treatment during EM in patients who's HAE attacks are preceded by EM in a considerable proportion of the cases. Based on the data of the Hungarian HAE Registry, 49 among 173 C1-INH-HAE patients (28.3%) from 32 families had EM in their life. According to the clinical data and the patient's HAE diaries, two patients (Patient #1, Patient #2) were selected who frequently had EM as a prodromal symptom. Both patients were instructed to administer plasma-derived C1-inhibitor concentrate (pdC1-INH) as soon as possible after the onset of EM, in order to prevent the development of HAE attack. Interestingly, HAE attacks never developed if pdC1-INH was administered within 6h from the occurrence of EM in both patients. In contrast, without pdC1-INH treatment, in Patient 1 and Patient 2, 97.0% and 44.3% of the EM were followed by a HAE attack, respectively (p<0.0001, Fisher's exact test). As a novel prophylaxis in C1-INH-HAE, intravenous administration of pdC1-INH concentrate during EM might be an effective, individual therapeutic strategy in those patients who's HAE attacks are often preceded by EM. Besides it can improve the quality of life of these selected patients, pdC1-INH administration during EM provides the lowest effective dose for the prophylaxis of their HAE attacks.


Molecular farming of human tissue transglutaminase in tobacco plants.
In this study we have utilized Nicotiana tabacum with a molecular farming purpose in attempt of producing transgenic plants expressing the human tissue transglutaminase (htTG). Three plant expression constructs were used enabling targeting and accumulation of the recombinant protein into the plant cell cytosol (cyto), the chloroplasts (chl) and the apoplastic space (apo). Analysis of transgenic T(0) plants revealed that recombinant htTG was detectable in all three transgenic lines and the accumulation levels were in a range of 18-75 microg/g of leaf material. In the T(1) generation, the recombinant htTG was still expressed at high level and a significant catalytic activity was detected into the leaf protein extracts. Southern blot analyses revealed that apo and chl plants of T(1) generation possess a high copy number of the recombinant htTG in their genome, while the cyto plants carry a single copy.


Myoblast fusion confusion: the resolution begins.
The fusion of muscle precursor cells is a required event for proper skeletal muscle development and regeneration. Numerous proteins have been implicated to function in myoblast fusion; however, the majority are expressed in diverse tissues and regulate numerous cellular processes. How myoblast fusion is triggered and coordinated in a muscle-specific manner has remained a mystery for decades. Through the discovery of two muscle-specific fusion proteins, Myomaker and Myomerger-Minion, we are now primed to make significant advances in our knowledge of myoblast fusion. This article reviews the latest findings regarding the biology of Myomaker and Minion-Myomerger, places these findings in the context of known pathways in mammalian myoblast fusion, and highlights areas that require further investigation. As our understanding of myoblast fusion matures so does our potential ability to manipulate cell fusion for therapeutic purposes.


[Whipple's disease endocarditis: report of 5 cases and review of the literature].
Endocarditic lesions (infectious endocarditis) associated with Whipple's disease are exceptional. We report five cases from the cardiovascular and pneumologic hospital Louis Pradel in Lyon. We have collected all cases of Tropheryma whipplei endocarditis diagnosed between 1995 and 2004. Five men with a mean age of 53 years at time of diagnosis. The symptoms were essentially cardiovascular: murmur, embolism in 3 cases, and heart failure secondary to valvular insufficiency in 2 cases. The valvular involvement, double in 3 cases, was more often aortic. Vegetations were present in all patients and valvular destruction sometimes very important. A low grade fever was present in 4 cases, associated with weight loss in 2 cases. The only extra-cardiac symptoms were arthralgias or arthritis in all cases, considered in 3 patients as seronegative rheumatoid arthritis, B27+ spondylarthritis, and psoriasic arthritis. Their was no other clinical manifestations of Whipple's disease, particularly digestive, ocular, neurologic or adenopathy, and duodenal biopsies secondarily performed in 4 cases were non contributive. This differs from literature as an extra-cardiac location was identified in 11 out of 17 cases. The diagnosis was obtained by histology and PCR on the cardiac valves, as all the patients underwent surgery. The evolution was favourable with a prolonged antibiotic therapy. These report confirms the existence of endocarditic forms of the Whipple's disease, in which the single extra-cardiac manifestation is rheumatologic, and reminds us the usefulness of histology and PCR on the cardiac valves at the time of valvular surgery.


Validating electronic cancer quality measures at Veterans Health Administration.
To assess the feasibility and validity of developing electronic clinical quality measures (eCQMs) of cancer care quality from existing metrics, using electronic health records, administrative, and cancer registry data. Retrospective comparison of quality indicators using chart abstracted versus electronically available data from multiple sources. We compared the sensitivity and specificity of eCQMs created from structured data from electronic health records (EHRs) linked to administrative and cancer registry data to data abstracted from patients' electronic health records. Twenty-nine measures of care were assessed in 15,394 patients with either incident lung or prostate cancer from 2007 and 2008, respectively, and who were treated in the Veteran's Health Administration (VHA). It was feasible to develop eCQMs for 11 of 18 (61%) lung cancer measures, 4 (22%) of which were considered to be valid measures of the care constructs. Among prostate cancer measures, 6 of 11 (55%) were feasible, and 4 (36%) were both feasible and valid. Of the 29 metrics, data was available to create eCQMs for 17 (59%) cancer care metrics, and 8 (28%) were considered valid. In a large integrated healthcare system with nationally standardized electronic health records, administrative, and cancer registry data, 28% of cancer quality measures developed for chart abstraction could be translated into valid eCQMs. These results raise much concern about the development of electronic clinical quality measures for cancer care, particularly in healthcare environments where data are disparate in both form and location.


Effects of the intracerebroventricular administration of ketamine on centrogenic arrhythmias in anesthetized rats.
In urethane anesthetized rats the icv (lateral cerebral ventricle) administration of ketamine, at the highest utilized doses, induced bradypnea and sinus bradycardia in spontaneously breathing rats. Moreover, it partially antagonized the arrhythmogenic activities of sodium glutamate and sodium aspartate, as well as desipramine and ouabain. From these results, we conclude that ketamine had an inhibitory effect on the centrogenic arrhythmias not only acting at the level of NMDA subtype receptor, but also at beta 1 adrenergic central receptors. Moreover at high doses, ketamine can also induce centrogenic arrhythmias in spontaneously breathing rats.


[A randomized controlled trail of intensive and usual community-based education for blood pressure control].
A 1.5 year community-based hypertension education program was conducted and evaluated for the feasibility and effectiveness as a program for primary prevention of cardiovascular disease. The subjects were determined to be hypertensive from cardiovascular examinations and composed of 104 untreated men and women aged 35-69 whose blood pressure levels were between 140 and 179 mmHg for systolic and/or between 90 and 109 mmHg for diastolic and who had no evidence of hypertensive end organ effects in the 1990 examination. They were randomly assigned to either an intensive education (IE) group (n = 53) or a usual education (UE) group (n = 51) and invited to education classes six months later. The IE consisted of four education classes in the first six months and another 4 classes in the next 12 months. For the UE, one class in the first 6 months and another class in the next 12 months were held. Health education was focused on reduction of sodium intake, a 30 minutes of walking, and if necessary, reduction of alcohol and sugar intake. Mean (SD) values of systolic blood pressure at the start of the education program were 144.8 (11.7) mmHg in IE and 144.5 (12.2) mmHg in UE. The respective diastolic means (SD) were 80.6 (7.8) mmHg and 80.3 (8.6) mmHg. The proportion of persons who started to receive antihypertensive medication was 8-9% in both groups at six months, and 13% in IE and 29% in UE at 1.5 years. IE showed a 6 mmHg greater reduction in mean systolic blood pressure than UE at both six months and 1.5 years. No significant difference was found in diastolic blood pressure levels over time between the two groups. Dietary improvements related to reduction of salt intake were more evident in IE than in UE. There was no significant changes in means and distributions of relative weight index and alcohol intake in either group. Subgroup analysis according to antihypertensive medication use indicated that reduction of systolic blood pressure levels was significantly larger in IE than in UE for both no medication and medication subgroups at 6 months and 1.5 years. While it was difficult to evaluate an effect of the program at 1.5 years because of the difference in the proportion of medication use between IE and UE, the results at 6 months suggest that this community-based program was effective in reducing systolic blood pressure levels.


Benign paroxysmal positional vertigo: 10-year experience in treating 592 patients with canalith repositioning procedure.
To assess the long-term efficacy of canalith repositioning procedure (CRP) in the treatment of patients with benign paroxysmal positional vertigo (BPPV). Alternative theories for the pathophysiology of BPPV have been redefined in the past few years. CRP is considered to be the standard technique for its management. However, long-term follow-up results have been minimally reported in the literature. Five hundred ninety-two patients, 290 (49%) men and 302 (51%) women, were enrolled in this prospective study; their ages ranged from 18 to 84 (mean 59) years. At the time of their first examination, patients reported the duration of symptoms varied from 1 day to 18 months. Inclusion criteria were patient history compatible with BPPV and positive provocative maneuver (either Dix-Hallpike or Roll test). A variant of Epley and Barbeque maneuver was used. The Epley maneuver was used for posterior and anterior canal involvement, and "Barbeque roll" was used for horizontal canal involvement. Short-term follow-up was obtained 48 hours and 7 days after initial treatment, whereas long-term follow-up was obtained at repeated 6 month intervals. The posterior semicircular canal was involved in 521 (88%) patients treated, whereas the horizontal and anterior semicircular canals were involved in 59 (10%) and 12 (2%) patients, respectively. Symptoms subsided immediately in 497 (84%) patients. In 77 (13%) patients, the Dix-Hallpike maneuver remained positive after 48 hours, and CRP was performed again. Patients' mean follow-up was 46 months; 544 (92%) of 592 patients treated reported no symptoms of vertigo. Our data, based on long-term follow-up, suggest that CRP remains an efficient and long-lasting noninvasive treatment for BPPV.


FRAIL-HF, a study to evaluate the clinical complexity of heart failure in nondependent older patients: rationale, methods and baseline characteristics.
The clinical scenario of heart failure (HF) in older hospitalized patients is complex and influenced by acute and chronic comorbidities, coexistent geriatric syndromes, the patient's ability for self-care after discharge, and degree of social support. The impact of all these factors on clinical outcomes or disability evolution is not sufficiently known. FRAIL-HF is a prospective observational cohort study designed to evaluate clinical outcomes (mortality and readmission), functional evolution, quality of life, and use of social resources at 1, 3, 6, and 12 months after admission in nondependent elderly patients hospitalized for HF. Clinical features, medical treatment, self-care ability, and health literacy were prospectively evaluated and a comprehensive geriatric assessment with special focus on frailty was systematically performed in hospital to assess interactions and relationships with postdischarge outcomes. Between May 2009 and May 2011, 450 consecutive patients with a mean age of 80 ± 6 years were enrolled. Comorbidity was high (mean Charlson index, 3.4 ± 2.9). Despite being nondependent, 118 (26%) had minor disability for basic activities of daily living, only 76 (16.2%) had no difficulty in walking 400 meters, and 340 (75.5%) were living alone or with another elderly person. In addition, 316 patients (70.2%) fulfilled frailty criteria. Even nondependent older patients hospitalized for HF show a high prevalence of clinical and nonclinical factors that may influence prognosis and are usually not considered in routine clinical practice. The results of FRAIL-HF will provide important information about the relationship between these factors and different postdischarge clinical, functional, and quality-of-life outcomes.


Clinical findings in 40 dogs with hypersensitivity associated with administration of potentiated sulfonamides.
The purpose of this study was to summarize the clinical findings in 40 dogs with systemic hypersensitivity reactions associated with the administration of potentiated sulfonamides. Dogs ranged from 6 months to 14 years of age, with a mean of 5.7 +/- 3.2 years. Spayed female dogs were overrepresented (24 of 40, or 60% of the dogs), as were Samoyeds (3 of 40; 8%) and Miniature Schnauzers (5 of 40; 13%). Mean dosages of potentiated sulfonamides were 47.0 +/- 14.9 mg/kg/d (range, 23.4-81.4 mg/kg/d). The time from the 1st administration of the drug to the onset of the clinical signs of hypersensitivity ranged from 5 to 36 days, with a mean of 12.1 +/- 5.9 days. There was no relationship between either the dosage or type of sulfonamide given and the time to the onset of the clinical signs. Fever was the most common clinical sign observed (55% of the dogs); thrombocytopenia was 2nd (54%), and hepatopathy (28%) was 3rd. Neutropenia, keratoconjunctivitis sicca (KCS), hemolytic anemia. arthropathy, uveitis, skin and mucocutaneous lesions, proteinuria, facial palsy, suspected meningitis, hypothyroidism, pancreatitis, facial edema, and pneumonitis were also observed in some patients. Of 39 dogs with adequate follow-up, 30 (77%) recovered, whereas 8 (21%) either died or were euthanized, and 1 recovered clinically but had persistent increases in alanine aminotransferase (ALT) activity. Dogs with hepatopathy generally had a poorer prognosis (46% recovery) than dogs without hepatopathy (89% recovery; P = .0035). Sixty-three percent of the dogs with thrombocytopenia recovered, compared to 90% of the dogs without thrombocytopenia (P = .042). Recovery was not associated with sex, age, breed, or type of sulfonamide administered.


Yeast-based microporous carbon materials for carbon dioxide capture.
A hierarchical microporous carbon material with a Brunauer-Emmett-Teller surface area of 1348 m(2) g(-1) and a pore volume of 0.67 cm(3) g(-1) was prepared from yeast through chemical activation with potassium hydroxide. This type of material contains large numbers of nitrogen-containing groups (nitrogen content >5.3 wt%), and, consequently, basic sites. As a result, this material shows a faster adsorption rate and a higher adsorption capacity of CO(2) than the material obtained by directly carbonizing yeast under the same conditions. The difference is more pronounced in the presence of N(2) or H(2)O, showing that chemical activation of discarded yeast with potassium hydroxide could afford high-performance microporous carbon materials for the capture of CO(2).


Malignancies of the ear.
Cancer of the ear is an uncommon occurrence and rarely diagnosed early it its development. Routine biopsy of all granulomatous and neoplastic diseases of the ear is essential to early diagnosis. Polytomography is an aid in documenting the extent of the disease in bone. The surgical anatomy of the region of the ear imposes special disadvantages upon any type of surgical technique employed and supervoltage irradiation given. Temporal bone resection and its modifications, combined with irradiation, enhance the cure rate in the advanced cases and add significantly to the local control of this disease. A review of 273 cases is presented.


Experimental evidence for a neural origin of Ewing's sarcoma of bone.
The histogenesis of Ewing's sarcoma remains unknown. Recent studies have suggested a relationship to an unusual form of childhood neural tumor, often termed peripheral neuroepithelioma or primitive neuroectodermal tumor. Five Ewing's sarcoma tumor cell lines were studied for evidence of a neural phenotype. Under normal culture conditions, no morphologic evidence of neural differentiation was detected. Treatment with retinoic acid, an agent known to induce marked neural differentiation in neuroblastoma, had no demonstrable effect. Treatment with either cyclic AMP or TPA, in contrast, induced pronounced morphologic evidence of neural differentiation. Cells developed elongate processes with varicosities by phase-contrast microscopy; filaments, microtubules, and uraniffin-positive dense core granules were present by electron microscopy. Three neural markers (NSE, NFTP, and cholinesterase) were absent or barely detectable in untreated cells, but became abundant after treatment. These results provide convincing evidence for a neural histogenesis of Ewing's sarcoma. They also suggest a close relationship between Ewing's sarcoma and peripheral neural tumors, including the chest wall tumor described by Askin, but only a distant relationship to neuroblastoma.


Determination of diminazene in plasma by high-performance liquid chromatography.
An analytical method is described for determining diminazene levels in plasma of cattle. Diminazene is reduced to 4-aminobenzamidine which is extracted and assayed by high-performance ion pair reverse phase partition chromatography. 3,4-Dimethoxybenzamidine served as an internal standard. Diminazene levels as low as 0.1 microgram per ml were detected.


Mechanism, effects, and reversal of left ventricular hypertrophy in hypertension.
Left ventricular hypertrophy is a common manifestation of systemic hypertension and a strong independent risk factor for adverse cardiovascular events and death. This article reviews studies that have defined the strength and scope of the association between increased left ventricular mass and prognosis, techniques of measuring left ventricular mass, and mechanisms believed responsible for left ventricular hypertrophy. Recent data suggesting the benefit of left ventricular mass reduction during hypertension treatment and the role of echocardiography in assessing patients with elevated blood pressure are discussed.


Risk of recurrent venous thromboembolism among deep vein thrombosis and pulmonary embolism patients treated with warfarin.
Guidelines for warfarin treatment of venous thromboembolism (VTE) recommend targeting an international normalized ratio (INR) level of 2-3. This study examines the association between INR levels and VTE recurrence among warfarin-treated patients. A retrospective cohort study in the MedMining electronic health record database included adults treated with warfarin for VTE in 2004-2011. INR levels during warfarin use were categorized as below therapeutic range (<2), in range (2-3), or above range (>3), with time in each category estimated using the Rosendaal method. Recurrent VTE was noted from 30 days after the initial VTE to end of follow-up, which ranged up to 8 years. The incidence of recurrent VTE was calculated, and association with time-varying INR levels estimated using Cox models. Of 1753 qualifying patients, 867 had deep vein thrombosis, and 886 had pulmonary embolism. Mean age was 58 years, and 50.7% were female. Across all follow-up time, VTE recurrences were observed in 134 (7.6%) patients, at a rate of 3.2 (95% confidence interval [CI]: 0.7-9.1) events per 100 person-years. The risk of VTE recurrence was greater during time spent with INR <2 than with INR in the therapeutic range (hazard ratio [HR]: 3.37; 95% CI: 2.16-5.27). Low platelet counts also predicted greater risk of VTE recurrence (HR: 2.13; 95% CI: 1.24-3.67). Exposure to warfarin and other anticoagulants was estimated based on prescription data and may be inaccurate. The study data include care within a single health system; thus, care received outside of the health system may be missing, and results may not be generalizable to the broader US population. Approximately 8% of patients experienced a recurrent VTE during follow-up. Subtherapeutic INR levels were associated with a more than three-fold increased risk of VTE recurrence.


An evolutionary approach to mania studying Sardinian immigrants to Argentina.
To ascertain lifetime prevalence of positivity to a screening questionnaire for bipolar disorders (BD) in Sardinian immigrants to Argentina and residents of Sardinia and assess whether such positivity affects quality of life (QoL) in either group. Our hypothesis is that screen positivity for BD may be more frequent in immigrants. Observational study. Subjects were randomly selected from the membership lists of associations of Sardinian immigrants in Argentina. A study carried out in Sardinia using the same methodology was used for comparison. The Mood Disorder Questionnaire was used to screen for mania/hypomania and the Short-Form Health Survey-12 to measure QoL. A higher prevalence of manic/hypomanic episodes was found in Sardinian immigrants to Argentina (p < 0.0001; odds ratio = 3.0, 95% confidence interval 1.87-4.77). Positivity at screening was associated with a lower QoL both in Sardinian immigrants to Argentina and in residents of Sardinia. To the best of our knowledge, this is the first study to show a higher lifetime prevalence of manic/hypomanic episodes in a general-population sample of individuals who migrated to a foreign country. Our results are in agreement with the hypothesis that hyperactive/novelty-seeking features may represent an adaptive substrate in certain conditions of social change.


[Disorders of water and electrolyte metabolism and changes in acid-base balance in patients with ascitic liver cirrhosis].
In patients with advanced cirrhosis with ascites disorders of water and electrolyte metabolism are often present and they are associated with changes in acid-base balance. These changes can be very complicated, their diagnosis and treatment difficult. Dilutional hyponatremia is the most common disorder. Hyponatremia in these patients is associated with increased morbidity and mortality before and after liver transplantation. Other common disorders include hyperchloremic acidosis, hypokalemia, metabolic alkalosis, lactic acidosis, respiratory alkalosis. If renal impairment occurs (for example hepatorenal syndrome), metabolic acidosis and retention of acid metabolites may develop. The pathogenesis of these conditions applies primarily hemodynamic changes. Activation of renin-angiotensin-aldosterone system and non-osmotic stimulation of antidiuretic hormone trigger serious changes in water and natrium-chloride metabolism. This activation is clinically expressed like oedema, ascites, hydrothorax, low to zero natrium concentration in urine and increased urinary osmolality, which is higher than serum osmolality. In practice, the evaluation can be significantly modified by the ongoing diuretic therapy. Closer monitoring of water and electrolyte metabolism together with acid-base balance in patients with ascitic liver cirrhosis is important, not only in terms of diagnosis but especially in terms of therapy.


Safety and Effectiveness of Stent Placement for Iliofemoral Venous Outflow Obstruction: Systematic Review and Meta-Analysis.
Endovenous recanalization of iliofemoral stenosis or occlusion with angioplasty and stent placement has been increasingly used to maintain long-term venous patency in patients with iliofemoral venous outflow obstruction. The purpose of this systematic review and meta-analysis was to determine safety and effectiveness of venous stent placement in patients with iliofemoral venous outflow obstruction. We searched MEDLINE and EMBASE for studies evaluating safety or effectiveness of stent placement in patients with iliofemoral venous outflow obstruction. Data were extracted by disease pathogenesis: nonthrombotic, acute thrombotic, or chronic post-thrombotic. Main outcomes included technical success, periprocedural complications, symptom relief at final follow-up, and primary/secondary patency through 5 years. A total of 37 studies reporting 45 treatment effects (nonthrombotic, 8; acute thrombotic, 19; and chronic post-thrombotic, 18) from 2869 patients (nonthrombotic, 1122; acute thrombotic, 629; and chronic post-thrombotic, 1118) were included. Technical success rates were comparable among groups, ranging from 94% to 96%. Complication rates ranged from 0.3% to 1.1% among groups for major bleeding, from 0.2% to 0.9% for pulmonary embolism, from 0.1% to 0.7% for periprocedural mortality, and from 1.0% to 6.8% for early thrombosis. Patient symptom relief data were reported inconsistently. At 1 year, primary and secondary patency were 96% and 99% for nonthrombotic, 87% and 89% for acute thrombotic, and 79% and 94% for chronic post-thrombotic. Stent placement for iliofemoral venous outflow obstruction results in high technical success and acceptable complication rates regardless of cause of obstruction.


Counterpropagating frequency mixing with terahertz waves in diamond.
Frequency conversion by means of Kerr nonlinearity is one of the most common and exploited nonlinear optical processes in the UV, visible, IR, and mid-IR spectral regions. Here we show that wave mixing of an optical field and a terahertz wave can be achieved in diamond, resulting in the frequency conversion of the terahertz radiation either by sum- or difference-frequency generation. In the latter case, we show that this process is phase matched and most efficient in a counterpropagating geometry.


Reticulated platelets interfere with flow cytometric reticulocyte counts.
As part of an iron absorption study, we needed to accurately count reticulocytes in the peripheral blood of healthy human volunteers before measuring their enrichment with stable iron isotopes given in an oral dose. Recent studies have suggested the usefulness of reticulocyte counting by flow cytometry, through a combination of differential light scatter and measurement of the stoichiometric binding of thiazole orange (TO) to RNA within the maturing erythrocyte. Using this method we set out to improve the precision of our quantitative analysis by counting more cells, as reticulocytes normally comprise <2% of the red cell population. To ensure exclusion of other cell types, we identified WBCs and platelets with CD16+CD45- allophycocyanin and CD61- phycoerythrin, respectively. After removal of CD16(+) CD45(+) TO(+) WBCs and CD61(+) TO(-) platelets from analysis, the remaining cells were a combination of CD61(-) TO(-) erythrocytes, CD61(-) TO(+) reticulocytes and CD61(+) TO(+) reticulated platelets. Reticulocyte counts were lower after exclusion of CD61(+) TO(+) cells from analysis. They were similarly lower when erythrocyte precursors were positively identified through their glycophorin A expression and TO uptake. We conclude that it is necessary to exclude reticulated platelets from flow cytometric reticulocyte analysis.


beta-Glucanases from Candida albicans: purification, characterization and the nature of their attachment to cell wall components.
beta-Glucanase activities were found associated with Candida albicans and their culture fluids. Mild acid treatment of the organisms led to rapid inactivation of beta-glucanase activities, the degree of loss increasing with the age of the cultures; the results suggested an extracytoplasmic location of the cell-associated enzymes. Most of the beta-glucanase activities were associated with the cell walls in organisms phenotypically resistant to amphotericin B methyl ester (AME). Two proteins (I and II) exhibiting beta-glucanase activity were isolated and purified by conventional procedures from cell-free extracts, cell-wall autolysates and culture fluids of C. albicans sensitive and phenotypically resistant to AME. The purified enzymes appeared homogeneous on isoelectric focusing, gel electrophoresis and ultracentrifugation, with molecular weights of 150000 (I) and 49000 (II). Both enzymes hydrolysed cell walls purified from AME-sensitive and phenotypically resistant organisms, but showed different substrate specificities and patterns of activity. Enzyme II hydrolysed (1 leads to 3)-beta-glycans by an endolytic mechanism releasing laminaritetraose as the initial product. Glucose was the only product released by enzyme I. The properties of th individual enzymes were unaffected by their localization or the age of the culture of the organisms. The loosening of the polysaccharide packing by ultrasonic treatment of cell walls purified from AME-resistant organisms increased the beta-glucanase activities bound to the walls, but did not solubilize them. Autolysis of cell walls released 58 to 66% of their beta-glucanase activity in 20 h, but no further release was attained on prolonged incubation. The amount of beta-glucanase activity released by autolysis was increased by a variety of pretreatments. Diethyl pyrocarbonate inhibited beta-glucanase activity and prevented autolysis. Evidence is presented indicating that interactions with lipids, polysaccharides and other cell wall proteins may be involved in the control of the activity of the cell wall-associated beta-glucanases in organisms phenotypically resistant to AME.


Orientational properties of poly-gamma-benzyl-L-glutamate: influence of molecular weight and solvent on order parameters of the solute.
Residual dipolar couplings (RDCs) have recently become increasingly important in organic structure determination due to their unique information content. One main limitation for the use of RDCs in organic compounds, however, is that the compound in question needs to be oriented with respect to the magnetic field in order to measure RDCs. So far, there are very few possibilities for modulating the induced degree of orientation. The situation is even worse when chiral orienting media are considered, which could allow absolute configuration determination in the future. We have conducted a systematic investigation into modulating the orientation induced by one chiral orienting medium, namely organic solutions of PBLG (poly-gamma-benzyl-L-glutamate), as a function of its molecular weight and the organic co-solvent used, and have obtained significant insights into factors that influence the order induced. With increasing molecular weight of the polypeptide the orientation of the solutes decreases, leading to well-resolved spectra with improved line shapes. This can be attributed exclusively to the fact that the critical concentration of the liquid-crystalline phase decreases with increasing molecular weight (pure dilution effect). Any influence of increasing flexibility on the orientation can be ruled out.


[Treatment of megaureter in children by Cohen's operation combined with ureteral reconstruction. 81 reconstructed and reimplanted ureters].
From January 1973 to June 1983, 69 children have been operated on: remodeling of a primary mega-ureter and reimplantation of the tailored ureter with the Cohen technique. 81 ureters have been treated this way. 68 children have been followed and the results of this operation are evaluated on 80 ureters. There are 65 satisfactory results, 5 mediocre and 10 bad (5 stenosis, 5 reflux); another operation has been done for these cases: 3 nephrectomy, 7 conservative treatments have been successful.


Exploring gene function: use of yeast artificial chromosome transgenesis.
Transgenesis is a very powerful tool in functional analysis of proteins and control of gene expression. One of the main drawbacks has been the low levels of expression, lack of tissue specificity, and inappropriate expression frequently observed for transgenes made with small plasmid-based constructs. The use of much larger DNA fragments cloned in yeast artificial clones (YACs), bacterial artificial clones, or P1-based artificial clones has been found to give much better levels of expression, generally very close to that of an endogenous gene, and tissue-specific expression matching that of the endogenous gene. In addition, the large DNA can easily be subtly modified by homologous recombination. This article describes the background and methods of YAC transgenesis.


CACNA1C genotype explains interindividual differences in amygdala volume among patients with schizophrenia.
Affective deficits are one common denominator of schizophrenia (SZ), bipolar disorder (BD) and obsessive compulsive disorder (OCD) with the amygdala indicated as one of the major structures involved in emotion regulation. Previous findings of differences in amygdala volume between healthy controls and patients with SZ, BD or OCD diverge with respect to the affected hemisphere, size and direction of the effect. Variability in the CACNA1C gene has been linked to BD, SZ as well as structural and functional variation in the amygdala in healthy people and patients with BD. We were interested to investigate whether amygdala volumes differ between hemispheres, diagnostic or genotype groups, and whether any interactive effects exist. We combined genotyping of SNP rs1006737 in CACNA1C with structural MRI measurements of relative gray matter (GM) amygdala volume in patients with SZ, BD or OCD as well as healthy controls (N Total = 72). The CACNA1C genotype showed a significant effect on relative GM amygdala volume in patients with SZ. There was a significant left versus right relative GM amygdala volume decrease in patients with SZ or BD. The effects of hemisphere and diagnosis (controls vs. patients with SZ) on relative GM amygdala volume were genotype specific. Our data suggest that the CACNA1C genotype may account for some heterogeneity in the effects of hemisphere and diagnosis on amygdala volume when comparing patients with SZ and controls and point to disturbed Ca(2+)-signaling as a plausible mechanism contributing to the pathology in patients with SZ.


Short-term efficacy of robotic and laparoscopic spleen-preserving splenic hilar lymphadenectomy via Huang's three-step maneuver for advanced upper gastric cancer: Results from a propensity score-matched study.
Robotic surgery has been considered to be significantly better than laparoscopic surgery for complicated procedures. To explore the short-term effect of robotic and laparoscopic spleen-preserving splenic hilar lymphadenectomy (SPSHL) for advanced gastric cancer (GC) by Huang's three-step maneuver. A total of 643 patients who underwent SPSHL were recruited from April 2012 to July 2017, including 35 patients who underwent robotic SPSHL (RSPSHL) and 608 who underwent laparoscopic SPSHL (LSPSHL). One-to-four propensity score matching was used to analyze the differences in clinical data between patients who underwent robotic SPSHL and those who underwent laparoscopic SPSHL. In all, 175 patients were matched, including 35 patients who underwent RSPSHL and 140 who underwent LSPSHL. After matching, there were no significant differences detected in the baseline characteristics between the two groups. Significant differences in total operative time, estimated blood loss (EBL), splenic hilar blood loss (SHBL), splenic hilar dissection time (SHDT), and splenic trunk dissection time were evident between these groups (P < 0.05). Furthermore, no significant differences were observed between the two groups in the overall noncompliance rate of lymph node (LN) dissection (62.9% vs 60%, P = 0.757), number of retrieved No. 10 LNs (3.1 ± 1.4 vs 3.3 ± 2.5, P = 0.650), total number of examined LNs (37.8 ± 13.1 vs 40.6 ± 13.6, P = 0.274), and postoperative complications (14.3% vs 17.9%, P = 0.616). A stratified analysis that divided the patients receiving RSPSHL into an early group (EG) and a late group (LG) revealed that the LG experienced obvious improvements in SHDT and length of stay compared with the EG (P < 0.05). Logistic regression showed that robotic surgery was a significantly protective factor against both SHBL and SHDT (P < 0.05). RSPSHL is safe and feasible, especially after overcoming the early learning curve, as this procedure results in a radical curative effect equivalent to that of LSPSHL.


The biosynthesis of heme O and heme A is not regulated by copper.
Heme A is an obligatory cofactor in all eukaryotic and many prokaryotic cytochrome c oxidase (CcO) enzymes. Despite its obvious importance to CcO and the electron transport pathway, essentially nothing is known concerning the regulation of heme A. Because CcO is the only natural target for heme A and copper is also required for CcO activity, it was postulated that copper might regulate heme A homeostasis. Work reported previously demonstrated that there is often a strong connection between copper and iron homeostasis in general, and circumstantial evidence pointed to a possible specific link between copper and heme A. To address this question, we conducted experiments to determine rigorously whether copper plays a role in heme A homeostasis. The two enzymes responsible for the conversion of heme B to heme A, heme O synthase (HOS) and heme A synthase (HAS), were separately genomically epitope-tagged in Saccharomyces cerevisiae, and their expression under various copper conditions was quantified by Western blot analysis. These results demonstrated that the sum of transcription, translation, and stability of HOS and HAS were independent of copper. Additionally, the effects of intracellular copper concentrations on the activity of HOS and HAS from Bacillus subtilis (expressed in Escherichia coli) and Rhodobacter sphaeroides were examined by analysis of cellular heme extracts. No trends with respect to intracellular copper were observed. In combination, our results demonstrate that intracellular copper levels do not affect the transcription, translation, stability, or activity of either HOS or HAS.


Attitudes of dentists and dental patients toward advertising.
Twenty years ago, Hite, Bellizzi, and Andrus (1988) examined the attitudes of dentists and consumers toward advertising. This study re-examines those attitudes to see if significant differences still exist. Based on a sample of dentists and consumers, significant differences were found. While attitude of dentists toward advertising is not as negative as it was 20 years ago, their views still tend to lag behind that of consumers. Further, the marketing tools used by dentists today are not consistent with what is seen by consumers and what consumers view as effective. Implications of these findings are discussed.


Friedel oscillations in microwave billiards.
Friedel oscillations of electron densities near step edges have an analog in microwave billiards. A random plane-wave model, normally only appropriate for the eigenfunctions of a purely chaotic system, can be applied and is tested for non-purely-chaotic dynamical systems with measurements on pseudointegrable and mixed dynamics geometries. It is found that the oscillations in the pseudointegrable microwave cavity match the random plane-wave modeling. Separating the chaotic from the regular states for the mixed system requires incorporating an appropriate phase-space projection into the modeling in multiple ways for good agreement with experiment.


[Measurement of sputum viscosity with the Jenssen viscometer].
The authors measured the viscosity of sputum with a Jenssen type capillary viscometer. The repeated assessment of the viscosity of the same sample of sputum showed that the results are reproducible and the instrument does not disrupt markedly the structure of the sputum. After measuring the viscosity of 35 patients with different types of pulmonary disease the authors state, in accordance with the data found in literature, that the measurement of the viscosity of sputum by itself cannot help in the differential diagnosis of pulmonary diseases. The authors suggest the determination of the Biochemical constituents of sputum to supplement the measurement of the viscosity of sputum.


Whole Exome Sequencing Confirms Molecular Diagnostics of Three Pakhtun Families With Autosomal Recessive Epidermolysis Bullosa.
Epidermolysis bullosa (EB) is a genetic skin disorder that shows heterogeneous clinical fragility. The patients develop skin blisters congenitally or in the early years of life at the dermo-epithelial junctions, including erosions, hyperkeratosis over the palms and soles. The other associated features are hypotrichosis on the scalp, absent or dystrophic nails, and dental anomalies. Molecular diagnosis through whole-exome sequencing (WES) has become one of the successful tool in clinical setups. In this study, three Pakhtun families from the Khyber Pakhtunkhwa province of Pakistan were ascertained. WES analysis of a proband in each family revealed two novel variants (COL17A1: NM_000494.4: c.4041T>G: p.Y1347* and PLEC: NM_201380.3: c.1283_1285delGCT: p.L426del) and one previously known COL17A1: NM_000494.4:c.3067C>T: p.Q1023*) variant in homozygous forms. Sanger sequencing of the identified variants confirmed that the heterozygous genotypes of the obligate carriers. The identified variants have not only increased the mutation spectrum of the COL17A1 and PLEC but also confirms their vital role in the morphogenesis of skin and its associated appendages. WES can be used as a first-line diagnostic tool in genetic testing and counselling families from Khyber Pakhtunkhwa, Pakistan.


[Establish predictive model of colorectal cancer by using surface enhanced laser desorption/ionization-time of flight-mass spectrometry].
To establish serum proteome fingerprinting predictive models and search for proteins associated with colorectal cancer. Thirty-six randomly selected colorectal cancer patients and 36 cases with hernia or gall bladder diseases scheduled for elective operation were enrolled as cancer group and control group respectively. Peripheral venous blood samples were collected before the operations. Special serum protein or peptide fingerprint was investigated by using surface enhanced laser desorption/ ionization-time of flight-mass spectrometry (SELDI-TOF-MS) measurement after blood sample had been treated with weak cation exchange protein chip (CM10) for each case. The obtained data were analyzed by Biomarker Wizard software to screen serum proteome tumor markers and set up diagnosis predictive model for colorectal cancer. Blind validation of the model with 44 healthy controls and 88 colorectal cancer patients were carried out by using Biomarker Patterns Software. In comparing colorectal cancer group with control group, 5 specific protein peaks (P < 0.05) were found. The predictive model had a sensitivity of 100% and a specificity of 97.2%. A sensitivity of 71.6% and a specificity of 72.7% was got with the blind validation. The specific protein peaks with a mass-to-charge ratio (m/z) of 8908 and 13,707 showed in all the results and it showed their strong relationship with colorectal cancer. The predictive models built by the differences of serum proteome fingerprint could be a very useful diagnostic tool in colorectal cancer. Proteins with m/z of 8908 and 13,707 would possibly be the tumor markers of colorectal cancer.


Antibiotic susceptibility of Streptococcus pneumoniae in New Zealand.
To determine the current antibiotic susceptibility patterns of Streptococcus pneumoniae from four centres in New Zealand. Over a six-month period in 1997, 386 consecutive clinical isolates of S pneumoniae were collected by four laboratories (Auckland, Wellington, Hamilton and Christchurch) from general practice or inpatients. Susceptibility testing for seven antibiotics was performed by each centre using the Etest. Eighty-three-percent of isolates were penicillin susceptible, 12% showed intermediate resistance to penicillin and 5% were penicillin resistant. Overall, 93 and 91% of isolates were susceptible to amoxicillin/clavulanic acid and ceftriaxone, respectively. Erythromycin and tetracycline had similar rates of susceptibility (88 and 87%, respectively). Resistance to cotrimoxazole was common, with only 57% of isolates susceptible to this combination. No National Committee for Clinical Laboratory Standard (NCCLS) breakpoints were available for cefaclor to allow interpretation of the minimum inhibitory concentration data for this agent. Wellington had lower resistance rates than Auckland, Christchurch and Hamilton. Isolates from children had consistently higher resistance rates (two- to five-fold greater for beta-lactams and 1.2 to 1.3-fold for other agents) compared with isolates from adult patients. Resistance to multiple antibiotics among S pneumoniae is now evident in New Zealand, although rates varied between study centres. The overall rate of penicillin resistance is 5%, which is similar to that observed in many European and US cities but lower than the rates reported in badly affected areas (> 30%). These data suggest that amoxicillin (+/- clavulanic acid), erythromycin or tetracycline are appropriate agents for empirical use in less serious community acquired infections when S pneumoniae is suspected. Ceftriaxone, with or without vancomycin, should be considered in the empirical treatment of invasive, disease until sensitivities are known.


Rationale for chemotherapeutic approaches to prostate cancer.
The problems of curing tumors with a low growth fraction with cytotoxic chemotherapeutic agents include 1) the fact that such agents attack biochemical pathways common and vital to all cells, 2) the existence in a tumor of cells with both temporary and permanent resistance to specific agents, and 3) the exponential nature of cell kill, which necessitates a much more intensive treatment to effect cure than to effect remission. The possible bases for selectivity of anticancer drugs include those factors that affect the concentration of the active form of the drug at the active site, those that affect the drug receptor interaction and those that determine whether this interaction will lead to cell death. Possible ways of overcoming resistance include combination chemotherapy, more intensive chemotherapy, adjuvant chemotherapy, and maneuvers leading to recruitment of cells into cycle. Because of tumor cell heterogeneity a different approach may be needed to effect cure from that required to induce complete remission.


Validation of a bone loading estimation algorithm for patient-specific bone remodelling simulations.
Patient-specific simulations of bone remodelling could enable predicting how bone micro-structural integrity would be affected by bone diseases, drugs or other factors, and, ultimately could help clinicians to improve their prognoses. To simulate load-adaptive remodelling, however, knowledge about the physiological external loading acting on the bone is required. Assuming that load adaptation leads to homogeneous tissue loading, we previously developed a method to estimate the physiological loading history from bone micro-structural morphology. We were able to reconstruct the loading history of a simple load case that was applied in an animal experiment. However, we found considerable inhomogeneity in tissue loading suggesting that the bones were not fully adapted. Also, we noted differences in bone micro-architecture between animals despite common loading history, possibly due to differences caused by the stochastic nature of the bone remodelling process. In the present study, we aim at validating the load estimation algorithm in a well-controlled environment in which more complicated loading conditions are applied. Specifically, we want to test its accuracy for partially and fully developed bone structures and for differences in bone micro-architectures as they can occur due to stochastic events, even for bones with a common loading history. This was possible by using synthetic micro-architectures obtained from bone remodelling simulations as the basis for our load estimation algorithm. Loading histories based on fully adapted structures were predicted with a maximum error of 4.4% and predictions were not affected by differences in bone micro-architecture. These results show that our load estimation algorithm produces reasonable predictions and might be a suitable tool to define in vivo loading for patient-specific bone remodelling studies.


Methods for diagnosing hepatic encephalopathy in patients with cirrhosis: a multidimensional approach.
There is no "gold standard" for diagnosing hepatic encephalopathy in patients with cirrhosis. In consequence, the presence of this condition, unless floridly overt, is often missed. As a result, the majority of patients are denied the benefits of treatment. There are a number of individual techniques, which access different aspects of cerebral function that can be used, singly or in combination, to provide diagnostic information in this condition, including mental state assessment, psychometric testing, electroencephalography, sensory and cognitive evoked potentials, and neuroimaging. These have been variously applied to the study of hepatic encephalopathy but fundamental differences in the essential aims of the studies, as well as differences in the patient populations and the acquisition and analysis of the data, have made comparisons difficult. Thus, there is no clear consensus as to the sensitivity, specificity, or validity of these tests when used alone or in combination. There are, however, a number of additional methods that could be used to analyze the electrophysiological data, and a number of alternative evoked potentials that could be measured to provide better diagnostic information. In addition, there are a number of techniques, such as critical flicker frequency and smooth pursuit eye movements, which have not yet been applied systematically in this condition and which may provide useful diagnostic information. Clearly the methods for assessing hepatic encephalopathy need to be reviewed, newer methods for analyzing the electrophysiological data and newer techniques for assessing alternative aspects of cerebral function need to be explored for their diagnostic utility. This process should aim at developing a multidimensional diagnostic tool.


Reliability of ultrasound imaging in the assessment of the dorsal Lisfranc ligament.
The Lisfranc ligament plays an integral role in providing stability to the midfoot. Variable clinical presentations and radiographic findings make injuries to the Lisfranc ligament notoriously difficult to diagnose. Currently, radiographic evaluation is the mainstay in imaging such injuries; however, ultrasound has been suggested as a viable alternative. The objective of this study was to evaluate the intra-rater and inter-rater reliability in the measurement of the length of the dorsal Lisfranc ligament using ultrasound imaging in healthy, asymptomatic subjects. The dorsal Lisfranc ligaments of fifty asymptomatic subjects (n = 100 feet) were imaged using a Siemens SONOLINE Antares Ultrasound Imaging System© under low, medium, and high stress loads at 0° and 15° abducted foot positions. The lengths of the ligaments were measured, and Interclass correlation coefficients were used to calculate within-session intra-rater reliability (n = 100 feet) as well as between-session intra-rater reliability (n = 40 feet) and between-session inter-rater reliability (n = 40 feet). The within-session intra-rater reliability results for dorsal Lisfranc ligament length had an average ICC of 0.889 (min 0.873 max 0.913). The average ICC for between-session intra-rater reliability was 0.747 (min 0.607 max 0.811). The average ICC for between-session inter-rater reliability was 0.685 (min 0.638 max 0.776). The measurement of the dorsal Lisfranc ligament length using ultrasound imaging shows substantial to almost perfect reliability when evaluating asymptomatic subjects. This imaging modality methodology shows promise and lays the foundation for further work in technique development towards the diagnostic identification of pathology within the Lisfranc ligament complex.


Altered linkage of hydroxyacyl chains in lipid A of Campylobacter jejuni reduces TLR4 activation and antimicrobial resistance.
Modification of the lipid A moiety of bacterial lipopolysaccharide influences cell wall properties, endotoxic activity, and bacterial resistance to antimicrobial peptides. Known modifications are variation in the number or length of acyl chains and/or attached phosphoryl groups. Here we identified two genes (gnnA and gnnB) in the major foodborne pathogen Campylobacter jejuni that enable the synthesis of a GlcN3N precursor UDP 2-acetamido-3-amino-2,3-dideoxy-alpha-D-glucopyranose (UDP-GlcNAc3N) in the lipid A backbone. Mass spectrometry of purified lipooligosaccharide verified that the gene products facilitate the formation of a 2,3-diamino-2,3-dideoxy-D-glucose (GlcN3N) disaccharide lipid A backbone when compared with the beta-1'-6-linked D-glucosamine (GlcN) disaccharide observed in Escherichia coli lipid A. Functional assays showed that inactivation of the gnnA or gnnB gene enhanced the TLR4-MD2-mediated NF-kappaB activation. The mutants also displayed increased susceptibility to killing by the antimicrobial peptides polymyxin B, colistin and the chicken cathelicidin-1. The gnnA and gnnB genes are organized in one operon with hemH, encoding a ferrochelatase catalyzing the last step in heme biosynthesis. These results indicate that lipid A modification resulting in amide-linked acyl chains in the lipid A is an effective mechanism to evade activation of the innate host defense and killing by antimicrobial peptides.


Effect of length on the position of negative differential resistance and realization of multifunction in fused oligothiophenes based molecular device.
The length modulation of electron transport properties for molecular devices based on fused oligothiophenes has been investigated theoretically using a combination of non-equilibrium Green's functions and first-principles density functional theory. The results show that the lengths of the molecules have a distinct influence on the position of negative differential resistance (NDR) of the molecular devices. By exploring the effect on transmission properties of substituent groups, hexathieno[3,2-b:2',3'-d]thiophene with -NH2 and -NO2 substituents (model L) can be regard as a good candidate of multifunctional molecular device, which shows excellent rectifying performance (the largest rectification ration is 14.3 at 1.2 V) and clear NDR behavior (at 1.4 V).