MI-Lab - A Laboratory Environment for Medical Informatics Students.
Medical research and health care highly depend on the use of information technology. There is a wide range of application systems (patient administration system, laboratory information system, communication server etc.) and heterogeneous data types (administrative data, clinical data, laboratory data, image data, genomic data etc.). Students and researchers do not often have the possibility to use productive application systems of e.g. hospitals or medical practices to gain practical experiences or examine new components and technologies. Therefore, the aim of this project is to develop a dedicated laboratory environment for patient health care and clinical research. Essential application systems were identified and a suitable architecture was designed for this purpose. It is accompanied by a teaching plan that considers learning modules for bachelor and master degrees in medical informatics. We implemented the laboratory environment called MI-Lab with multiple free and open source software components. All components are installed on virtual machines and/or Docker containers. This modular architecture creates a flexible system which can be deployed in various scenarios. The preliminary evaluation results suggests that laboratory environments like MI-Lab work well in teaching practical aspects of medical informatics and are widely accepted by students.


Repair of rectal prolapse using a puborectal sling procedure.
Many procedures have been described for the repair of rectal prolapse. Some are associated with a high recurrence rate and do not correct associated fecal incontinence. During the last four years, we have operated on 15 patients using a puborectal sling fashioned of polypropylene mesh. Nine were women and six were men, with ages ranging from 25 to 72 years. Eight patients had fecal incontinence. During a follow-up of six months to four years, rectal prolapse did not recur. Fecal incontinence was totally resolved in all cases. The morbidity and death rates were both 0%, and no long-term problems have been associated with use of the synthetic material. This procedure is a sound alternative for patients with complete rectal procidentia and fecal incontinence, as it corrects the associated anatomic defect of the anorectal angle.


An exploration of protective factors supporting desistance from sexual offending.
This article considers factors that support or assist desistance from sexual offending in those who have previously offended. Current risk assessment tools for sexual offending focus almost exclusively on assessing factors that raise the risk for offending. The aim of this study was to review the available literature on protective factors supporting desistance from sexual offending. This article discusses the potential value of incorporating protective factors into the assessment process, and examines the literature on this topic to propose a list of eight potential protective domains for sexual offending. The inclusion of notions of desistance and strengths may provide additional guidance to the assessment and treatment of those who sexually offend. Further research investigations are recommended to consolidate the preliminary conclusions from this study regarding the nature and influence of protective factors in enabling individuals to desist from further offending.


MicroRNA profiles discriminate among colon cancer metastasis.
MicroRNAs are being exploited for diagnosis, prognosis and monitoring of cancer and other diseases. Their high tissue specificity and critical role in oncogenesis provide new biomarkers for the diagnosis and classification of cancer as well as predicting patients' outcomes. MicroRNAs signatures have been identified for many human tumors, including colorectal cancer (CRC). In most cases, metastatic disease is difficult to predict and to prevent with adequate therapies. The aim of our study was to identify a microRNA signature for metastatic CRC that could predict and differentiate metastatic target organ localization. Normal and cancer tissues of three different groups of CRC patients were analyzed. RNA microarray and TaqMan Array analysis were performed on 66 Italian patients with or without lymph nodes and/or liver recurrences. Data obtained with the two assays were analyzed separately and then intersected to identify a primary CRC metastatic signature. Five differentially expressed microRNAs (hsa-miR-21, -103, -93, -31 and -566) were validated by qRT-PCR on a second group of 16 American metastatic patients. In situ hybridization was performed on the 16 American patients as well as on three distinct commercial tissues microarray (TMA) containing normal adjacent colon, the primary adenocarcinoma, normal and metastatic lymph nodes and liver. Hsa-miRNA-21, -93, and -103 upregulation together with hsa-miR-566 downregulation defined the CRC metastatic signature, while in situ hybridization data identified a lymphonodal invasion profile. We provided the first microRNAs signature that could discriminate between colorectal recurrences to lymph nodes and liver and between colorectal liver metastasis and primary hepatic tumor.


Hereditary emphysema in the tight-skin mouse. Evaluation of pathogenesis.
The tight-skin (Tsk/+) mouse is a genetically determined model characterized by alveolar enlargement and physiologic evidence of emphysema. Morphologic evaluation of the lungs of these animals demonstrated increased numbers of potential protease-secreting cells (alveolar macrophages and neutrophils) in the lower respiratory tract prior to development of the emphysematous lesions. Quantitation of the neutrophils in the lungs of these animals was carried out by bronchoalveolar lavage. In the Tsk/+ mice, neutrophils constituted 3.5 +/- 2% of all inflammatory and immune effector cells present compared with 0.4 +/- 0.1% in control (+/+) mice (p less than 0.01). The Tsk/+ animals had no evidence of infection to explain the presence of the neutrophils and had normal proportions of lung T- and B-lymphocytes, suggesting that their lungs were immunologically normal. There was no evidence that the Tsk/+ mice have an antiprotease deficit; the capacity of serum of Tsk/+ mice to inhibit neutrophil elastase was no different from that of control +/+ animals. However, the fact that these animals have a persistent low level macrophage-neutrophil alveolitis prior to the development of the emphysematous lesion implies that the lung destruction may be associated, in part, with a chronic protease-antiprotease imbalance, similar to that hypothesized for human emphysema.


Examining the Influence of Early Life Stress on Serum Lipid Profiles and Cognitive Functioning in Depressed Patients.
Early childhood adversity is a strong predictor of the development of major depressive disorder (MDD), but not all depressed patients experience early life stress (ELS). Cardio-metabolic diseases and cognitive deficits often coincide in MDD and worsen its course and outcome. Adverse childhood experiences have been associated with elevated risk for cardiovascular disease (CVD), but little is known on the impact of ELS on cardiovascular risk factors in MDD. Here, we examined MDD patients with and without ELS to explore the effects of ELS on serum lipid and lipoprotein levels and on cognitive performances of the patients. Participants with a mean age of 35 years (18-55 years) were recruited from the university mental health clinic and general community. Three groups, matched in age, gender and lifestyle were examined: MDD patients with ELS (n = 21), MDD patients without ELS (n = 21), and healthy controls (n = 20). The following CVD risk factors were assessed: serum lipids (total cholesterol, triglycerides, high- and low-density lipoproteins), body mass index and exercise in a typical week. MDD severity was measured by the Beck Depression Inventory. Childhood Trauma Questionnaire was used to assess early life adversities. Executive functions and attentional processes were assessed by the Wisconsin Card Sorting and Conners' Continuous Performance tests. Major depressive disorder patients with ELS had higher serum triglyceride and lower HDL-cholesterol concentrations compared to MDD patients without ELS. Linear regression analysis revealed that the severity of ELS had a significant negative association with HDL-cholesterol levels and significant positive associations with the serum levels of TG and TC/HDL-cholesterol index. We also found significant associations between some specific trauma types and lipid profiles. Finally, we could detect significant associations between depression severity and specific domains of the cognitive tests as well as between lipid profiles and certain domains of the Wisconsin Card Sorting Test. However, we could not detect any association between the severity of ELS and cognitive performance. After controlling for depressive symptom severity and lifestyle variables, ELS was found to be a strong predictor of serum lipid alterations. Several, inter-correlated pathways may mediate the undesirable effects of ELS on the course and outcome of MDD.


Cyclosporine and the immune response: basic aspects.
Cyclosporine (CsA) is a novel immunosuppressive agent currently used clinically, to prevent rejection of solid organ allografts and to prevent graft-vs.-host disease. Early studies in a variety of animal models exhibited transplantation tolerance after limited treatment with this unique agent. The apparent specific immunological unresponsiveness induced by CsA is thought to be maintained by antigen-specific suppressor T lymphocytes. Studies attempting to dissect the mechanism of action of this unique agent suggested that CsA selectively affected different T lymphocyte populations. Cyclosporine was very effective at inhibiting the production of interleukin-2 (IL-2), a soluble lymphokine known to amplify cytotoxic T cell responses and was also capable of preventing IL-2 receptor expression on the precursor cytotoxic T lymphocyte. In contrast, to the effect on T helper cells and on the precursor cytotoxic T lymphocyte, studies in vitro and in vivo demonstrated that CsA had a sparing effect on suppressor T cell induction. More recent studies have indicated that CsA allows for the amplification of suppressor T lymphocytes independent of interleukin-2 indicating that other cellular and/or soluble factors are important for potentiation of suppressor T lymphocyte activity. However, the molecular action of CsA at the cellular level still remains unresolved. Thus, CsA is not only a useful drug in clinical transplantation but it has become increasingly important as an immunologic probe allowing the dissection of complex cellular interactions involved in the immune response.


Improvement of the novel inhibitor for Mycobacterium enoyl-acyl carrier protein reductase (InhA): a structure-activity relationship study of KES4 assisted by in silico structure-based drug screening.
InhA or enoyl-acyl carrier protein reductase of Mycobacterium tuberculosis (mtInhA), which controls mycobacterial cell wall construction, has been targeted in the development of antituberculosis drugs. Previously, our in silico structure-based drug screening study identified a novel class of compounds (designated KES4), which is capable of inhibiting the enzymatic activity of mtInhA, as well as mycobacterial growth. The compounds are composed of four ring structures (A-D), and the MD simulation predicted specific interactions with mtInhA of the D-ring and methylene group between the B-ring and C-ring; however, there is still room for improvement in the A-ring structure. In this study, a structure-activity relationship study of the A-ring was attempted with the assistance of in silico docking simulations. In brief, the virtual chemical library of A-ring-modified KES4 was constructed and subjected to in silico docking simulation against mtInhA using the GOLD program. Among the selected candidates, we achieved synthesis of seven compounds, and the bioactivities (effects on InhA activity and mycobacterial growth and cytotoxicity) of the synthesized molecules were evaluated. Among the compounds tested, two candidates (compounds 3d and 3f) exhibited superior properties as mtInhA-targeted anti-infectives for mycobacteria than the lead compound KES4.


Crystal structure of the self-complementary 5'-purine start decamer d(GCGCGCGCGC) in the Z-DNA conformation. I.
Alternating self-complementary oligonucleotides starting with a 5'-pyrimidine usually form left-handed Z-DNA; however, with a 5'-purine start sequence they form the right-handed A-DNA. Here we report the crystal structure of the decamer d(GCGCGCGCGC) with a 5'-purine start in the Z-DNA form. The decamer crystallizes in the hexagonal space group P6(5)22, unit cell dimensions a = b = 18.08 and c = 43.10 A, with one of the following four dinucleotide diphosphates in the asymmetric unit: d(pGpC)/d(GpCp)/d(pCpG)/d(CpGp). The molecular replacement method, starting with d(pGpC) of the isomorphous Z-DNA hexamer d(araC-dG)3 without the 2'-OH group of arabinose, was used in the structure analysis. The method gave the solution only after the sugar-phosphate conformation of the GpC step was manipulated. The refinement converged to a final R value of 18.6% for 340 unique reflections in the resolution range 8.0-1.9 A. A result of the sequence alternation is the alternation in the nucleotide conformation; guanosine is C3'-endo, syn, and cytidine is C2'-endo, anti. The CpG step phosphodiester conformation is the same as ZI or ZII, whereas that of the GpC step phosphodiester is "intermediate" in the sense that zeta (O3'-P bond) is the same as ZII but alpha (P-O5' bond) is the same as ZI. The duplexes generated from the dinucleotide asymmetric unit are stacked one on top of the other in the crystal to form an infinite pseudocontinuous helix. This renders it a quasi-polymerlike structure that has assumed the Z-DNA conformation further strengthened by the long inner Z-forming stretch d(CG)4. An interesting feature of the structure is the presence of water strings in both the major and the minor grooves. In the minor groove the cytosine carbonyl oxygen atoms of the GpC and CpG steps are cross-bridged by water molecules that are not themselves hydrogen bonded but are enclosed by the water rings in the mouth of the minor groove. In the major groove three independent water molecules form a zigzagging continuous water string that runs throughout the duplex.


Potassium permeability in -thalassemia minor red blood cells.
The intracellular content of K(+) in thalassemia minor red blood cells is markedly reduced after incubation in autologous serum for 24 hr at 37 degrees C. There is no compensatory increase in intracellular Na(+) concentration of the cell thus reduced. This change is due to an acquired increase in selective permeability of the membrane to K(+). This phenomenon follows the depletion of energy sources in the thalassemia minor cells but does not follow comparable depletion in normal cells. The loss of osmotically active intracellular contents probably accounts for the increased resistance of incubated thalassemia minor red blood cells to osmotic lysis.


A case study of in silico modelling of ciprofloxacin hydrochloride/metallic compound interactions.
With the development of physiologically based absorption models, there is an increased scientific and regulatory interest in in silico modelling and simulation of drug-drug and drug-food interactions. Clinically significant interactions between ciprofloxacin and metallic compounds are widely documented. In the current study, a previously developed ciprofloxacin-specific in silico absorption model was employed in order to simulate ciprofloxacin/metallic compound interaction observed in vivo. Commercially available software GastroPlus™ (Simulations Plus Inc., USA) based on the ACAT model was used for gastrointestinal (GI) simulations. The required input parameters, relating to ciprofloxacin hydrochloride physicochemical and pharmacokinetic characteristics, were experimentally determined, taken from the literature or estimated by GastroPlus™. Parameter sensitivity analysis (PSA) was used to assess the importance of selected input parameters (solubility, permeability, stomach and small intestine transit time) in predicting percent drug absorbed. PSA identified solubility and permeability as critical parameters affecting the rate and extent of ciprofloxacin absorption. Using the selected input parameters, it was possible to generate a ciprofloxacin absorption model, without/with metal cation containing preparations co-administration, which matched well the in vivo data available. It was found that reduced ciprofloxacin absorption in the presence of aluminium hydroxide, calcium carbonate or multivitamins/zinc was accounted for by reduced drug solubility. The impact of solubility-permeability interplay on ciprofloxacin absorption can be observed in the ciprofloxacin-aluminium interaction, while in ciprofloxacin-calcium and ciprofloxacin-zinc interactions, effect of solubility was more pronounced. The results obtained indicate that in silico model developed can be successfully used to complement relevant in vitro studies in the simulation of physicochemical ciprofloxacin/metallic compound interactions.


Genomic DNA fingerprinting by pulsed-field gel electrophoresis as an epidemiological marker for study of nosocomial infections caused by methicillin-resistant Staphylococcus aureus.
In this study, we have compared genomic DNA fingerprintings among isolates of methicillin-resistant Staphylococcus aureus (MRSA) by using pulsed-field gel electrophoresis (PFGE). Chromosomal fragments digested with SmaI were most suitable for the PFGE separation. SmaI cut genomic DNA into 15 to 20 fragments whose sizes ranged from about 30 to 1,500 kb. Thirty-one distinctive fragment patterns were identified in 111 infecting and colonizing MRSA isolates from six different hospitals in Japan. On the basis of the genomic typing by PFGE, we performed an epidemiological investigation of an outbreak of nosocomial MRSA infections among inpatients in Nagoya University Hospital. Ten types of chromosomal digestion were identified in the 20 strains isolated from 18 infected patients and 1 from colonized hospital personnel. According to the restriction patterns, we found that four types of these strains had caused epidemic infections among 13 patients in the outbreak. Two types (types 1 and 4) of the strains were involved in the death of five patients. The other infections were sporadic. The clarity and polymorphism of the chromosomal digestion patterns enabled us to discriminate between isolates which could not be differentiated by antibiogram or plasmid analysis. Classification of the genomic DNA fingerprinting patterns by PFGE is therefore proposed as a useful method for investigating the source, transmission, and spread of nosocomial MRSA infections.


The F-Actin Binding Protein Cortactin Regulates the Dynamics of the Exocytotic Fusion Pore through its SH3 Domain.
Upon cell stimulation, the network of cortical actin filaments is rearranged to facilitate the neurosecretory process. This actin rearrangement includes both disruption of the preexisting actin network and de novo actin polymerization. However, the mechanism by which a Ca2+ signal elicits the formation of new actin filaments remains uncertain. Cortactin, an actin-binding protein that promotes actin polymerization in synergy with the nucleation promoting factor N-WASP, could play a key role in this mechanism. We addressed this hypothesis by analyzing de novo actin polymerization and exocytosis in bovine adrenal chromaffin cells expressing different cortactin or N-WASP domains, or cortactin mutants that fail to interact with proline-rich domain (PRD)-containing proteins, including N-WASP, or to be phosphorylated by Ca2+-dependent kinases, such as ERK1/2 and Src. Our results show that the activation of nicotinic receptors in chromaffin cells promotes cortactin translocation to the cell cortex, where it colocalizes with actin filaments. We further found that, in association with PRD-containing proteins, cortactin contributes to the Ca2+-dependent formation of F-actin, and regulates fusion pore dynamics and the number of exocytotic events induced by activation of nicotinic receptors. However, whereas the actions of cortactin on the fusion pore dynamics seems to depend on the availability of monomeric actin and its phosphorylation by ERK1/2 and Src kinases, cortactin regulates the extent of exocytosis by a mechanism independent of actin polymerization. Together our findings point out a role for cortactin as a critical modulator of actin filament formation and exocytosis in neuroendocrine cells.


Investigation of the formation of CuInS2 nanoparticles by the oleylamine route: comparison of microwave-assisted and conventional syntheses.
The formation of copper indium disulfide nanoparticles via the oleylamine route using copper iodide, indium chloride, and elemental sulfur has been investigated by applying conventional thermal heating as well as microwave irradiation. Oleylamine thereby acts as a capping ligand as well as a solvent. In an initial set of experiments, the onset of the reaction was determined to be around 115 °C by an in situ X-ray study using Synchrotron radiation. Using comparatively low synthesis temperatures of 120 °C, it is already possible to obtain nanoparticles of 2-4 nm with both heating methods but with irregular shape and size distribution. By applying higher temperatures of 220 °C, more crystalline and larger nanoparticles were obtained with slight differences in crystallite size and size distribution depending on the synthesis route. The size of the nanoparticles is in the range of 3-10 nm depending on the heating time. Using microwave irradiation, it is possible to obtain nanoparticles in only 90 s of total synthesis time. Control experiments to probe a nonthermal microwave effect were carried out ensuring an identical experimental setup, including the heating profile, the stirring rate, and the volume and concentration of the solutions. These experiments clearly demonstrate that for the preparation of CuInS(2) nanoparticles described herein no differences between conventional and microwave heating could be observed when performed at the same temperature. The nanoparticles obtained by microwave and thermal methods have the same crystal phase, primary crystallite size, shape, and size distribution. In addition, they show no significant differences concerning their optical properties.


Using Neck Muscle Afferentation to Control an Ongoing Limb Movement? Individual Differences in the Influence of Brief Neck Vibration.
When preparing and executing goal-directed actions, neck proprioceptive information is critical to determining the relative positions of the body and target in space. While the contribution of neck proprioception for upper-limb movements has been previously investigated, we could not find evidence discerning its impact on the planning vs. online control of upper-limb trajectories. To investigate these distinct sensorimotor processes, participants performed discrete reaches towards a virtual target. On some trials, neck vibration was randomly applied before and/or during the movement, or not at all. The main dependent variable was the medio-lateral/directional bias of the reaching finger. The neck vibration conditions induced early leftward trajectory biases in some participants and late rightward trajectory biases in others. These different patterns of trajectory biases were explained by individual differences in the use of body-centered and head-centered frames of reference. Importantly, the current study provides direct evidence that sensory cues from the neck muscles contribute to the online control of goal-directed arm movements, likely accompanied by significant individual differences.


An urgent need for integration of family planning services into HIV care: the high burden of unplanned pregnancy, termination of pregnancy, and limited contraception use among female sex workers in Côte d'Ivoire.
HIV infection and unintended pregnancy are occupational risks of commercial female sex work (FSW). The burden of unintended pregnancy among FSW including maternal and infant outcomes in the context of HIV is largely unknown. FSW ≥18 years were recruited through respondent driven sampling into a cross-sectional study in Abidjan, Côte d'Ivoire. Participants completed a sociobehavioral questionnaire and HIV counseling and testing. Pregnancy history by HIV status and contraceptive use were described, and Poisson regression used to estimate correlates of termination of pregnancy (TOP). From March to July 2014, 466 FSW were enrolled. Unintended pregnancy was common, and 64% of participants had ≥1 TOP. Half of FSW experiencing TOPs did so without a medical professional, resulting in frequent complications. Contraceptive use was lowest among younger FSW, and 37% of 20-24 year olds reported multiple TOPs. FSW with a TOP history reported 19% less consistent condom use with clients than women who never had a TOP (adjusted-prevalence ratio, 0.81; 95% confidence interval: 0.74 to 0.88), whereas use of reliable nonbarrier contraceptive methods was comparable between the groups. Although FSW were engaged in HIV testing and prevention services, only 59% of FSW had received HIV testing before childbirth during their last pregnancy, and 30% of HIV-infected FSW had lost ≥1 children. Low contraceptive use and high burden of unintended pregnancy result in poor reproductive outcomes for FSW and avoidable mother-to-child HIV transmission risks. Integration of family planning and antenatal services into HIV prevention and care programs accessed by FSW could enhance reproductive outcomes and HIV prevention goals.


ERGIC-53 is a functional mannose-selective and calcium-dependent human homologue of leguminous lectins.
Based on sequence homologies with leguminous lectins, the intermediate compartment marker ERGIC-53 was proposed to be a member of a putative new class of animal lectins associated with the secretory pathway. Independent, a promyelocytic protein, MR60, was purified by mannose-column chromatography, and a cDNA was isolated that matched MR60 peptide sequences. This cDNA was identical to that of ERGIC-53 and homologies with the animal lectin family of the galectins were noticed. Not all peptide sequences of MR60, however, were found in ERGIC-53, raising the possibility that another protein associated with ERGIC-53 may possess the lectin activity. Here, we provide the first direct evidence for a lectin function of ERGIC-53. Overexpressed ERGIC-53 binds to a mannose column in a calcium-dependent manner and also co-stains with mannosylated neoglycoprotein in a morphological binding assay. By using a sequential elution protocol we show that ERGIC-53 has selectivity for mannose and low affinity for glucose and GlcNAc, but no affinity for galactose. To experimentally address the putative homology of ERGIC-53 to leguminous lectins, a highly conserved protein family with an invariant asparagine essential for carbohydrate binding, we substituted the corresponding asparagine in ERGIC-53. This mutation, as well as a mutation affecting a second site in the putative carbohydrate recognition domain, abolished mannose-column binding and co-staining with mannosylated neoglycoprotein. These findings establish ERGIC-53 as a lectin and provide functional evidence for its relationship to leguminous lectins. Based on its monosaccharide specificity, domain organization, and recycling properties, we propose ERGIC-53 to function as a sorting receptor for glyco-proteins in the early secretory pathway.


The 340B drug discount program: hospitals generate profits by expanding to reach more affluent communities.
The federal 340B program gives participating hospitals and other medical providers deep discounts on outpatient drugs. Named for a section of the Veterans Health Care Act of 1992, the program's original intent was to help low-income and uninsured patients. But the program has come under scrutiny by critics who contend that some hospitals exploit the drug discounts to generate profits instead of either investing in programs for the poor or passing the discounts along to patients and insurers. We examined whether the program is expanding in ways that could maximize hospitals' ability to generate profits from the 340B drug discounts. We matched data for 960 hospitals and 3,964 affiliated clinics registered with the 340B program in 2012 with the socioeconomic characteristics of their communities from the US Census Bureau's American Community Survey. We found that hospital-affiliated clinics that registered for the 340B program in 2004 or later served communities that were wealthier and had higher rates of health insurance compared to communities served by hospitals and clinics that registered for the program before 2004. Our findings support the criticism that the 340B program is being converted from one that serves vulnerable patient populations to one that enriches hospitals and their affiliated clinics.


[Experimental Evaluation of the Adhear, a Novel Transcutaneous Bone Conduction Hearing Aid].
Different bone conduction hearing aids (BCHA) are commercially available. They are attached to the head in different ways. The aim of this work is an experimental evaluation of the performance of a new transcutaneous (surface mounted via adhesive pad) actuator of a BCHA. Experiments were conducted on a Thiel embalmed whole head cadaver specimen. The electromagnetic actuators from a commercial BCHA (Adhear) was used to provide stepped sine stimulus in the range of 0.1-10 kHz. The BCHA was coupled to a skin surface adhesion that was placed on the mastoid. The response was monitored as motions of the ipsi- and contralateral promontory, and as motions of the ipsi-, top- and contralateral skull surface. Promontory motion was quantified via a three-dimensional laser Doppler vibrometer (3D LDV) system. Analogously, surface motion was registered by sequentially measuring ~200 points on the skull surface (~ 15-20 mm pitch) via 3D LDV. The data were compared to corresponding measurements obtained with a Baha Power that was coupled to skin on the Mastoid via a 5 Newton steelband. Ipsilateral and contralateral promontory vibration for stimulation with the Adhear are comparable to stimulation with the Baha Power on the 5 Newton steelband with regard to frequency dependent amplitude and phase, as well as the contribution of the motion components. The surface motion of the skull experiences a similar complex motion for both stimulation modes. Although the Adhear is coupled without any pressure to the skin over the mastoid whereas the Baha power is attached with a 5 Newton steelband, the vibration parameters investigated are comparable.


BmATG5 and BmATG6 mediate apoptosis following autophagy induced by 20-hydroxyecdysone or starvation.
Autophagy and apoptosis, which could be induced by common stimuli, play crucial roles in development and disease. The functional relationship between autophagy and apoptosis is complex, due to the dual effects of autophagy. In the Bombyx Bm-12 cells, 20-hydroxyecdysone (20E) treatment or starvation-induced cell death, with autophagy preceding apoptosis. In response to 20E or starvation, BmATG8 was rapidly cleaved and conjugated with PE to form BmATG8-PE; subsequently, BmATG5 and BmATG6 were cleaved into BmATG5-tN and BmATG6-C, respectively. Reduction of expression of BmAtg5 or BmAtg6 by RNAi decreased the proportion of cells undergoing both autophagy and apoptosis after 20E treatment or starvation. Overexpression of BmAtg5 or BmAtg6 induced autophagy but not apoptosis in the absence of the stimuli, but promoted both autophagy and apoptosis induced by 20E or starvation. Notably, overexpression of cleavage site-deleted BmAtg5 or BmAtg6 increased autophagy but not apoptosis induced by 20E or starvation, whereas overexpression of BmAtg5-tN and BmAtg6-C was able to directly trigger apoptosis or promote the induced apoptosis. In conclusion, being cleaved into BmATG5-tN and BmATG6-C, BmATG5 and BmATG6 mediate apoptosis following autophagy induced by 20E or starvation in Bombyx Bm-12 cells, reflecting that autophagy precedes apoptosis in the midgut during Bombyx metamorphosis.


Ischemic Cerebroprotection Conferred by Myeloid Lineage-Restricted or Global CD39 Transgene Expression.
Cerebral tissue damage after an ischemic event can be exacerbated by inflammation and thrombosis. Elevated extracellular ATP and ADP levels are associated with cellular injury, inflammation, and thrombosis. Ectonucleoside triphosphate diphosphohydrolase-1 (CD39), an enzyme expressed on the plasmalemma of leukocytes and endothelial cells, suppresses platelet activation and leukocyte infiltration by phosphohydrolyzing ATP/ADP. To investigate the effects of increased CD39 in an in vivo cerebral ischemia model, we developed a transgenic mouse expressing human CD39 (hCD39). A floxed-stop sequence was inserted between the promoter and the hCD39 transcriptional start site, generating a mouse in which the expression of hCD39 can be controlled tissue-specifically using Cre recombinase mice. We generated mice that express hCD39 globally or in myeloid-lineage cells only. Cerebral ischemia was induced by middle cerebral artery occlusion. Infarct volumes were quantified by MRI after 48 hours. Both global and transgenic hCD39- and myeloid lineage CD39-overexpressing mice (transgenic, n=9; myeloid lineage, n=6) demonstrated significantly smaller cerebral infarct volumes compared with wild-type mice. Leukocytes from ischemic and contralateral hemispheres were analyzed by flow cytometry. Although contralateral hemispheres had equal numbers of macrophages and neutrophils, ischemic hemispheres from transgenic mice had less infiltration (n=4). Transgenic mice showed less neurological deficit compared with wild-type mice (n=6). This is the first report of transgenic overexpression of CD39 in mice imparting a protective phenotype after stroke, with reduced leukocyte infiltration, smaller infarct volumes, and decreased neurological deficit. CD39 overexpression, either globally or in myeloid lineage cells, quenches postischemic leukosequestration and reduces stroke-induced neurological injury.


Effect of nitric oxide compounds on monkey ciliary muscle in vitro.
The effects of various nitric oxide compounds and their inhibitors on monkey ciliary muscle contraction in vitro were investigated in both the longitudinal and circular vectors. The responses to nitric oxide compounds in carbachol precontracted ciliary muscle consisted of an initial relaxation often followed by recovery to near carbachol precontracted levels while the compound was still present. Sodium nitroprusside produced the greatest relaxation responses (nearly 100% relaxation in both vectors at 10(-3) M). The highest concentrations of isosorbide dinitrate (10(-4) M) and L-arginine (10(-3) M) produced relaxation responses of approximately 50% in both vectors. 8-Bromo cyclic GMP produced the smallest relaxation responses (25-35%). Nitric oxide synthase inhibition enhanced carbachol contraction up to 20% in the longitudinal but not the circular vector. Phosphodiesterase inhibition did not further enhance the relaxation response to L-arginine. Guanylate cyclase inhibition partially attenuated the relaxation response to sodium nitroprusside. Nitric oxide generating compounds were effective in relaxing precontracted monkey ciliary muscle in vitro. Endogenous production of nitric oxide is likely involved in the regulation of the contractile response in monkey ciliary muscle. Nitric oxide generating compounds may have potential value in therapeutic areas where modulation of ciliary muscle tension is desirable.


Evaluation of colitis: usefulness of CT enterography technique.
Computed tomographic enterography (CTE) is a useful technique for evaluating the small bowel and has the capability to include the colon for evaluation of patients with inflammatory bowel disease (IBD). The aims of this study are (1) to determine if CTE is a sensitive method for detecting Crohn colitis and ulcerative colitis and (2) to assess the accuracy of determining the extent and activity of colonic disease in patients with proven IBD. Seventy patients (35 patients with proven colitis at colonoscopy and 35 negative patients with a proven normal colon) having both a CTE examination and recent colonoscopy formed the retrospective study group. A radiologist evaluated the examinations in a blinded fashion for disease presence, activity, and extent. Sensitivity was 93% for the detection of moderate and severe disease in well-distended colons. Specificity was 91%. In good to excellent distended colons, mild, moderate, and severe disease was detected with a sensitivity of 67%, 90%, and 100%, respectively. Severe disease activity was commonly underestimated, and mild disease when detected was usually overestimated. The full extent of colonic disease at CTE was usually underestimated. CTE is a valid technique for detecting colitis in the colon in patients with IBD. Better methods for assessing disease activity and extent are needed.


Supplementing intensive targeted computerized cognitive training with social cognitive exercises for people with schizophrenia: An interim report.
Individuals with schizophrenia demonstrate cognitive, social cognitive, and motivational deficits that contribute to impairment in real-world functioning. In the current study, we investigated the effects of supplementing computerized neurocognitive training with social cognitive exercises, as compared with neurocognitive training alone. In this ongoing, double-blind, randomized controlled trial of 111 participants with psychosis, we compare the effects of supplementing intensive targeted cognitive training with social cognitive training exercises (TCT + SCT) with the effects of targeted cognitive training alone (TCT-only). Participants were assessed on cognition, symptoms, functional capacity, and functional outcomes, as well as social cognition and measures related to reward processing. Both treatment groups showed significant improvement in multiple cognitive domains and improvement in functional capacity. However, as predicted, TCT + SCT group participants showed significant improvement in prosody identification and reward processing relative to TCT-only participants. Our findings indicate that supplementing intensive computerized cognitive training with social cognitive exercises in people with psychosis confers greater benefits in prosody identification and reward processing relative to cognitive training alone, even though both approaches drive significant improvements in cognition and functional capacity. Impairments in both prosody identification and reward processing have been associated with greater negative symptoms and poorer functional outcomes in schizophrenia, raising the possibility that this form of treatment may lead to better long-term outcomes than traditional cognitive training approaches. Follow-up assessments will determine whether results are durable and generalize over time to improvements in symptoms and functioning. (PsycINFO Database Record


The metabolism of labelled hexadecyl sulphate salts in the rat, dog and human.
The metabolic fate of [1-14-C]hexadecylsulphate and hexadecyl[35-S]sulphate, administered intravenously as the sodium and trimethylammonium salt to dogs and orally as the erythromycin salt to dogs, rats and humans, was studied. Studies with rats indicated that the compounds were well absorbed and rapidly excreted in the urine. However, after oral administration of the 14-C-and 35-S-labelled hexadecyl sulphate erythromycin salt to dogs, considerable amounts of radioactivity were excreted in the faeces as unmetabolized hexadecyl sulphate. Studies with two humans showed that orally administered erythromycin salt of [1-14C]hexadecyl sulphate was well absorbed in one person but poorly absorbed in the other. Radioactive metabolites in urine were separated by t.l.c. in two solvent systems. The main metabolite of hexadecyl sulphate in the dog, rat and human was identified as the sulphate ester of 4-hydroxybutyric acid. In addition, psi-[14-C]butyrolactone as a minor metabolic product of [1-14-C]hexadecyl sulphate was also isolated from the urine of rat, dog and man. However, there was still another metabolite in dog urine, which comprised about 20% of the total urinary radioactivity and carried both 14-C and 35-S labels. This metabolite was absent from rat urine. The metabolite in dog urine was isolated and subsequently identified by t.l.c. and g.l.c. and by isotope-dilution experiments as the sulphate ester of glycollic acid. Small amounts (about 5% of the total recovered radioactivity in excreta) of labelled glycollic acid sulphate were also found in human urine after ingestion of erythromycin [1-14-C]hexadecyl sulphate.


Trends in neonatal morbidity and mortality for very low birthweight infants: a 20-year single-center experience.
To describe trends in mortality and morbidity rates of very low birth weight infants as well as their pre-, peri- and postnatal characteristics over a period of 20 years' time. Retrospective study in all very low birth weight infants admitted to the neonatal intensive care unit of the University Hospitals Ghent from 1 January 2000, to 31 December 2020. Mortality was the primary outcome variable with major morbidities being co-primary outcome variables. Pre-, peri- and postnatal characteristics are secondary outcome variables. We compared pre-, peri- and postnatal characteristics, as well as major morbidities between different groups with comparable rates of mortality. We included a total of 2037 very low birth weight infants and divided them in 3 epochs based on stepwise reductions in mortality in 2008 and 2013: 2000-2007 (n = 718), 2008-2012 (n = 506) and 2013-2020 (n = 813). Mortality decreased significantly over the years in all gestational ages, but predominantly in those with the youngest gestational age. Changes in obstetric and neonatal care were observed over time. Most significant changes were the increased use of antenatal corticosteroids, magnesium sulfate and surfactant. Intraventricular hemorrhage grade III/IV decreased significantly in all gestational ages. Significant increase in retinopathy of prematurity was observed. Bronchopulmonary dysplasia at 36 weeks and discharge home with oxygen is increasing in the total group. In those born below 26 weeks a slight increase in all major morbidities was observed especially of patent ductus arteriosus and retinopathy of prematurity. Increase of all other major morbidities seems to stabilize in epoch 3. The number of infants surviving without any major morbidity increases to almost 1/2 in all very low birth weight infants and to 1/10 in those born 24-25 weeks gestation. Analysis of the real-life experience showed that survival in very low birth weight infants significantly increased over time. Evolution of major morbidities will have to be carefully watched in the future.


Screening of the human tumor necrosis factor-alpha (TNF-alpha) gene promoter polymorphisms by PCR-DGGE analysis.
We have designed a new PCR-DGGE technique that enables detection of base changes in the TNF-alpha gene promoter. Screening of 130 samples from Spanish children has shown that this technique accurately detects the altered band patterns induced by the presence of the polymorphisms at positions -376, -308, -238 and -163 of the promoter sequence. Although further analysis are needed to fully characterise the alterations detected, we believe that this PCR-DGGE technique is a rapid and sensitive first approach to the genetic characterisation of the TNF-alpha promoter.


The influence of temperature, humidity, and simulated sunlight on the infectivity of SARS-CoV-2 in aerosols.
Recent evidence suggests that respiratory aerosols may play a role in the spread of SARS-CoV-2 during the ongoing COVID-19 pandemic. Our laboratory has previously demonstrated that simulated sunlight inactivated SARS-CoV-2 in aerosols and on surfaces. In the present study, we extend these findings to include the persistence of SARS-CoV-2 in aerosols across a range of temperature, humidity, and simulated sunlight levels using an environmentally controlled rotating drum aerosol chamber. The results demonstrate that temperature, simulated sunlight, and humidity are all significant factors influencing the persistence of infectious SARS-CoV-2 in aerosols, but that simulated sunlight and temperature have a greater influence on decay than humidity across the range of conditions tested. The time needed for a 90% decrease in infectious virus ranged from 4.8 min at 40 °C, 20% relative humidity, and high intensity simulated sunlight representative of noon on a clear day on the summer solstice at 4°N latitude, to greater than two hours under conditions representative of those expected indoors or at night. These results suggest that the persistence of infectious SARS-CoV-2 in naturally occurring aerosols may be affected by environmental conditions, and that aerosolized virus could remain infectious for extended periods of time under some environmental conditions. The present study provides a comprehensive dataset on the influence of environmental parameters on the survival of SARS-CoV-2 in aerosols that can be utilized, along with data on viral shedding from infected individuals and the inhalational infectious dose, to inform future modeling and risk assessment efforts.


A case of asymptomatic, localized, and idiopathic diffuse alveolar damage.
Diffuse alveolar damage (DAD) is a histological change in lung tissue, and is generally caused by an acute lung injury, which is characterized by bilateral and widespread damages. Localized DAD occurs very rarely. The causes for DAD are numerous, but the chief cause is acute interstitial pneumonia or acute exacerbation of idiopathic interstitial pneumonia, in cases of idiopathic manifestation. The 82-year-old patient, in this case study, showed a DAD lesion in only 1 lobe. The patient was otherwise healthy, with no previous symptoms of DAD. He was admitted to our medical center owing to localized infiltration, observed on his chest radiograph. Laboratory studies showed no signs of infections. DAD was confirmed by a surgical lung biopsy. The patient received corticosteroid treatment and had gradually improved. We report the case of a patient with localized, idiopathic DAD that cannot be classified as acute interstitial pneumonia or acute exacerbation of idiopathic interstitial pneumonia.


A human monoclonal IgE antibody defines a highly allergenic fragment of the major timothy grass pollen allergen, Phl p 5: molecular, immunological, and structural characterization of the epitope-containing domain.
Almost 90% of grass pollen-allergic patients are sensitized against group 5 grass pollen allergens. We isolated a monoclonal human IgE Fab out of a combinatorial library prepared from lymphocytes of a grass pollen-allergic patient and studied its interaction with group 5 allergens. The IgE Fab cross-reacted with group 5A isoallergens from several grass and corn species. By allergen gene fragmentation we mapped the binding site of the IgE Fab to a 11.2-kDa N-terminal fragment of the major timothy grass pollen allergen Phl p 5A. The IgE Fab-defined Phl p 5A fragment was expressed in Escherichia coli and purified to homogeneity. Circular dichroism analysis revealed that the rPhl p 5A domain, as well as complete rPhl p 5A, assumed a folded conformation consisting predominantly of an alpha helical secondary structure, and exhibited a remarkable refolding capacity. It reacted with serum IgE from 76% of grass pollen-allergic patients and revealed an extremely high allergenic activity in basophil histamine release as well as skin test experiments. Thus, the rPhl p 5A domain represents an important allergen domain containing several IgE epitopes in a configuration optimal for efficient effector cell activation. We suggest the rPhl p 5A fragment and the corresponding IgE Fab as paradigmatic tools to explore the structural requirements for highly efficient effector cell activation and, perhaps later, for the development of generally applicable allergen-specific therapy strategies.


Techniques for direct experimental evaluation of structure-transport relationships in disordered porous solids.
Determining structure-transport relationships is critical to optimising the activity and selectivity performance of porous pellets acting as heterogeneous catalysts for diffusion-limited reactions. For amorphous porous systems determining the impact of particular aspects of the void space on mass transport often requires complex characterization and modelling steps to deconvolve the specific influence of the feature in question. These characterization and modelling steps often have limited accuracy and precision. It is the purpose of this work to present a case-study demonstrating the use of a more direct experimental evaluation of the impact of pore network features on mass transport. The case study evaluated the efficacy of the macropores of a bidisperse porous foam structure on improving mass transport over a purely mesoporous system. The method presented involved extending the novel integrated gas sorption and mercury porosimetry method to include uptake kinetics. Results for the new method were compared with those obtained by the alternative NMR cryodiffusometry technique, and found to lead to similar conclusions. It was found that the experimentally-determined degree of influence of the foam macropores was in line with expectations from a simple resistance model for a disconnected macropore network.


Effects of estrogen and raloxifene on synaptic density in the hippocampal CA1 region of ovariectomized rats.
The CA1 region of the hippocampus has an important role in learning and memory. It has been shown that estrogen deficiency may reduce the synaptic density in the region and that hormone replacement therapy may attenuate the reduction. This study aimed to evaluate the effects of estrogen and raloxifene on the synaptic density profile in the CA1 region of the hippocampus in ovariectomized rats. Sixty ovariectomized three-month-old virgin rats were randomized into six groups (n = 10). Treatments started either three days (early treatment) or sixty days (late treatment) after ovariectomy. The groups received propylene glycol vehicle (0.5 mL/animal/day), equine conjugated estrogens (50 μg/animal/day), or raloxifene (3 mg/kg/day) either early or late after ovariectomy. The drugs were administered orally by gavage for 30 days. At the end of the treatments, the animals were anesthetized and transcardially perfused with ether and saline solution. The brains were removed and prepared for analysis under transmission electron microscopy and later fixed. Results showed a significant increase in the synaptic density profile of the hippocampal CA1 region in both the early estrogen (0.534 ± 0.026 µ/m2) and the early raloxifene (0.437 ± 0.012 µ/m2) treatment groups compared to the early or late vehicle-treated control groups (0.338 ± 0.038 µ/m2 and 0.277 ± 0.015 µ/m2 respectively). The present data suggest that the raloxifene effect may be lower than that of estrogen, even early or late treatment, on synaptic density in the hippocampus.


Effect of Familial Mutations on the Interconversion of α-Helix to β-Sheet Structures in an Amyloid-Forming Peptide: Insight from Umbrella Sampling Simulations.
Understanding the initial events of aggregation of amyloid β monomers to form β-sheet rich fibrils is useful for the development of therapeutics for Alzheimer's disease. In this context, the changes in energetics involved in the aggregation of helical amyloid β monomers into β-sheet rich dimers have been investigated using umbrella sampling simulations and density functional theory calculations. The results from umbrella sampling simulations for the free energy profile for the interconversion closely agree with the results of density functional theory calculations. The results reveal that helical peptides converted to β-sheet structures through coil-like conformations as intermediates that are mostly stabilized by intramolecular hydrogen bonds. The stabilization of intermediate structures could be a possible way to inhibit fibril formation. Mutations substantially decrease the height of the energy barrier for interconversion from α-helix to β-sheet structure when compared to that of the wild type, something that is attributed to an increase in the number of intramolecular hydrogen bonds between backbone atoms in the coil structures that correspond to a maximum value on the free energy surface. The reduction of the energy barrier leads to an enhancement of the rate of aggregation of amyloid β monomers upon introduction of various familial mutations, which is consistent with previous experimental reports.


Immunogenicity of Isogenic IgG in Aggregates and Immune Complexes.
A paradox in monoclonal antibody (mAb) therapy is that despite the well-documented tolerogenic properties of deaggregated IgG, most therapeutic IgG mAb induce anti-mAb responses. To analyze CD4 T cell reactions against IgG in various physical states, we developed an adoptive transfer model using CD4+ T cells specific for a Vκ region-derived peptide in the hapten-specific IgG mAb 36-71. We found that heat-aggregated or immune complexes (IC) of mAb 36-71 elicited anti-idiotypic (anti-Id) antibodies, while the deaggregated form was tolerogenic. All 3 forms of mAb 36-71 induced proliferation of cognate CD4+ T cells, but the aggregated and immune complex forms drove more division cycles and induced T follicular helper cells (TFH) development more effectively than did the deaggregated form. These responses occurred despite no adjuvant and no or only trace levels of endotoxin in the preparations. Physical analyses revealed large differences in micron- and nanometer-sized particles between the aggregated and IC forms. These differences may be functionally relevant, as CD4+ T cell proliferation to aggregated, but not IC mAb 36-71, was nearly ablated upon peritoneal injection of B cell-depleting antibody. Our results imply that, in addition to denatured aggregates, immune complexes formed in vivo between therapeutic mAb and their intended targets can be immunogenic.


The effect of non-contrast enhanced MRA on patients with renal insufficiency and foot pain.
To investigate the feasibility of non-contrast magnetic resonance angiography of arteries and veins (NATIVE) sampling perfection with application optimized contrasts by using different flip angle evolution (SPACE) and quiescent interval single shot (QISS) in assessing foot arteries of patients with renal insufficiency and foot pain. Fifty-three patients (mean age = 44.2 ± 11.4 years, male: female = 27:26) underwent QISS and NATIVE-SPACE. The source images were reconstructed to maximum intensity projection and volume render. The image quality of QISS and NATIVE-SPACE was rated (0-3, poor to excellent), and was compared using Wilcoxon test. True or false positive was determined by comparing the findings of QISS and NATIVE-SPACE. The relative signal intensity of artery was obtained for each case, and was compared between QISS and NATIVE-SPACE using Mann Whitney test. The acquisition time of NATIVE-SPACE was significantly longer than that of QISS (178.4 ± 35.7 seconds vs 45.4 ± 8.9 seconds, P < .001). QISS had significantly lower image quality score versus NATIVE-SPACE (1.4 ± 0.5 vs 2.4 ± 0.6, P = .02). Fifteen percentage (8/53) NATIVE-SPACE cases had poor image quality due to the similarity of peak flow and minimum flow. The relative signal intensity was significantly lower in QISS versus NATIVE-SPACE (9.7 ± 1.3 vs 68.2 ± 12.4, P < .001). NATIVE-SPACE is valuable in evaluating foot arteries of patients with renal insufficiency. QISS can serve as an alternative test to NATIVE-SPACE.


The prevalence of problematic gambling behaviour: a Scandinavian comparison.
On the basis of a new large-scale screening for the prevalence of problematic gambling behaviour in Denmark, the aim of the study was: (a) to evaluate the effect of applying different screening tools; and (b) to compare gambling behaviour in Denmark with the prevalence of problematic gambling behaviour in other Scandinavian countries. The screening tools applied were the internationally validated SOGS-R and NODS. These were used within the same survey, thus allowing for comparison with surveys conducted in other Scandinavian countries where either the one or the other tool has been utilized. The prevalence of at-risk gamblers, problematic gamblers and pathological gamblers was significantly lower in Denmark than in the other Scandinavian countries. This held true for both genders as well as for different age groups in comparisons of Denmark and Norway. There is a considerable variation in the prevalence of problematic gambling between the Scandinavian countries, with Denmark having the smallest number of gamblers with problematic behaviour. The variation might be due to national differences in gambling preferences, access to games, public policies concerning gambling, etc., but investigation of this would require further comparative research.


A Comparison of Squatting Exercise on a Centrifuge and With Earth Gravity.
Purpose: Long-duration space missions require countermeasures against the muscular wasting and cardiovascular deconditioning associated with microgravity. Replacing gravitational acceleration by means of centrifugation is a promising alternative as it challenges all physiological systems at once. The aim of this study is to examine the metabolic energy costs of squatting on a centrifuge in comparison with squatting in an upright standing posture under natural gravity. Methods: 24 subjects (11 male, 13 female) performed continuous squatting exercise for 9 min with increasing cadence (10, 12, and 15 squats min-1). This was done under three conditions: Upright under natural gravity and lying supine on a centrifuge at two radii (2.5 and 3.5 m) at 1 g of centrifugal acceleration at the subject's average center of mass during the exercise. Results: Generally, subjects did not suffer from motion sickness. Exercise under natural gravity led to a higher Δ V'O2/body mass (7.1 ± 2.0, ml min-1 kg-1, mean ± SD) compared with exercise on the centrifuge (6.1 ± 1.6, ml min-1 kg-1, mean ± SD). Exercise efficiency was also reduced under natural 1 g at 28.2 ± 1.0% compared to 40.4 ± 1.5% on the centrifuge. As expected, oxygen consumption increased with increasing cadences. The Coriolis effect had a negligible impact as there was no significant difference in V'O2 between the two radii. However, during centrifugation and upward movement the right leg was more loaded than the leg left and vice versa during downward movement (centrifuge running clockwise looking down, so to the subjects' right). Conclusion: The lower V'O2 on the centrifuge may be attributed to the unloading of trunk muscles while subjects were lying on the sled, which in the upright condition leaning against the sled were still working to stabilize the torso. Subjects tolerated high rotational rates combined with exercise very well.


Is Loop Ileostomy in Patients with Cecal Bascule a Viable Option?
Cecal bascule, initially described in 1899 by Treves, is the rarest form of cecal volvulus and represents a phenomenon when a redundant and distended cecum folds anteriorly over the ascending colon causing an intestinal obstruction. Patients with cerebral palsy are at increased risk for this condition. We present a 28-year-old male with cerebral palsy, functionally dependent in all activities of daily living, who had undergone a loop ileostomy for cecal bascule. He then presented to our emergency department with a large loop ileostomy prolapse, which was the result of an inverted prolapsed cecum through the efferent ileostomy limb. He underwent a right hemicolectomy with end ileostomy and transverse mucous fistula creation through the previous ostomy site. He progressed well appropriately postoperatively and was discharged home. While cecal bascule is a rare form of bowel obstruction, patients with cerebral palsy are at an increased risk for this condition. The treatment options are numerous and are primarily surgical. Diverting loop ileostomy alone is not a recommended treatment. A high index of suspicion is warranted in all cases of large bowel obstruction to minimize risk of recurrence, morbidity, and mortality for patients afflicted by this condition.


"Meaningful use" of electronic health records and its relevance to laboratories and pathologists.
Electronic health records (EHRs) have emerged as a major topic in health care and are central to the federal government's strategy for transforming healthcare delivery in the United States. Recent federal actions that aim to promote the use of EHRs promise to have significant implications for laboratories and for pathology practices. Under the HITECH (Health Information Technology Economic and Clinical Health) Act, an EHR incentive program has been established through which individual physicians and hospitals can qualify to receive incentive payments if they achieve "meaningful use" of "certified" EHR technology. The rule also establishes payment penalties in future years for eligible providers who have not met the requirements for meaningful use of EHRs. Meaningful use must be achieved using EHR technology that has been certified in accordance with functional and technical criteria that are set forth a regulation that parallels the meaningful use criteria in the incentive program. These actions and regulations are important to laboratories and pathologists for a number of reasons. Several of the criteria and requirements in the meaningful use rules and EHR certification criteria relate directly or indirectly to laboratory testing and laboratory information management, and future stage requirements are expected to impact the laboratory as well. Furthermore, as EHR uptake expands, there will be greater expectations for electronic interchange of laboratory information and laboratory information system (LIS)-EHR interfaces. Laboratories will need to be aware of the technical, operational, and business challenges that they may face as expectations for LIS-EHR increase. This paper reviews the important recent federal efforts aimed at accelerating EHR use, including the incentive program for EHR meaningful use, provider eligibility, and EHR certification criteria, from a perspective of their relevance for laboratories and pathology practices.


A single-transformation gene function test in diploid Candida albicans.
The fungal pathogen Candida albicans is naturally diploid, and current gene disruption strategies require two successive transformations. We describe here a genetic construct (UAU1) for which two copies may be selected. Insertion of UAU1 into one genomic site, after a single transformation, allows selection for segregants with two copies of the insertion. Major classes of segregants are those carrying homozygous insertion mutations and allelic triplications, which have two insertion alleles and a wild-type allele. Thus nonessential and essential genes may be distinguished rapidly through PCR tests for homozygosis and triplication. We find that homozygous mutations may be isolated at three nonessential loci (ADE2, RIM20, and YGR189), while only allelic triplications were found at two essential loci (SNF1 and CDC28). We have unexpectedly isolated homozygous mutants with mutations at CDC25; they are viable but defective in filamentation on serum-containing medium. The UAU1 cassette is thus useful to assess rapidly the essentiality of C. albicans genes.


Use of hyperimmune serum, vaccination, and certain management procedures for control of pseudorabies in swine.
A program involving use of hyperimmune serum, vaccination, and certain management procedures for the control of pseudorabies was evaluated on several farms on which the disease was enzootic. Neonatal mortality and reproductive failures on farms utilizing the program were compared with death losses and reproductive failures on farms not utilizing the program. The reduction in preweaning mortality and reproductive failures between the treated and nontreated groups were 42.1% and 39.6%, respectively.


Phase I/II clinical trial of the targeted chemotherapeutic drug, folate-tubulysin, in dogs with naturally-occurring invasive urothelial carcinoma.
The purpose was to determine the safety and antitumor activity of a folate-tubulysin conjugate (EC0531) in a relevant preclinical animal model, dogs with naturally-occurring invasive urothelial carcinoma (iUC). Canine iUC is an aggressive cancer with high folate receptor (FR) expression similar to that in certain forms of human cancer. A 3+3 dose escalation study of EC0531 (starting dose 0.2 mg/kg given intravenously at two-week intervals) was performed in dogs with iUC expressing high levels of FRs (>50% positive tumor cells). Pharmacokinetic (PK) analysis was performed, and the maximum tolerated dose (MTD) was determined. The dose cohort at the MTD was expanded to determine antitumor activity. The MTD of EC0531 was 0.26 mg/kg every two weeks, with grade 3-4 neutropenia and gastrointestinal toxicity observed at higher doses. Treatment at the MTD was well tolerated. Clinical benefit was found in 20 of 28 dogs (71%), including three dogs with partial remission and 17 dogs with stable disease. Plasma EC0531 concentrations in the dogs far exceeded those required to inhibit proliferation of FR-expressing cell in vitro. Unlike human neutrophils, canine neutrophils were found to express FRs, which contributes to the neutropenia at higher doses of EC0531 in dogs. EC0531 was well tolerated and had good antitumor activity in dogs with iUC. It is likely that humans will tolerate higher, potentially more effective doses of folate-tubulysin without myelotoxicity because of the absence of FRs on human neutrophils. The results clearly justify the evaluation of folate-tubulysin in human clinical trials.


Mapping publication status and exploring hotspots in a research field: chronic disease self-management.
To provide insight into the characteristics of chronic disease self-management by mapping publication status and exploring hotspots. Chronic disease is becoming a major public health issue worldwide, highlighting the importance of self-management in this area. Despite the volume and variety of publications, little is known about how 'chronic disease self-management' has developed, since the first publication 40 years ago. Such is the number of publications in the area, that there is a need for a systematic bibliographic examination to enable clinicians and researchers to navigate this literature. A bibliometric analysis of publications was used. Publication status was achieved using BICOMB software, whereas hotspots were identified with Ucinet software. A search of PubMed was conducted for papers published between 1971-2012. By 2011, the number of publications reached 696, a fourfold increase from the previous 10 years, of which 75% came from the USA and UK. There were 1284 journals, which published chronic disease self-management research, involving various disciplines. The research hotspots highlighted various self-management strategies for the following: diabetes; cardiac vascular and pulmonary chronic disease; pain relief for neoplasms; and obesity. Psychological adjustment was a permeating theme in self-management processes as was using internet-based interventions. Self-management in chronic disease publication has been most evident in developed countries. The bibliographic mapping and identification of publication hotspots provides scholars and practitioners with key target journals, as well as a rigorous overview of the field for use in further research, evidence-based practice and health policy development.


Glycerol-3-phosphate levels are associated with basal resistance to the hemibiotrophic fungus Colletotrichum higginsianum in Arabidopsis.
Glycerol-3-phosphate (G3P) is an important component of carbohydrate and lipid metabolic processes. In this article, we provide evidence that G3P levels in plants are associated with defense to a hemibiotrophic fungal pathogen Colletotrichum higginsianum. Inoculation of Arabidopsis (Arabidopsis thaliana) with C. higginsianum was correlated with an increase in G3P levels and a concomitant decrease in glycerol levels in the host. Plants impaired in utilization of plastidial G3P (act1) accumulated elevated levels of pathogen-induced G3P and displayed enhanced resistance. Furthermore, overexpression of the host GLY1 gene, which encodes a G3P dehydrogenase (G3Pdh), conferred enhanced resistance. In contrast, the gly1 mutant accumulated reduced levels of G3P after pathogen inoculation and showed enhanced susceptibility to C. higginsianum. Unlike gly1, a mutation in a cytosolic isoform of G3Pdh did not alter basal resistance to C. higginsianum. Furthermore, act1 gly1 double-mutant plants were as susceptible as the gly1 plants. Increased resistance or susceptibility of act1 and gly1 plants to C. higginsianum, respectively, was not due to effects of these mutations on salicylic acid- or ethylene-mediated defense pathways. The act1 mutation restored a wild-type-like response in camalexin-deficient pad3 plants, which were hypersusceptible to C. higginsianum. These data suggest that G3P-associated resistance to C. higginsianum occurs independently or downstream of the camalexin pathway. Together, these results suggest a novel and specific link between G3P metabolism and plant defense.


Which way in? The necessity of multiple approaches to transcatheter valve therapy.
TAVI (transcatheter aortic valve implantation) is a less invasive treatment of the stenotic aortic valve while avoiding midline sternotomy and cardiopulmonary bypass. A crimped biological valve on a self-expanding or balloonexpandable stent is inserted antegradely or retrogradely under fluoroscopy, and deployed on the beating heart. Among the worldwide TAVI programs, many different concepts have been established for the choice of the access site. Whether retrograde or antegrade TAVI should be considered the superior approach is matter of an ongoing debate. The published literature demonstrates safety of all techniques if performed within a dedicated multidisciplinary team. Since there is no data providing evidence if one approach is superior to another, we conclude that an individualized patient-centered decision making process is most beneficial, taking advantage of the complementarity of the different access options. The aim of this article is to give an overview of the current practice of access techniques for transcatheter based valve treatment and to outline the respective special characteristics.


A pilot study of mitomycin-C and tamoxifen (MT) versus dibromodulcitol, adriamycin, and tamoxifen (DAT).
The aim of this study was to compare the treatment efficacy of mitomycin-C plus tamoxifen (MT) to adriamycin, dibromodulcitol and tamoxifen (DAT) in previously treated patients with metastatic breast cancer. Thirty-two patients with measurable or evaluable disease were entered on the study. Twenty-three were prospectively randomized to receive DAT (Group 1) or MT (Group 2). Nine patients with prior exposure to adriamycin were directly assigned to receive MT (Group 3). Thirty-one patients were evaluable for response and toxicity. The hematological toxicities were comparable among the three treatment groups. DAT gave more nausea and vomiting than MT. One patient developed irreversible fatal congestive heart failure while receiving DAT. The response for Group 1 was 5/11, Group 2, 3/12, and Group 3, 3/8. The duration of response for patients in Group 1 was 455+, 315, 251, 239, 231 days, in Group 2 it was 328+, 144+, 119, and in Group 3 it was 35+, 84, and 112 days. The median time to treatment failure did not differ significantly between Group 1 (114 days), 2 (83 days) and 3 (61 days) (p = 0.24). The median survival time was similar among the three groups (p = 0.41). This pilot study suggests that MT and DAT are both effective treatment programs in patients with metastatic breast cancer who have failed prior chemotherapy regimens.


Ongoing initiatives within the Scottish National Health Service to affect the prescribing of selective serotonin reuptake inhibitors and their influence.
Aim: Increasing use of selective serotonin-reuptake inhibitors (SSRIs) in Scotland, coupled with safety concerns with some SSRIs, and the increasing availability of generic SSRIs, have resulted in multiple initiatives to improve the quality and efficiency of their prescribing in Scotland. Our aim is to assess their influence to provide future direction. Materials & methods: The prescription costs analysis database was used to document utilization and expenditure on SSRIs between 2001 and 2017 alongside documenting the initiatives. Results: Multiple interventions over the years increased international nonproprietary name prescribing up to 99.9% lowering overall costs. This, coupled with initiatives to limit escitalopram prescribing due to concerns with its value, resulted in a 73.7% reduction in SSRI expenditure between 2001 and 2017 despite a 2.34-fold increase in utilization. Safety warnings resulted in a significant reduction in the prescribing of paroxetine, citalopram and escitalopram alongside a significant increase in sertraline Conclusion: Multiple initiatives have increased the quality and efficiency of SSRI prescribing in Scotland providing direction to others.


Computer-aided discovery in antimicrobial research: In silico model for virtual screening of potent and safe anti-pseudomonas agents.
Resistance of bacteria to current antibiotics is an alarming health problem. In this sense, Pseudomonas represents a genus of Gram-negative pathogens, which has emerged as one of the most dangerous species causing nosocomial infections. Despite the effort of the scientific community, drug resistant strains of bacteria belonging to Pseudomonas spp. prevail. The high costs associated to drug discovery and the urgent need for more efficient antimicrobial chemotherapies envisage the fact that computeraided methods can rationalize several stages involved in the development of a new drug. In this work, we introduce a chemoinformatic methodology devoted to the construction of a multitasking model for quantitative-structure biological effect relationships (mtk-QSBER). The purpose of this model was to perform simultaneous predictions of anti-Pseudomonas activities and ADMET (absorption, distribution, metabolism, elimination, and toxicity) properties of organic compounds. The mtk-QSBER model was created from a large and heterogeneous dataset (more than 54000 cases) and displayed accuracies higher than 90% in both training and prediction sets. In order to demonstrate the applicability of our mtk-QSBER model, we used the investigational antibacterial drug delafloxacin as a case of study, for which experimental results were recently reported. The predictions performed for many biological effects of this drug exhibited a remarkable convergence with the experimental assays, confirming that our model can serve as useful tool for virtual screening of potent and safer anti-Pseudomonas agents.


Effects of metapopulation processes on measures of genetic diversity.
Many species persist as a metapopulation under a balance between the local extinction of subpopulations or demes and their recolonization through dispersal from occupied patches. Here we review the growing body of literature dealing with the genetic consequences of such population turnover. We focus our attention principally on theoretical studies of a classical metapopulation with a 'finite-island' model of population structure, rather than on 'continent-island' models or 'source-sink' models. In particular, we concern ourselves with the subset of geographically subdivided population models in which it is assumed that all demes are liable to extinction from time to time and that all demes receive immigrants. Early studies of the genetic effects of population turnover focused on population differentiation, such as measured by F(ST). A key advantage of F(ST) over absolute measures of diversity is its relative independence of the mutation process, so that different genes in the same species may be compared. Another advantage is that F(ST) will usually equilibrate more quickly following perturbations than will absolute levels of diversity. However, because F(ST) is a ratio of between-population differentiation to total diversity, the genetic effects of metapopulation processes may be difficult to interpret in terms of F(ST) on its own, so that the analysis of absolute measures of diversity in addition is likely to be informative. While population turnover may either increase or decrease F(ST), depending on the mode of colonization, recurrent extinction and recolonization is expected always to reduce levels of both within-population and species-wide diversity (piS and piT, respectively). One corollary of this is that piS cannot be used as an unbiased estimate of the scaled mutation rate, theta, as it can, with some assumptions about the migration process, in species whose demes do not fluctuate in size. The reduction of piT in response to population turnover reflects shortened mean coalescent times, although the distribution of coalescence times under extinction colonization equilibrium is not yet known. Finally, we review current understanding of the effect of metapopulation dynamics on the effective population size.


Responses of GABA shunt coupled with carbon and nitrogen metabolism in poplar under NaCl and CdCl2 stresses.
The γ-aminobutyric acid (GABA) shunt is closely associated with plant tolerance; however, little is known about its mechanism. This study aimed to decipher the responses of the GABA shunt and related carbon-nitrogen metabolism in poplar seedlings (Populus alba × Populus glandulosa) treated with different NaCl and CdCl2 concentrations for 30 h. The results showed that the activities of glutamate decarboxylase (GAD) and GABA-transaminase (GABA-T) were activated, as well as α-ketoglutarate dehydrogenase (α-KGDH) and succinate dehydrogenase (SDH) activities were enhanced by NaCl and CdCl2 stresses, except for SDH under CdCl2 stress. Meanwhile, the expression levels of GADs, GABA-Ts SDHs, succinyl-CoA ligases (SCSs), and succinic acid aldehyde dehydrogenases (SSADHs) were also increased. Notably, significant increases in the key components of GABA shunt, Glu and GABA, were observed under both stresses. Soluble sugars and free amino acids were enhanced, whereas citrate, malate and succinate were almost inhibited by both NaCl and CdCl2 stresses except that citrate was not changed or just increased by 50-mM NaCl stress. Thus, these results suggested that the carbon-nitrogen balance could be altered by activating the GABA shunt when main TCA-cycle intermediates were inhibited under NaCl and CdCl2 stresses. This study can enhance the understanding about the functions of the GABA shunt in woody plants under abiotic stresses and may be applied to the genetic improvement of trees for phytoremediation.


Use of mental health services by the rural aged: longitudinal study.
Recent longitudinal research investigating historic shifts in attitudes toward mental health services reveal a positive cohort shift. Most likely, this shift equates to greater use of mental health services. The purpose of this study was to examine historic shifts in the use of mental health services in a rural population. In 1987, we administered a survey to 358 randomly selected rural individuals investigating their willingness to use mental health services. In 1994, we resurveyed 110 individuals from our original sample. As predicted, we found that there was a shift in our participants' willingness to use mental health services, increasing from 5% to 18%. This increased use, although improved, still fell somewhat below the actual need for mental health services, which had remained constant (about 25%). Interestingly, there was no greater reliance on psychotropic medication in lieu of psychotherapy (about 10%). In 1987, we found that those rural elderly who had the greatest need for mental health services were the least likely to use them. This trend may be shifting as well, although it requires further investigation and confirmation. The salient implications for the design and implementation of rural mental health services for baby boomers are noted.


Patient/service user involvement in medical education: A best evidence medical education (BEME) systematic review: BEME Guide No. 58.
Background: The extent to which patients and service users are involved in medical education varies widely. There is a need for an up to date systematic review of the literature that examines what involvement (description), the potential outcome of such involvement (justification) and 'why' such involvement impacts students (clarification).Methods: Systematic searches of four databases were undertaken. Citations were screened and consensus reached for inclusion/exclusion of studies. Quality of study design and interventional presentation were assessed.Results: Of the 39 studies included in the review, 4 studies were encounter based, 17 sharing experiences, 16 with patients involved in teaching, 2 studies describing consumers as tutors, and none with involvement at the institutional level. Outcomes in terms of benefits to learners included increased empathy and understanding of illness as experienced by patients, improved communication with patients and a greater understanding of patient-center care. Educational quality assessment showed specific weaknesses in theoretical underpinning, curriculum outcomes, content or pedagogy.Conclusions: Patients can enrich medical education by allowing learners to explore patient-centered perspectives in holistic care. For educators this review highlights the lack of an underpinning conceptual basis for which to translate theory into practice.


Arctic sea ice, Eurasia snow, and extreme winter haze in China.
The East China Plains (ECP) region experienced the worst haze pollution on record for January in 2013. We show that the unprecedented haze event is due to the extremely poor ventilation conditions, which had not been seen in the preceding three decades. Statistical analysis suggests that the extremely poor ventilation conditions are linked to Arctic sea ice loss in the preceding autumn and extensive boreal snowfall in the earlier winter. We identify the regional circulation mode that leads to extremely poor ventilation over the ECP region. Climate model simulations indicate that boreal cryospheric forcing enhances the regional circulation mode of poor ventilation in the ECP region and provides conducive conditions for extreme haze such as that of 2013. Consequently, extreme haze events in winter will likely occur at a higher frequency in China as a result of the changing boreal cryosphere, posing difficult challenges for winter haze mitigation but providing a strong incentive for greenhouse gas emission reduction.


Sudden infant death syndrome: a subject of medicolegal research.
During the last decade, much attention has been paid to the risk factors of sudden infant death syndrome (SIDS). Many researchers have demonstrated that infant-care practices are linked to the risk of SIDS. Prone sleeping, bed sharing, maternal substance abuse, and cigarette smoking have been reported to be significant potentially modifiable risk factors for SIDS. Despite the reports that the incidence of SIDS has decreased by 38% in the United States, it remains the leading cause of death in the first year of life. Deaths resulting from child abuse or neglect inflicted or permitted by their caretakers being second only to SIDS in infant mortalities and some recommendations regarding the differentiation of SIDS and child abuse have generated speculation that some cases of infanticide were misdiagnosed as SIDS. To reach a proper conclusion as to the cause and manner of death of an infant who died suddenly and unexpectedly, investigation must be thorough and professional.


Changing needs of community-acquired pneumonia.
Community-acquired pneumonia (CAP) is a serious condition associated with significant morbidity and potential long-term mortality. Although the majority of patients with CAP are treated as outpatients, the greatest proportion of pneumonia-related mortality and healthcare expenditure occurs among the patients who are hospitalized. There has been considerable interest in determining risk factors and severity criteria assessments to assist with site-of-care decisions. For both inpatients and outpatients, the most common pathogens associated with CAP include Streptococcus pneumoniae, Haemophilus influenzae, group A streptococci and Moraxella catarrhalis. Atypical pathogens, Gram-negative bacilli, methicillin-resistant Staphylococcus aureus (MRSA) and viruses are also recognized aetiological agents of CAP. Despite the availability of antimicrobial therapies, the recent emergence of drug-resistant pneumococcal and staphylococcal isolates has limited the effectiveness of currently available agents. Because early and rapid initiation of empirical antimicrobial treatment is critical for achieving a favourable outcome in CAP, newer agents with activity against drug-resistant strains of S. pneumoniae and MRSA are needed for the management of patients with CAP.


Glucosinolate variability between turnip organs during development.
Turnip (Brassica rapa spp. rapa) is an important vegetable species, with a unique physiology. Several plant parts, including both the turnip tubers and leaves, are important for human consumption. During the development of turnip plants, the leaves function as metabolic source tissues, while the tuber first functions as a sink, while later the tuber turns into a source for development of flowers and seeds. In the present study, chemical changes were determined for two genotypes with different genetic background, and included seedling, young leaves, mature leaves, tuber surface, tuber core, stalk, flower and seed tissues, at seven different time points during plant development. As a basis for understanding changes in glucosinolates during plant development, the profile of glucosinolates was analysed using liquid chromatography (LC) coupled to mass spectrometry (MS). This analysis was complemented by a gene expression analysis, focussed on GLS biosynthesis, which could explain part of the observed variation, pointing to important roles of specific gene orthologues for defining the chemical differences. Substantial differences in glucosinolate profiles were observed between above-ground tissues and turnip tuber, reflecting the differences in physiological role. In addition, differences between the two genotypes and between tissues that were harvested early or late during the plant lifecycle. The importance of the observed differences in glucosinolate profile for the ecophysiology of the turnip and for breeding turnips with optimal chemical profiles is discussed.


Dissecting the Racial/Ethnic Disparity in Frailty in a Nationally Representative Cohort Study with Respect to Health, Income, and Measurement.
Racial/ethnic frailty prevalence disparities have been documented. Better elucidating how these operate may inform interventions to eliminate them. We aimed to determine whether physical frailty phenotype (PFP) prevalence disparities (i) are explained by health aspects, (ii) vary by income, or (iii) differ in degree across individual PFP criteria. Data came from the 2011 National Health and Aging Trends Study baseline evaluation. The study sample (n = 7,439) included persons in all residential settings except nursing homes. Logistic regression was used to achieve aims (i)-(iii) listed above. In (i), health aspects considered were body mass index (BMI) status and number of chronic diseases. Analyses incorporated sampling weights and adjusted for sociodemographic factors. Comparisons are versus non-Hispanic whites: Non-Hispanic blacks (odds ratio [OR] = 1.46, 95% confidence interval [CI]: 1.21-1.76) and Hispanics (1.56, 1.20-2.03) continued to have higher odds of frailty after accounting for BMI status and number of chronic diseases. Non-Hispanic blacks had elevated odds of frailty in all income quartiles, including the highest (OR = 2.19, 1.24-3.397). Racial/ethnic disparities differed considerably across frailty criteria, ranging from a twofold increase in odds of slowness to a 25%-30% decrease in odds of self-reported exhaustion. BMI and disease burden do not explain racial/ethnic frailty disparities. Black-white disparities are not restricted to low-income groups. Racial/ethnic differences vary considerably by NHATS PFP criteria. Our findings support the need to better understand mechanisms underlying elevated frailty burden in older non-Hispanic black and Hispanic Americans, how phenotypic measures capture frailty in racial/ethnic subgroups and, potentially, how to create assessments more comparable by race/ethnicity.


Phase I trial of nelarabine in indolent leukemias.
To test whether nelarabine is an effective agent for indolent leukemias and to evaluate whether there is a relationship between cellular pharmacokinetics of the analog triphosphate and clinical responses. Thirty-five patients with relapsed/refractory leukemias (n = 24, B-cell chronic lymphocytic leukemia and n = 11, T-cell prolymphocytic leukemia) were entered onto three different protocols. For schedule A, patient received nelarabine daily for 5 days, whereas for schedule B, nelarabine was administered on days 1, 3, and 5. Schedule C was similar to schedule B except that fludarabine was also infused. Plasma and cellular pharmacokinetics were studied during the first cycle. Responses were achieved in 20%, 15%, and 63% of patients receiving schedule A, B, and C, respectively. Histologic category, number of prior therapies, and fludarabine refractoriness did not influence the response rate. The most common nonhematologic toxicity was peripheral neuropathy. Grade 4 neutropenia and thrombocytopenia complicated 23% and 26% of courses respectively, and were significantly more frequent among patients with pre-existing marrow failure. Pharmacokinetics of plasma nelarabine and arabinosylguanine (ara-G) and of cellular ara-G triphosphate (ara-GTP) were similar in the two groups of diagnoses, and the elimination of ara-GTP from leukemia cells was slow (median, > 24 hours). The median peak intracellular concentrations of ara-GTP were significantly different (P = .0003) between responders (440 micromol/L; range, 35 to 1,438 micromol/L; n = 10) and nonresponders (50 micromol/L; range, 22 to 178 micromol/L; n = 15). Nelarabine is an effective regimen against indolent leukemias, and combining it with fludarabine was most promising. Determination of tumor cell ara-GTP levels may provide a predictive test for response to nelarabine.


Late-recovery from "permanent" vegetative state in the context of severe traumatic brain injury: A case report exploring objective and subjective aspects of recovery and rehabilitation.
This article provides a detailed outline of the recovery of a young male patient during his emergence from a vegetative state (VS) 19 months after suffering a severe traumatic brain injury. Several similar cases have been documented, but these tend not to consider the subjective experience of the patient or family; our aim was therefore to provide a detailed account that emphasises our neuropsychological exploration of the impact of the injury on this person, and looks at the experience of his mother along the timeline from his accident to the end of a successful period in rehabilitation. Clinical details are presented including standardised and non-standard assessments, neuropsychological interventions, as well as reflections from the patient himself. Moreover, qualitative data from an interview with his mother is used to illustrate the emotional impact on family of such a vacillating diagnostic status and prognosis for the future. We conclude that late-emergence from VS is increasingly documented and further cases must be published to better understand this phenomenon. The present case illustrates the emotional impact this situation can have on a patient and his or her family, and gives an important insight into a patient's view of his or her life and identity following such an event.


The promotional role of school and community contexts for military students.
This article examines how supportive public school environments can serve as a promotional context for the development of children and adolescents from military families. The authors integrate theory and research from multiple research strands (e.g., human development, studies of at-risk youth, educational reform, goodness of fit theory, and school climate) to outline how public schools can support the development of all children and adolescents. This article provides further support for the supposition that school climates and the social-ecological contexts surrounding a school (e.g., universities, communities, school districts) have the potential to protect at-risk children and adolescents from an array of negative social, emotional, and psychological outcomes. The authors draw linkages between these research domains and the development of military children and adolescents. Promotional civilian school environments embedded within supportive and inclusive contexts can create a social infrastructure that supports the development of military children and adolescents. The authors argue that this conceptual approach can create a foundation for interventions and research that focuses on schools as normative supportive developmental settings for military children and youth during challenging times of war (e.g., deployments and multiple school transitions). This article concludes with a discussion of future directions in research on the development of military children and adolescents. Based on a heuristic conceptual model that outlines areas needing further research, the authors call for a deeper theoretical and empirical integration of school climate and external contextual factors surrounding the school. Investigating the social and organizational dynamics within these contexts can result in a more comprehensive picture of the development of military children and adolescents.


Reversal of multidrug resistance by synthetic and natural compounds in drug-resistant MCF-7 cell lines.
Ineffectiveness of anticancer drugs is frequently observed in cancer chemotherapy. The resistance of tumor cells to various cytotoxic drugs is defined as multidrug resistance (MDR). The purpose of this study is to investigate the potential reversal effect of some synthetic and natural chemicals on drug-resistant MCF-7 cell lines. The effects of potential MDR modulators combined with some anticancer drugs were also studied. Flow cytometry, MTT cytotoxicity assays and checkerboard combination assays were performed to study the reversal of drug resistance and to investigate the antiproliferative effects of the combination of anticancer drugs and the potential modulators. The results indicated that verapamil, capsanthin, zeaxanthin and promethazine inhibited P-gp effectively, but chrysin was not effective at reversing the resistance in MCF-7 sublines. Four selective anticancer drugs (paclitaxel, docetaxel, doxorubicin and vincristine) and 4 effective MDR modulators (verapamil, capsanthin, zeaxanthin and promethazine) were applied to the sublines in combination. Fractional inhibitory indices show that verapamil and zeaxanthin seem to be the most effective MDR reversal agents that may be used together with paclitaxel, docetaxel, vincristine and doxorubicin in drug-resistant mammary carcinoma sublines. In conclusion, this report represents the importance to find out active and efficient drug resistance modulators for improving the efficacy of chemotherapy.


Streptococcus plasmid pAM alpha 1 is a composite of two separable replicons, one of which is closely related to Bacillus plasmid pBC16.
A tetracycline resistance plasmid of Streptococcus faecalis, pAM alpha 1, is shown to contain two independent sets of replication functions, separated from each other on either side by short (300- to 400-base-pair) sequences of homology. The homologous sequences are oriented as direct repeats and therefore permit the dissociation of pAM alpha 1 into its component replicons, referred to here as pAM alpha 1 delta 1 and pAM alpha 1 delta 2, as the reciprocal products of a simple intramolecular recombination. pAM alpha 1 delta 1 is a 4.6-kilobase plasmid which carries the tet gene, and pAM alpha 1 delta 2 is a 5.1-kilobase plasmid which carries no known selectable marker. pAM alpha 1 delta 1 is shown to replicate efficiently in Bacillus subtilis and to confer tetracycline resistance on Bacillus hosts. We demonstrate by restriction mapping analysis that pAM alpha 1 delta 1 is virtually identical to a 4.6-kilobase tetracycline resistance plasmid of Bacillus cereus, pBC16, which is known to show extensive homology to plasmid isolates from Staphylococcus species (such as pUB110), as well as from other Bacillus species. The pAM alpha 1 delta 1-pBC16-pUB110 replicon thus exists naturally in at least three different gram-positive genera, indicating that these plasmids have a high degree of interspecific functional adaptability and supporting the view that plasmid DNA is commonly exchanged among many species of gram-positive bacteria in their natural environments.