Mechanisms of hypervirulent Clostridium difficile ribotype 027 displacement of endemic strains: an epidemiological model.
Following rapid, global clonal dominance of hypervirulent ribotypes, Clostridium difficile now constitutes the primary infectious cause of nosocomial diarrhoea. Evidence indicates at least three possible mechanisms of hypervirulence that facilitates the successful invasion of these atypical strains: 1) increased infectiousness relative to endemic strains; 2) increased symptomatic disease rate relative to endemic strains; and 3) an ability to outcompete endemic strains in the host's gut. Stochastic simulations of an infection transmission model demonstrate clear differences between the invasion potentials of C. difficile strains utilising the alternative hypervirulence mechanisms, and provide new evidence that favours certain mechanisms (1 and 2) more than others (3). Additionally, simulations illustrate that direct competition between strains (inside the host's gut) is not a prerequisite for the sudden switching that has been observed in prevailing ribotypes; previously dominant C. difficile strains can be excluded by hypervirulent ribotypes through indirect (exploitative) competition.


Platelet-Rich Plasma in a Patient with Cerebral Palsy.
The use of platelet-rich plasma is a now a common medical technique known as regenerative medicine, through power cell activation and differentiation, which produces growth factors called platelets derived both locally and systematically. Here, we report the case of a cerebral palsy patient who received intravenous platelet-rich plasma. We administered an intravenous injection of concentrated platelet-rich plasma (25 cc) in a 6-year-old boy with perinatal cerebral palsy, cognitive impairment, and marked and severe generalized spasticity. We performed follow-up at 3 and 6 months after the injection. All serum samples for determination were obtained by ELISA technique. Cognitive scales (Bayley, Battelle, M.S.C.A, Kaufman ABC, and Stanford-Binet Intelligence scale) were used before and after treatment. The determination protocol that was applied before the analysis was performed manually and the autotransfusion was considered suitable for treatment. We determined the plasma levels of factor similar to insulin-1 (IGF-1), platelet-derived growth factor (PDGF), vasculo-endothelial growth factor (VEGF), and transforming growth factor B (TGF-B) before and during treatment monitoring. No adverse effects were observed in the patient except for a small hematoma in the area channeling venous access. We observed a clear improvement in the cognitive sphere (memory, ability to perform more complex tasks, and acquisition of new skills) and in language, maintaining stable levels of growth factor in plasma 3-5 times higher than average for his age group at both 3- and 6-month follow-up. Positron emission tomography (PET) images showed an evident increased demarcation in the cerebral cortex. We propose that this therapy is useful in these patients to harness the neurostimulative and neuroregenerative power of endogenous growth factors derived from platelets.


Comparison of trauma center patient self-reports and proxy reports on the Alcohol Use Identification Test (AUDIT).
There has been increased attention on identifying alcohol problems among individuals admitted to trauma centers. Reports about patients' drinking made by significant others represent one potential method to address both concerns about the validity of patients' self-reports and the need to have a proxy measure for trauma patients who are unable to provide information about their drinking behavior. The present study evaluated the level of agreement between trauma patients' self-report and proxy report on the Alcohol Use Disorders Identification Test (AUDIT). The study consisted of patients admitted to a Level I trauma center who screened positive for potential alcohol problems, who completed the AUDIT and National Institute of Mental Health Diagnostic Interview Schedule (Form III-R), and who had a collateral who provided proxy information about the patient. Proxy informants completed the AUDIT on the basis of their knowledge and perception of patients' drinking behavior, as well as a checklist of alcohol-related problems experienced by the patients in the 30 days before admission. Patient- and proxy-completed AUDIT total and subscale scores were highly correlated and did not differ from one another except for the dependence subscale, with proxies indicating a higher number of symptoms than did patients. A relatively high percentage of agreement (77.5%) was found overall in the classification of patients as having or not having problem drinking on the basis of self-report and proxy AUDITs; 56.4% of both sources indicated a drinking problem and 21.1% of both agreed that there was not a problem. Patients classified as having problem drinking on self-report AUDITs were rated by proxies as having significantly higher levels of hazardous drinking, alcohol-related problems, and dependence symptoms than patients whose AUDIT classified their drinking as nonproblematic. The relative comparability of proxy- and patient-completed AUDIT scores and classifications suggests that patient and proxy reports corroborate and, in cases of trauma patients' inability to provide self-reports, may serve as proxies for patients' reports of drinking.


Nicotinic Acetylcholine Receptor Subunit Alpha-5 Promotes Radioresistance via Recruiting E2F Activity in Oral Squamous Cell Carcinoma.
Radiotherapy is commonly used to treat patients with oral squamous cell carcinoma (OSCC), but a subpopulation of OSCC patients shows a poor response to irradiation treatment. Therefore, identifying a biomarker to predict the effectiveness of radiotherapy in OSCC patients is urgently needed. In silico analysis of public databases revealed that upregulation of CHRNA5, the gene encoding nicotinic acetylcholine receptor subunit alpha-5, is extensively detected in primary tumors compared to normal tissues and predicts poor prognosis in OSCC patients. Moreover, CHRNA5 transcript level was causally associated with the effective dose of irradiation in a panel of OSCC cell lines. Artificial silencing of CHRNA5 expression enhanced, but nicotine reduced, the radiosensitivity of OSCC cells. Gene set enrichment analysis demonstrated that the E2F signaling pathway is highly activated in OSCC tissues with high levels of CHRNA5 and in those derived from patients with cancer recurrence after radiotherapy. CHRNA5 knockdown predominantly suppressed E2F activity and decreased the phosphorylation of the Rb protein; however, nicotine treatment dramatically promoted E2F activity and increased Rb phosphorylation, which was mitigated after CHRNA5 knockdown in OSCC cells. Notably, the signature combining increased mRNA levels of CHRNA5 and the E2F signaling gene set was associated with worse recurrence-free survival probability in OSCC patients recorded to be receiving radiotherapy. Our findings suggest that CHRNA5 is not only a useful biomarker for predicting the effectiveness of radiotherapy but also a druggable target to enhance the cancericidal effect of irradiation on OSCC.


Closed-Loop Haptic Feedback Control Using a Self-Sensing Soft Pneumatic Actuator Skin.
In this article, we achieve a closed-loop control over haptic feedback, first time for an entirely soft platform. We prototyped a novel self-sensing soft pneumatic actuator (SPA) with soft strain sensors, called SPA-skin, which withstands large multiaxial strains and is capable of high-frequency sensing and actuation. To close-loop control the haptic feedback, the platform requires a cohesively integrated system. Our system consists of a stretchable low profile (<500 μm) SPA and an ultra-compliant thin-metal film strain sensor that create a novel bidirectional platform for tactile sensing via force-tunable vibratory feedback. With this prototype, we demonstrated control of the actuator shape in real time up to 100 Hz at output forces up to 1 N, maintained under variable mechanical loadings. We further characterized the SPA-skin platform for its static and dynamic behavior over a range of actuation amplitudes and frequencies as well as developed an analytical model of this system to predict the actuator inflation state only using the embedded sensor's resistance. Our SPA-skin is a multifunctional multilayer system that can readily be implemented as a high-speed wearable bidirectional interface for contact sensing and vibrotactile feedback.


Effects of the August 2003 blackout on the New York City healthcare delivery system: a lesson for disaster preparedness.
On August 14, 2003, the United States and Canada suffered the largest power failure in history. We report the effects of this blackout on New York City's healthcare system by examining the following: 1) citywide 911 emergency medical service (EMS) calls and ambulance responses; and 2) emergency department (ED) visits and hospital admissions to one of New York City's largest hospitals. Citywide EMS calls and ambulance responses were categorized by 911 call type. Montefiore Medical Center (MMC) ED visits and hospital admissions were categorized by diagnosis and physician-reviewed for relationship to the blackout. Comparisons were made to the week pre- and postblackout. Citywide EMS calls numbered 5,299 on August 14, 2003, and 5,021 on August 15, 2003, a 58% increase (p < .001). During the blackout, there were increases in "respiratory" (189%; p < .001), "cardiac" (68%; p = .016), and "other" (40%; p < .001) EMS call categories, but when expressed as a percent of daily totals, "cardiac" was no longer significant. The MMC-ED reflected this surge with only "respiratory" visits significantly increased (expressed as percent of daily total visits; p < .001). Respiratory device failure (mechanical ventilators, positive pressure breathing assist devices, nebulizers, and oxygen compressors) was responsible for the greatest burden (65 MMC-ED visits, with 37 admissions) as compared with 0 pre- and postblackout. The blackout dramatically increased EMS and hospital activity, with unexpected increases resulting from respiratory device failures in community-based patients. Our findings suggest that current capacity to respond to public health emergencies could be easily overwhelmed by widespread/prolonged power failure(s). Disaster preparedness planning would be greatly enhanced if fully operational, backup power systems were mandated, not only for acute care facilities, but also for community-based patients dependent on electrically powered lifesaving devices.


Molecular characterization of the GTPase-activating domain of ADP-ribosylation factor domain protein 1 (ARD1).
ADP-ribosylation factors (ARFs) are approximately 20-kDa guanine nucleotide-binding proteins recognized as critical components in intracellular vesicular transport and phospholipase D activation. Both guanine nucleotide-exchange proteins and GTPase-activating proteins (GAPs) for ARFs have been cloned recently. A zinc finger motif near the amino terminus of the ARF1 GAP was required for stimulation of GTP hydrolysis. ARD1 is an ARF family member that differs from other ARFs by the presence of a 46-kDa amino-terminal extension. We had reported that the ARF domain of ARD1 binds specifically GDP and GTP and that the amino-terminal extension acts as a GAP for the ARF domain of ARD1 but not for ARF proteins. The GAP domain of ARD1, synthesized in Escherichia coli, stimulated hydrolysis of GTP bound to the ARF domain of ARD1. Using ARD1 truncations, it appears that amino acids 101-190 are critical for GAP activity, whereas residues 190-333 are involved in physical interaction between the two domains of ARD1 and are required for GTP hydrolysis. The GAP function of the amino-terminal extension of ARD1 required two arginines, an intact zinc finger motif, and a group of residues which resembles a sequence present in Rho/Rac GAPs. Interaction between the two domains of ARD1 required two negatively charged residues (Asp427 and Glu428) located in the effector region of the ARF domain and two basic amino acids (Arg249 and Lys250) found in the amino-terminal extension. The GAP domain of ARD1 thus is similar to ARF GAPs but differs from other GAPs in its covalent association with the GTP-binding domain.


Clinically relevant high levels of human C-reactive protein induces endothelial dysfunction and hypertension by inhibiting the AMPK-eNOS axis.
Successful treatment of resistant hypertension accompanied by elevated human C-reactive protein (hCRP) remains a key challenge in reducing the burden of cardiovascular diseases. It is still unclear whether clinically relevant high-level hCRP is merely a marker or a key driver of hypertension. Here, we investigated the role and mechanism of clinically relevant high level of hCRP in hypertension. Elevated blood pressure was observed in all three hCRP overexpression models, including adeno-associated virus 9 (AAV9)-transfected mice, AAV9-transfected rats and hCRP transgenic (hCRPtg) rats. hCRPtg rats expressing clinically relevant high-level hCRP developed spontaneous hypertension, cardiac hypertrophy, myocardial fibrosis and impaired endothelium-dependent relaxation. Mechanistically, studies in endothelial nitric oxide (NO) synthase (eNOS) knockout mice transfected with AAV9-hCRP and phosphoproteomics analysis of hCRP-treated endothelial cells revealed that hCRP inhibited AMP-activated protein kinase (AMPK)-eNOS phosphorylation pathway. Further, activation of AMPK by metformin normalized endothelial-dependent vasodilation and decreased the blood pressure of hCRPtg rats. Our results show that clinically relevant high-level hCRP induces hypertension and endothelial dysfunction by inhibiting AMPK-eNOS signaling, and highlight hCRP is not only an inflammatory biomarker but also a driver of hypertension. Treatment with metformin or a synthetic AMPK activator may be a potential strategy for vaso-dysfunction and hypertension in patients with high hCRP levels.


Cognitive behavioural group training (CBGT) for patients with type 1 diabetes in persistent poor glycaemic control: who do we reach?
Approximately a quarter of adults with type 1 diabetes do not succeed in achieving satisfactory glycaemic control, partly due to problems with the demanding self-management regimen. To improve glycaemic control, interventions with a cognitive behavioural approach, aimed at modifying dysfunctional beliefs, reducing negative emotions and enhancing self-care practices are a potentially successful tool. Little is known about the reach of such an approach. This article describes characteristics of participants in a randomized, controlled trial of cognitive behavioural group training for patients with type 1 diabetes in poor glycaemic control. Results show that outpatients from seven hospitals in the area of Amsterdam, selected on long-standing high HbA1c and volunteering to participate, report high levels of psychological distress and depressive symptoms. Furthermore, self-care behaviours were perceived as important, but burdensome. Diabetes-specific self-efficacy was relatively low. It is concluded that this selected group of adults with type 1 diabetes would potentially benefit from a cognitive-behavioural intervention in order to reduce negative emotions, enhance diabetes self-efficacy, self-care behaviour and glycaemic outcomes.


Establishment of a patterned GAL4-VP16 transactivation system for discovering gene function in rice.
A binary GAL4-VP16-UAS transactivation system has been established in rice (Oryza sativa L.) in this study for the discovery of gene functions. This binary system consists of two types of transgenic lines, pattern lines and target lines. The pattern lines were produced by transformation of Zhonghua 11, a japonica cultivar, with a construct consisting of the transactivator gene GAL4-VP16 controlled by a minimal promoter and the GUSplus reporter controlled by the upstream activation sequence (UAS; cis-element to GAL4). Target lines were generated by transformation of Zhonghua 11 with constructs carrying the EGFP reporter and target genes of interest, both controlled by the UAS but in opposite directions. Hybrid plants were obtained by crossing target lines of 10 putative transcription factor genes from rice with six pattern lines showing expression in anther, stigma, palea, lemma and leaves. The EGFP and target genes perfectly co-expressed in hybrid plants with the same expression patterns as in the pattern lines. Various phenotypic changes, such as delayed flowering, multiple pistils, dwarfism, narrow and droopy leaves, reduced tillers, growth retardation and sterility, were induced as a result of the expression of the target genes. It is concluded that this transactivation system can provide a useful tool in rice to unveil latent functions of unknown or known genes.


Chronic exposure to high fat diet triggers myelin disruption and interleukin-33 upregulation in hypothalamus.
Hypothalamic inflammation including astrogliosis and microglia activation occurs after intake of high fat diet (HFD) in rodent models or in obese individuals. However, the effect of chronic HFD feeding on oligodendrocytes (OLGs), a myelin-producing glial population in the central nervous system (CNS), remains unclear. In this study, we used 8-week old male C57BL/6 mice fed by HFD for 3-6 months to induce chronic obesity. The transmission electron microscopy imaging analysis showed that the integrity of hypothalamic myelin was disrupted after HFD feeding for 4 and 6 months. Moreover, the accumulation of Iba1+-microglia with an amoeboid hypertrophic form was continually observed in arcuate nucleus of HFD-fed mice during the entire feeding time period. Interleukin-33 (IL-33), a tissue alarmin upon injury to the CNS, was detected with an increased level in hypothalamus after HFD feeding for 3 and 4 months. Furthermore, the in vitro study indicated that exposure of mature OLGs to IL-33 impaired OLG cell structure along with a decline in the expression of myelin basic protein. Altogether, our findings demonstrate that chronic HFD feeding triggers hypothalamic myelin disruption in accompany with IL-33 upregulation and prolonged microglial activation in hypothalamus. Given that the addition of exogenous IL-33 was harmful for the maturation of OLGs, an increase in IL-33 by chronic HFD feeding might contribute to the induction of hypothalamic myelin disruption.


Water reorientation, hydrogen-bond dynamics and 2D-IR spectroscopy next to an extended hydrophobic surface.
The dynamics of water next to hydrophobic groups is critical for several fundamental biochemical processes such as protein folding and amyloid fiber aggregation. Some biomolecular systems, like melittin or other membrane-associated proteins, exhibit extended hydrophobic surfaces. Due to the strain these surfaces impose on the hydrogen (H)-bond network, the water molecules shift from the clathrate-like arrangement observed around small solutes to an anticlathrate-like geometry with some dangling OH bonds pointing toward the surface. Here we examine the water reorientation dynamics next to a model hydrophobic surface through molecular dynamics simulations and analytic modeling. We show that the water OH bonds lying next to the hydrophobic surface fall into two subensembles with distinct dynamical reorientation properties. The first is the OH bonds tangent to the surface; these exhibit a behavior similar to the water OHs around small hydrophobic solutes, i.e. with a moderate reorientational slowdown explained by an excluded volume effect due to the surface. The second is the dangling OHs pointing toward the surface: these are not engaged in any H-bond, reorient much faster than in the bulk, and exhibit an unusual anisotropy decay which becomes negative for delays of a few picoseconds. The H-bond dynamics, i.e. the exchanges between the different configurations, and the resulting anisotropy decays are analyzed within the analytic extended jump model. We also show that a recent spectroscopy technique, two-dimensional time resolved vibrational spectroscopy (2D-IR), can be used to selectively follow the dynamics of dangling OHs, since these are spectrally distinct from H-bonded ones. By computing the first 2D-IR spectra of water next to a hydrophobic surface, we establish a connection between the spectral dynamics and the dynamical properties that we obtain directly from the simulations.


Effect of reduced gravity on the preferred walk-run transition speed.
We investigated the effect of reduced gravity on the human walk-run gait transition speed and interpreted the results using an inverted-pendulum mechanical model. We simulated reduced gravity using an apparatus that applied a nearly constant upward force at the center of mass, and the subjects walked and ran on a motorized treadmill. In the inverted pendulum model for walking, gravity provides the centripetal force needed to keep the pendulum in contact with the ground. The ratio of the centripetal and gravitational forces (mv2/L)/(mg) reduces to the dimensionless Froude number (v2/gL). Applying this model to a walking human, m is body mass, v is forward velocity, L is leg length and g is gravity. In normal gravity, humans and other bipeds with different leg lengths all choose to switch from a walk to a run at different absolute speeds but at approximately the same Froude number (0.5). We found that, at lower levels of gravity, the walk-run transition occurred at progressively slower absolute speeds but at approximately the same Froude number. This supports the hypothesis that the walk-run transition is triggered by the dynamics of an inverted-pendulum system.


Primary cutaneous diffuse large B-cell lymphoma (PCDLBCL), leg-type and other: an update on morphology and treatment.
Primary cutaneous B-cell lymphoma (PCBCL) is an heterogeneous group of lymphoproliferative disorders, which account for 25-30% of all primary cutaneous lymphoma and include three main histotypes: 1) primary cutaneous marginal zone B-cell lymphoma (PCMZL); 2) primary cutaneous follicular center cell lymphoma (PCFCL); 3) primary cutaneous diffuse large B-cell lymphoma (DLBCL), leg type (PCDLBCL-LT). PCMZL and PCFCL are indolent lymphomas, with an excellent prognosis despite an high rate of cutaneous recurrences; in contrast, PCDLBCL-LT is clinically more aggressive and usually requires to be treated with multi-agent chemotherapy and anti-CD20 monoclonal antibodies. PCDLBCL-LT histologically consists of large round cells (centroblasts and immunoblasts), is characterized by strong bcl-2 expression, in the absence of t(14;18) translocation, and resembles the activated B-cell type of nodal DLBCL. Recently, the term primary cutaneous DLBCL-other (PCDLBCL-O) has been proposed to include diffuse lymphomas composed of large transformed B-cells that lack the typical features of PCDLBCL-LT and do not conform to the definition of PCFCL. Some clinical studies suggested that such cases have an indolent clinical course and may be treated in a conservative manner; however, data regarding the actual prognosis and clinical behaviour of these peculiar cases are still too limited. The spectrum of primary cutaneous DLBCL also encompasses some rare morphological variants, such as anaplastic or plasmablastic subtypes and T-cell rich B-cell lymphoma, and some recently described, exceedingly rare DLBCL subtypes, such as intravascular large B-cell lymphoma and EBV-associated large B-cell lymphoma of the elderly, which often present in the skin.


Glucagon-Like Peptide-1 Agonists for Treating Obesity in Patients With Immune-Mediated Skin Diseases.
Psoriasis and hidradenitis suppurativa are often associated with obesity. Because chronic low-grade inflammation underlies these 2 diseases, they can progress to more severe forms in patients with obesity if weight-reduction measures are not taken. This review covers pharmacologic alternatives for treating obesity, with emphasis on the benefits associated with the novel use of glucagon-like peptide-1 (GLP-1) agonists that act on satiety receptors. These drugs have led to greater weight loss in clinical trials and real-world settings than orlistat, which until recently was the only drug approved for treating obesity in the European Union. Although experience with GLP-1 agonists in patients with obesity and inflammatory skin diseases is currently scarce, the promising results reported suggest they may offer a useful tool for managing obesity.


A Catch-and-Release Approach to Selective Modification of Accessible Tyrosine Residues.
The tyrosine side chain is amphiphilic leading to significant variations in the surface exposure of tyrosine residues in the folded structure of a native sequence protein. This variability can be exploited to give residue-selective functionalization of a protein substrate by using a highly reactive diazonium group tethered to an agarose-based resin. This novel catch-and-release approach to protein modification has been demonstrated for proteins with accessible tyrosine residues, which are compared with a control group of proteins in which there are no accessible tyrosine residues. MS analysis of the modified proteins showed that functionalization was highly selective, but reactivity was further attenuated by the electrostatic environment of any individual residue. Automated screening of PDB structures allows identification of potential candidates for selective modification by comparison with the accessibility of the tyrosine residue in a benchmark peptide (GYG).


Fast MR imaging of fetal CNS anomalies in utero.
Although sonography is the primary imaging technique for evaluating the developing fetus, significant limitations exist in the sonographic prenatal diagnosis of many brain disorders. Fast MR imaging is increasingly being used to determine the underlying cause of nonspecific fetal CNS abnormalities detected sonographically and to confirm or provide further support for such anomalies. Our goal was to determine the value of MR imaging in establishing the diagnosis of fetal CNS anomalies, to ascertain how this information might be used for patient counseling, and to assess its impact on pregnancy management. We prospectively performed MR examinations of 73 fetuses (66 pregnancies) with suspected CNS abnormalities and compared these with available fetal sonograms, postnatal images, and clinical examinations. Retrospectively, the impact on patient counseling and pregnancy management was analyzed. Images of diagnostic quality were routinely obtained with in utero MR imaging, which was particularly valuable in detecting heterotopia, callosal anomalies, and posterior fossa malformations, and for providing excellent anatomic information. We believe that 24 (46%) of 52 clinical cases were managed differently from the way they would have been on the basis of sonographic findings alone. In every case, the referring physicians thought that MR imaging provided a measure of confidence that was not previously available and that was valuable for counseling patients and for making more informed decisions. Sonography is the leading technique for fetal assessment and provides reliable, inexpensive diagnostic images. Fast MR imaging is an important adjunctive tool for prenatal imaging in those instances in which a complex anomaly is suspected by sonography, when fetal surgery is contemplated, or when a definitive diagnosis cannot be determined.


Effects of a menthol-based analgesic balm on pressor responses evoked from muscle afferents in cats.
To evaluate changes in heart rate (HR) and mean arterial pressure (MAP) as indicators of changes in pressor response for muscle afferents after topical application of menthol (MEN)-based analgesic balm. 11 decerebrate cats. Pressor responses were reflexively evoked by static contraction of hind limb muscles, which are caused by group III and IV afferents. Responses were monitored without interference from anesthesia or effects of higher brain function by the use of decerebrate cats. After obtaining baseline data, MEN analgesic balm (1.9%) was applied to the skin over contracting muscles of 1 hind limb in 6 cats; petrolatum was applied to 5 control cats. Muscle contractions were evoked every 10 minutes, alternating between hind limbs, for 120 minutes. Peak MAP and HR were analyzed. Peak MAP responses evoked by static muscle contraction for the ipsilateral hind limb were significantly attenuated 20 minutes after application, but approached baseline values 40 minutes after application. The pressor response was significantly decreased 20 minutes after application during the last 12 seconds of the stimulus, which was attributed to group IV afferents. There were no significant differences in HR responses. Application of MEN analgesic balm to the skin over contracting muscles significantly decreased the pressor response to static muscle contractions. This suggests that topical application of MEN has effects on responses evoked from receptors located in muscles. The MEN analgesic balm appeared to attenuate the pressor response 20 minutes after application, but it was a short-term effect.


Combining AFM13, a Bispecific CD30/CD16 Antibody, with Cytokine-Activated Blood and Cord Blood-Derived NK Cells Facilitates CAR-like Responses Against CD30+ Malignancies.
Natural killer (NK)-cell recognition and function against NK-resistant cancers remain substantial barriers to the broad application of NK-cell immunotherapy. Potential solutions include bispecific engagers that target NK-cell activity via an NK-activating receptor when simultaneously targeting a tumor-specific antigen, as well as enhancing functionality using IL12/15/18 cytokine pre-activation. We assessed single-cell NK-cell responses stimulated by the tetravalent bispecific antibody AFM13 that binds CD30 on leukemia/lymphoma targets and CD16A on various types of NK cells using mass cytometry and cytotoxicity assays. The combination of AFM13 and IL12/15/18 pre-activation of blood and cord blood-derived NK cells was investigated in vitro and in vivo. We found heterogeneity within AFM13-directed conventional blood NK cell (cNK) responses, as well as consistent AFM13-directed polyfunctional activation of mature NK cells across donors. NK-cell source also impacted the AFM13 response, with cNK cells from healthy donors exhibiting superior responses to those from patients with Hodgkin lymphoma. IL12/15/18-induced memory-like NK cells from peripheral blood exhibited enhanced killing of CD30+ lymphoma targets directed by AFM13, compared with cNK cells. Cord-blood NK cells preactivated with IL12/15/18 and ex vivo expanded with K562-based feeders also exhibited enhanced killing with AFM13 stimulation via upregulation of signaling pathways related to NK-cell effector function. AFM13-NK complex cells exhibited enhanced responses to CD30+ lymphomas in vitro and in vivo. We identify AFM13 as a promising combination with cytokine-activated adult blood or cord-blood NK cells to treat CD30+ hematologic malignancies, warranting clinical trials with these novel combinations.


Pre-frailty factors in community-dwelling 40-75 year olds: opportunities for successful ageing.
There is little known about pre-frailty attributes or when changes which contribute to frailty might be detectable and amenable to change. This study explores pre-frailty and frailty in independent community-dwelling adults aged 40-75 years. Participants were recruited through local council networks, a national bank and one university in Adelaide, Australia. Fried frailty phenotype scores were calculated from measures of unintentional weight loss, exhaustion, low physical activity levels, poor hand grip strength and slow walking speed. Participants were identified as not frail (no phenotypes), pre-frail (one or two phenotypes) or frail (three or more phenotypes). Factor analysis was applied to binary forms of 25 published frailty measures Differences were tested in mean factor scores between the three Fried frailty phenotypes and ROC curves estimated predictive capacity of factors. Of 656 participants (67% female; mean age 59.9 years, SD 10.6) 59.2% were classified as not frail, 39.0% pre-frail and 1.8% frail. There were no gender or age differences. Seven frailty factors were identified, incorporating all 25 frailty measures. Factors 1 and 7 significantly predicted progression from not-frail to pre-frail (Factor 1 AUC 0.64 (95%CI 0.60-0.68, combined dynamic trunk stability and lower limb functional strength, balance, foot sensation, hearing, lean muscle mass and low BMI; Factor 7 AUC 0.55 (95%CI 0.52-0.59) comprising continence and nutrition. Factors 3 and 4 significantly predicted progression from pre-frail to frail (Factor 3 AUC 0.65 (95% CI 0.59-0.70)), combining living alone, sleep quality, depression and anxiety, and lung function; Factor 4 AUC 0.60 (95%CI 0.54-0.66) comprising perceived exertion on exercise, and falls history. This research identified pre-frailty and frailty states in people aged in their 40s and 50s. Pre-frailty in body systems performance can be detected by a range of mutable measures, and interventions to prevent progression to frailty could be commenced from the fourth decade of life.


A technique for recovering Doppler line profiles from fabry-perot interferometer fringes of very low intensity.
A technique for recovering doppler line profiles from Fabry-Perot interferometer fringes of very low intensity is described. The technique is based on a fourier decomposition of the data and a subsequent nonlinear least squares fit of the low order fourier coefficients to the fourier decomposition of an ideal instrument function. The ideal instrument function is expressed by the convolution of various instrument broadening functions and includes a parametric representation of the actual instrument. The method for recovering doppler temperature, emission line intensity, and mass motion of the emitting molecules is described. A theoretical analysis of errors for doppler temperature and emission line intensity is made for a statistical noise distribution superimposed upon a fringe profile of very low intensity. These errors are related to the emission line intensity, number of data points per fringe, background continuum level, and instrument parameters. As a specific example, the errors in retrieving the doppler temperature from the 6300-A atomic oxygen emission line OI((1)D - (3)P) in the nightglow are determined for the 15-cm Fabry-Perot interferometer at the University of Michigan Airglow Observatory.


Gastrointestinal Tract Vasculopathy: Clinicopathology and Description of a Possible "New Entity" With Protean Features.
Noninfectious gastrointestinal (GI) vasculopathic disorders are rare and are often overlooked in histopathologic examination or when forming differential diagnoses due to their rarity. However, involvement of the GI tract may lead to serious complications, including ischemia and perforation. Since awareness of the types of vasculopathy that may involve the GI tract is central to arriving at a correct diagnosis, we reviewed our institutional experience with GI tract vasculopathy in order to enhance diagnostic accuracy of these rare lesions. We report the clinical and histologic features of 16 cases (excluding 16 cases of immunoglobulin A vasculitis) diagnosed over a 20-year period. Of the 16 patients, 14 presented with symptoms related to the GI vasculopathy (including 2 presenting with a mass on endoscopic examination). The remaining 2 patients presented with incarcerated hernia and invasive adenocarcinoma. The vasculopathy was not associated with systemic disease and appeared limited to the GI tract in 8 patients. Eight had associated systemic disease, but only 6 had a prior diagnosis. The underlying diagnoses in these 6 patients included systemic lupus erythematosus (1), dermatomyositis (2), rheumatoid arthritis (1), eosinophilic granulomatosis with polyangiitis (1), and Crohn disease (1). One patient with granulomatous polyangiitis and 1 patient with systemic lupus erythematosus initially presented with GI symptoms. The 8 cases of isolated GI tract vasculopathy consisted of enterocolic lymphocytic phlebitis (4), idiopathic myointimal hyperplasia of the sigmoid colon (1), idiopathic myointimal hyperplasia of the ileum (1), granulomatous vasculitis (1), and polyarteritis nodosa-like arteritis (1). Isolated GI tract vasculopathy is rare, but appears to be almost as common as that associated with systemic disease. The chief primary vasculopathies are enterocolic lymphocytic colitis and idiopathic myointimal hyperplasia. Although the latter occurs predominantly in the left colon, rare examples occur in the small bowel and likely represent a complex, more protean disorder.


Genetic mapping and DNA sequence-based analysis of deleted regions on chromosome 16 involved in progression of bladder cancer from occult preneoplastic conditions to invasive disease.
Histologic and genetic mapping with 30 hypervariable markers mapped to chromosome 16 were performed on 234 DNA samples of five cystectomy specimens from patients with invasive bladder cancer. Allelic losses of individual markers were related to microscopically identified precursor conditions in the entire bladder mucosa and invasive cancer. Their significance for the development and progression of neoplasia from in situ preneoplastic conditions to invasive disease was analysed by the nearest neighbor algorithm and binomial maximum likelihood analysis. Using this approach we identified five distinct regions of allelic losses defined by their flanking markers and predicted size as follows. p13.3(D16S418-D16S406, 1.2 cM), p13.1(D16S748-D16S287, 12.9 cM), q12 1(D16S409-D16S514, 24.0 cM), q22.1 (D16S496-D16S515, 5.4 cM), and q24 (D16S507-D16S511, 5.9 cM and D16S402-D16S413, 17.4 cM). The regions mapping to p13.1 and q24 were involved in early intraurothelial phases of bladder neoplasia such as mild to moderate dysplasia. On the other hand the deleted region mapping to p13.3 was involved in progression of severe dysplasia/carcinoma in situ to invasive bladder cancer. Testing of markers that exhibited statistically significant LOH in relation to progression of neoplasia from precursor conditions to invasive cancer on 28 tumors and voided urine samples from 25 patients with bladder cancer revealed that q12.1 showed LOH in 46.4% of tumor and 32.0% of voided urine samples. The LOH of a single marker D16S541 could be detected in approximately 28% of tumors and 20% of voided urine samples of patients with bladder cancer. These data imply that the deleted region centered around marker D16S541 spanning approximately 10 cM and flanked by D16S409 and D16S415 contains a novel putative tumor suppressor gene or genes playing an important role in the development of human bladder cancer. To facilitate more precise positional mapping and identification of pathogenetically relevant genes, we analysed of human genome contig and sequence databases spanning the deleted regions. Multiple known candidate genes and several smaller gene-rich areas mapping to the target regions of chromosome 16 were identified.


Changes in brain oxysterols at different stages of Alzheimer's disease: Their involvement in neuroinflammation.
Alzheimer's disease (AD) is a gradually debilitating disease that leads to dementia. The molecular mechanisms underlying AD are still not clear, and at present no reliable biomarkers are available for the early diagnosis. In the last several years, together with oxidative stress and neuroinflammation, altered cholesterol metabolism in the brain has become increasingly implicated in AD progression. A significant body of evidence indicates that oxidized cholesterol, in the form of oxysterols, is one of the main triggers of AD. The oxysterols potentially most closely involved in the pathogenesis of AD are 24-hydroxycholesterol and 27-hydroxycholesterol, respectively deriving from cholesterol oxidation by the enzymes CYP46A1 and CYP27A1. However, the possible involvement of oxysterols resulting from cholesterol autooxidation, including 7-ketocholesterol and 7β-hydroxycholesterol, is now emerging. In a systematic analysis of oxysterols in post-mortem human AD brains, classified by the Braak staging system of neurofibrillary pathology, alongside the two oxysterols of enzymatic origin, a variety of oxysterols deriving from cholesterol autoxidation were identified; these included 7-ketocholesterol, 7α-hydroxycholesterol, 4β-hydroxycholesterol, 5α,6α-epoxycholesterol, and 5β,6β-epoxycholesterol. Their levels were quantified and compared across the disease stages. Some inflammatory mediators, and the proteolytic enzyme matrix metalloprotease-9, were also found to be enhanced in the brains, depending on disease progression. This highlights the pathogenic association between the trends of inflammatory molecules and oxysterol levels during the evolution of AD. Conversely, sirtuin 1, an enzyme that regulates several pathways involved in the anti-inflammatory response, was reduced markedly with the progression of AD, supporting the hypothesis that the loss of sirtuin 1 might play a key role in AD. Taken together, these results strongly support the association between changes in oxysterol levels and AD progression.


Psychosocial Aspects During the First Wave of COVID-19 Infection in South Africa.
Background: In South Africa, as in many countries, the nationwide spread of COVID-19 caused a public health emergency that resulted in the government implementing necessary restrictive measures such as the nationwide lockdown as a way of containing the pandemic. Such restrictive measure, while necessary, can disrupt many aspects of people's lives resulting in unprecedented psychosocial distress. Aim: The present study aims to describe the psychosocial health and situational factors associated with the novel coronavirus (COVID-19) in South Africa during the first wave of infection. Methods: This cross-sectional survey, recruited a total of 203 participants through convenience sampling via online platforms-WhatsApp, Facebook, emails, etc.-during COVID-19 lockdown in the country. Through the snowball technique, participants from across South Africa completed the online survey that assessed socio-demographic information, risk perception, history of mental health, COVID-19-related stress, and fears during the lockdown (first wave). Results: The majority of the participants who completed the survey were young, Black African, and female. Participants reported feelings of stress and anxiety (61.2%); stress about finances (39.5%); and feelings of sadness, anger, and/or frustration (31.6%) during the lockdown. Females compared to males were more likely to perceive COVID-19 as a risk to their household, X ( 20 ) 2 = 45,844, p < 0.001 and community, X ( 20 ) 2 = 40,047, p = 0.005. COVID-19 differentially impacted the mental health of participants with and without mental health diagnosis, X ( 4 ) 2 = 16.596, p = 0.002. Participants with a prior mental health diagnosis reported significant extra stress during lockdown (p < 0.05). Conclusion: The findings may be of significance to assist in the development of targeted psychosocial interventions to help people during and after the pandemic.


Developmental pathways linking childhood temperament with antisocial behavior and substance use in adolescence: Explanatory mechanisms in the peer environment.
This study investigated 3 developmental pathways involving the peer environment that may explain how certain temperamental dispositions in childhood may become manifested in later antisocial behavior and substance use. A total of 411 (52% boys) Canadian children were followed annually from ages 6 to 15 years. The study tested whether the temperamental traits approach, negative reactivity and attention (assessed at ages 6-7 years), were associated with overt antisocial behavior, covert antisocial behavior and illicit substance use (assessed at ages 14-15 years), via poor social preference among peers, inflated social self-perception and antisocial behavior of peer-group affiliates (assessed throughout ages 8-13 years). Results indicated that negative reactivity was indirectly associated with overt antisocial behavior and substance use via poor social preference. Specifically, negative reactivity in earlier childhood predicted poor social preference in later childhood and early adolescence. This poor social standing among peers, in turn, predicted more engagement in overt antisocial behavior but less substance use in later adolescence. Over and above the influence of social preference, negative reactivity predicted engagement in all 3 outcomes via children's antisocial behavior in childhood and early adolescence. Inflated social self-perception and antisocial behavior of peer-group affiliates did not mediate the link between temperament and the outcomes under scrutiny. No sex differences in developmental pathways from temperament to the outcomes were found. To further our understanding of the developmental link between childhood temperament and later antisocial behavior and substance use, we need to recognize the role of peer environmental factors, specifically poor preference among peers. (PsycINFO Database Record


Effect of olive oil on immune function in middle-aged men.
Consumption of diets rich in monounsaturated fatty acids (MUFAs) has been linked with a low prevalence of atherosclerosis and there has been great interest in the effects of MUFAs on lipoprotein metabolism. Less attention has been paid to the effects of MUFAs on the immune system, yet cells of the immune system are an inherent part of the inflammatory events involved in atherosclerosis and several animal studies showed that olive oil has some potent immunomodulatory actions. We therefore considered it important to investigate the effects of chronic consumption of MUFAs on several immune cell functions in healthy humans. Healthy middle-aged males entered a double-blind, randomized, controlled trial in which they consumed either a MUFA diet or a control diet for 2 mo. There was a significant decrease in the expression of intercellular adhesion molecule 1 by peripheral blood mononuclear cells from subjects consuming the MUFA diet. Consumption of the MUFA diet did not affect natural killer cell activity or proliferation of mitogen-stimulated leukocytes. The effects of a MUFA-rich diet on adhesion molecule expression may have implications for the influence of dietary fat on inflammatory diseases, including atherosclerosis.


Long-term survival and interruption of HAART in HIV-related pulmonary hypertension.
Reported here is a case of a patient with pulmonary arterial hypertension related to HIV (PAHRH) in which lipodystrophy necessitated interruption of highly active antiretroviral therapy (HAART) and long-term survival was the outcome. Although previous studies have suggested antiretroviral therapy may benefit patients with this rare complication of HIV infection, no worsening of PAHRH was observed when HAART was interrupted. Clinical and echocardiographic parameters remained stable during 7 months of follow up. In cases in which HAART is associated with relevant toxicity, interruption of HAART in patients with PAHRH can be considered, but should be used only if no alternatives are available. Close follow-up is warranted.


Biological versus nonbiological older brothers and men's sexual orientation.
The most consistent biodemographic correlate of sexual orientation in men is the number of older brothers (fraternal birth order). The mechanism underlying this effect remains unknown. In this article, I provide a direct test pitting prenatal against postnatal (e.g., social/rearing) mechanisms. Four samples of homosexual and heterosexual men (total n = 944), including one sample of men raised in nonbiological and blended families (e.g., raised with half- or step-siblings or as adoptees) were studied. Only biological older brothers, and not any other sibling characteristic, including nonbiological older brothers, predicted men's sexual orientation, regardless of the amount of time reared with these siblings. These results strongly suggest a prenatal origin to the fraternal birth-order effect.


Bipolar Spectrum Disorders in Patients With Cerebellar Lesions: A Comparison With Parkinson's Disease.
Nonmotor functions of the cerebellum are well known. Within this frame, the aim of this study was to compare psychiatric morbidity rates among patients affected by cerebellar diseases or Parkinson's disease (PD). Forty-seven patients (27 cerebellar and 20 PD) underwent a comprehensive psychiatric evaluation (psychopathological rating scales and the Structured Clinical Interview for DSM-IV-TR Axis I Disorders). Psychiatric disorders were slightly more frequent among cerebellar than among PD patients (89% vs. 75%; p = 0.21). Mood disorders were more frequent in the cerebellar than in the PD group (90% vs. 55%; p < 0.01). Among those subjects with no psychiatric history prior to the onset of neurological disease, bipolar spectrum disorders were more frequent within the cerebellar group (p < 0.01). These results confirm high rates of psychiatric disorders among cerebellar patients. The higher frequency of bipolar spectrum presentations found in the cerebellar group may suggest a specific involvement of cortico-cerebellar circuits in the pathophysiology of mood dysregulation.


Changes in bone metabolic profile associated with pregnancy or lactation.
Calcium and nutrients are transferred from mothers to fetuses or infants during pregnancy or lactation, respectively, promoting metabolic changes in the mother, many uncharacterized. To evaluate these changes, we undertook two parallel studies. In one we analyzed fourteen clinical cases of vertebral fragility fractures, at or before three months after partum, in mothers who breastfed their infants. In the other, we enrolled 79 additional pregnant subjects, some who chose to breastfeed and others who did not, and analyzed changes in bone metabolic status starting between 34 and 36 weeks of gestation and ending one month after partum. In the larger group, bone-resorbing and bone-forming parameters such as serum TRACP5b and osteocalcin, respectively, significantly increased after partum. Among parameters that changed after partum, serum PTH and the bone-resorbing markers serum TRACP5b and urine NTX were significantly higher in mothers who only breastfed infants compared to mothers who fed infants formula or a mix of both. However, bone-forming parameters were comparable between breastfeeding and non-breast-feeding groups after partum, suggesting that elevated bone-resorption occurs only in the breastfeeding group. Radiographic analysis after partum demonstrated that no subject among the 79 analyzed showed vertebral fractures, even those who breastfed exclusively. Among fracture cases analyzed, subjects exhibited significantly lower bone mineral density than did non-fracture cases in breastfeeding-only subjects. We conclude that bone metabolic status significantly changes over the period between pregnancy and post-partum lactation, and that low bone mineral density seen in a small subset of breastfeeding-only cases likely causes post-partum vertebral fragility fractures.


Rapid Determination of Amino Acids of Nitraria tangutorum Bobr. from the Qinghai-Tibet Plateau Using HPLC-FLD-MS/MS and a Highly Selective and Sensitive Pre-Column Derivatization Method.
Amino acids are indispensable components of living organisms. The high amino acid content in Nitraria tangutorum Bobr. fruit distinguishes it from other berry plants and is of great significance to its nutritional value. Herein, using 10-ethyl-acridine-3-sulfonyl chloride as a fluorescent pre-column labeling reagent, a method for the efficient and rapid determination of amino acid content in N. tangutorum by pre-column fluorescence derivatization and on-line mass spectrometry was established and further validated. The limits of detection (signal-to-noise ratio = 3) were between 0.13 and 1.13 nmol/L, with a linear coefficient greater than 0.997 and a relative standard deviation between 1.37% and 2.64%. In addition, the method required a short analysis time, separating 19 amino acids within 20 min. Subsequently, the method was used to analyze the amino acid content of Nitraria tangutorum Bobr. from tissues retrieved from seven regions of the Qinghai-Tibet Plateau. Nitraria tangutorum Bobr. was shown to contain a large amount of amino acids, with the total content and main amino acid varying between the different tissues. This research supports the nutritional evaluation, quality control, and development and utilization of Nitraria tangutorum Bobr.


Autologous peripheral blood stem cell transplantation for multiple myeloma: a report of 259 cases from the Spanish Registry. Spanish Registry for Transplant in MM (Grupo Español de Trasplante Hematopoyético-GETH) and PETHEMA.
Between January 1989 and November 1995, 259 patients with multiple myeloma (MM), 22 stage I, 57 stage II and 180 stage III at diagnosis were treated with myeloablative high-dose therapy followed by autologous peripheral blood stem cell (PBSC) transplantation. The median time from diagnosis to transplantation was 17 months (6-112). At the time of transplant, 56 patients were in CR, 153 in PR, 25 were nonresponders and 25 had progressive disease. Mobilization of stem cells was performed with G-CSF alone in 141 cases, chemotherapy plus G-CSF in 65, chemotherapy plus GM-CSF in 36 and chemotherapy alone in 17 patients. The conditioning regimen consisted of high-dose melphalan alone in 96 patients, melphalan plus TBI in 73, busulfan plus melphalan in 56, busulfan plus cyclophosphamide in 27 and cyclophosphamide plus TBI in seven. The median durations of neutropenia (>0.5 x 10(9)/l) and thrombocytopenia (>20 x 10(9)/l) were 12 (5-118) and 13 days (5-360), respectively. Transplant-related mortality occurred in 11 patients (4%). Once a stable graft was achieved, 114 patients (44%) received maintenance treatment with recombinant alpha interferon (IFN-alpha). Among the 248 patients evaluable for response 125 (51%) had a CR and 100 had a PR (40%). The median duration of progression-free survival (PFS) and overall survival (OS) after transplantation was 23 and 35 months, respectively. Univariate analysis showed that response status pretransplant, only one line of primary induction treatment and IFN-alpha maintenance treatment post-transplant significantly influenced OS. Female sex, pretransplant responsive disease, and treatment with IFN-alpha post-transplant were the factors significantly influencing PFS. The conditioning regimen and method of stem cell mobilization had no significant impact on OS and PFS. On multivariate analysis the only independent factors associated with a longer survival were the number of chemotherapy courses prior to autologous PBSC transplantation and the pretransplant response status. The present analysis from the Spanish Registry confirms the feasibility of autologous PBSC transplantation in myeloma patients with a very low toxicity (4% toxic deaths). The high complete response rate after transplantation is encouraging. The best results are obtained when the procedure is performed early after the first line of induction therapy and in patients with chemosensitive disease. Whether early high-dose therapy followed by autotransplantation in responding patients is superior to conventional chemotherapy is currently being investigated in prospective randomized studies.


A systemic approach to cancer treatment: tumor cell reprogramming focused on endocrine-related cancers.
The term "cancer cell reprogramming" is used to define any kind of intervention aimed at transforming cancer cells into terminally differentiated cells. Using this approach, new technologies have been applied with different methods for a more systemic approach to cancer treatment. This review reports on advances of these technologies, including our personal contributions, mainly carried out on endocrine-related cancers. Some of the interventions, aimed at reverting cancer cells into a normal phenotype, are based on the evidence that tumor development is suppressed by the embryonic microenvironment. On the basis of this rationale, experiments have been conducted using stem cell differentiation stage factors (SCDSFs) taken at different stages of development of Zebrafish embryos, oocyte extracts, or naïve human umbilical cord matrix derived stem cells (UMDSCs). SCDSFs induce significant growth inhibition on different tumor cell lines in vitro, likely because of increases in cell cycle regulatory molecules, such as p53 and pRb. Treatment with these factors activates apoptosis and differentiation related to caspase-3. This is achieved via p73 apoptotic-dependent pathway activation with a concurrent normalization of the E-cadherin and beta-catenin ratio. Extracts from prophase amphibian oocytes could reprogram relevant epigenetic alterations in MCF-7 and HCC1954 breast cancer cell lines, while un-engineered (naïve) human UMDSCs attenuated growth of MDA-231 human breast carcinoma cells. A product prepared for human treatments, containing SCDSFs at very low doses, yielded favorable results in breast cancer and in intermediate-advanced hepatocellular carcinoma. Other reprogramming interventions used in the models of breast, prostate and ovarian cancer cell lines are described. Finally, current and future perspectives of this novel technology are discussed and a new hallmark of cancer is suggested: the loss of differentiation of cancer cells.


[Enhanced regeneration of terminal axons after hyperbaric oxygen therapy in a patient resembling progressive postpoliomyelitis muscular atrophy].
We found an electromyographical proof of reconstruction of the motor nerve terminals following hyperbaric oxygen therapy. A 38-year-old man who had been partially recovered for thirty four months from acute onset paraplegia following a gastrointestinal infection developed progressive muscular atrophy and weakness of the lower limbs, and was first admitted to our hospital. Cerebrospinal fluid examination was normal and nerve conduction studies showed small compound muscle action potentials without an evidence of segmental demyelination. There were ample fibrillation potentials on electromyography. Single fiber electromyography (SFEMG) showed increased fiber density, abnormal jitter and blockings without neurogenic jitter, which were similar to findings in post-poliomyelitis syndrome. He was treated by hyperbaric oxygen consisting of two hour exposures to pressures of two atmospheres breathing 100% oxygen. These exposures continued for a month daily, and thereafter once a week for one year. Clinical improvement of the weakness and a decrease in amount of fibrillation potentials occurred on and after a month after treatment. We found significant changes on SFEMG a year later. There were increased fiber densities and decreased mean values of consecutive differences. These changes indicate diminished degeneration and enhanced regeneration of the terminal axons. We think that hyperbaric oxygen has a beneficial effect on oxygen metabolism of remaining motoneurons which may not be able to maintain excessive metabolic demands of all their sprouting axons.


Nitric oxide flow tagging in unseeded air.
A scheme for molecular tagging velocimetry is presented that can be used in air flows without any kind of seeding. The method is based on the local and instantaneous creation of nitric oxide (NO) molecules from N(2) and O(2) in the waist region of a focused ArF excimer laser beam. This NO distribution is advected by the flow and can be visualized any time later by laser-induced fluorescence in the gamma bands. The creation of NO is confirmed by use of an excitation spectrum. Two examples of the application of the new scheme for air-flow velocimetry are given in which single laser pulses are used for creation and visualization of NO.


High cell density media for Escherichia coli are generally designed for aerobic cultivations - consequences for large-scale bioprocesses and shake flask cultures.
For the cultivation of Escherichia coli in bioreactors trace element solutions are generally designed for optimal growth under aerobic conditions. They do normally not contain selenium and nickel. Molybdenum is only contained in few of them. These elements are part of the formate hydrogen lyase (FHL) complex which is induced under anaerobic conditions. As it is generally known that oxygen limitation appears in shake flask cultures and locally in large-scale bioreactors, function of the FHL complex may influence the process behaviour. Formate has been described to accumulate in large-scale cultures and may have toxic effects on E. coli.Although the anaerobic metabolism of E. coli is well studied, reference data which estimate the impact of the FHL complex on bioprocesses of E. coli with oxygen limitation have so far not been published, but are important for a better process understanding. Two sets of fed-batch cultures with conditions triggering oxygen limitation and formate accumulation were performed. Permanent oxygen limitation which is typical for shake flask cultures was caused in a bioreactor by reduction of the agitation rate. Transient oxygen limitation, which has been described to eventually occur in the feed-zone of large-scale bioreactors, was mimicked in a two-compartment scale-down bioreactor consisting of a stirred tank reactor and a plug flow reactor (PFR) with continuous glucose feeding into the PFR.In both models formate accumulated up to about 20 mM in the culture medium without addition of selenium, molybdenum and nickel. By addition of these trace elements the formate accumulation decreased below the level observed in well-mixed laboratory-scale cultures. Interestingly, addition of the extra trace elements caused accumulation of large amounts of lactate and reduced biomass yield in the simulator with permanent oxygen limitation, but not in the scale-down two-compartment bioreactor. The accumulation of formate in oxygen limited cultivations of E. coli can be fully prevented by addition of the trace elements selenium, nickel and molybdenum, necessary for the function of FHL complex. For large-scale cultivations, if glucose gradients are likely, the results from the two-compartment scale-down bioreactor indicate that the addition of the extra trace elements is beneficial. No negative effects on the biomass yield or on any other bioprocess parameters could be observed in cultures with the extra trace elements if the cells were repeatedly exposed to transient oxygen limitation.


Persisting growth after prophylactic single-screw epiphysiodesis in upper femoral epiphysis.
Prophylactic fixation of the contralateral hip in cases of slipped upper femoral epiphysis is controversial. Therefore, using a single-cannulated screw has been widely accepted. However, differing reports exist on the occurrence of persisting growth after prophylactic epiphysiodesis. The aim of this retrospective study was to evaluate the presence of persisting growth of the upper femoral epiphysis after prophylactic fixation. From 2006 until 2009, 11 children underwent prophylactic pinning using a single-cannulated 6.5-mm cancellous screw. Time to fusion, persisting growth, and overgrowing of the screw were measured on plain radiographs taken postoperatively and at least after the growth plate was fused. All patients except 1 (91%) showed a persisting growth of the epiphysis, and in 2 cases a hardware replacement was necessary. The mean increase of the femoral neck length was 8.2% (SEM 1.46%). Mean follow-up was 37 months (range, 12 to 49 mo). All patients had a Risser sign grade 0 at the time of surgery, and equal or less than grade 3, when the growth plate was fused. Despite previous reports that a prophylactic fixation using a single-cannulated cancellous screw is unproblematic and safe, we showed that in our series growth persistence was the rule and in some cases the physeal overgrowth necessitates a hardware replacement. Careful follow-up until fusion of the growth plate should be recommended.


Icatibant in hereditary angioedema: news and challenges.
Hereditary angioedema (HAE) is a rare condition. Its prognosis depends on whether there is laryngeal involvement with a risk of asphyxia, which is present in 25% of such cases. Improved understanding of the pathophysiology of this disease has resulted in the development of targeted therapies including icatibant, which acts as an antagonist at bradykinin B2 receptors. This agent has been shown to be effective in the treatment of attacks of HAE in three Phase III randomized double-blind published studies. Efficacy data have been collected in all types of attack: cutaneous, abdominal and laryngeal. Safety data are also encouraging. Icatibant is administered subcutaneously, with the potential for patients to self-administer. In the future, this therapy may offer increased independence for HAE patients.


A question of time: the land snail Murella muralis (Gastropoda: Pulmonata) reveals constraints on past ecological speciation.
The lively debate about speciation currently focuses on the relative importance of factors driving population differentiation. While many studies are increasingly producing results on the importance of selection, little is known about the interaction between drift and selection. Moreover, there is still little knowledge on the spatial-temporal scales at which speciation occurs, that is, arrangement of habitat patches, abruptness of habitat transitions, climate and habitat changes interacting with selective forces. To investigate these questions, we quantified variation on a fine geographical scale analysing morphological (shell) and genetic data sets coupled with environmental data in the land snail Murella muralis, endemic to the Mediterranean island of Sicily. Analysis of a fragment of the mitochondrial DNA cytochrome oxidase I gene (COI) and eight nuclear microsatellite loci showed that genetic variation is highly structured at a very fine spatial scale by local palaeogeographical events and historical population dynamics. Molecular clock estimates, calibrated here specifically for Tyrrhenian land snails, provided a framework of palaeogeographical events responsible for the observed geographical variations and migration routes. Finally, we showed for the first time well-documented lines of evidence of selection in the past, which explains divergence of land snail shell shapes. We suggest that time and palaeogeographical history acted as constraints in the progress along the ecological speciation continuum. Our study shows that testing for correlation among palaeogeography, morphology and genetic data on a fine geographical scale provides information fundamental for a detailed understanding of ecological speciation processes.


Structure and behaviour of vesicles in the presence of colloidal particles.
This review highlights recent studies that investigate the structural changes and behaviour of synthetic vesicles when they are exposed to colloidal particles. We will show examples to demonstrate the power of combining particles and vesicles in generating exciting supracolloidal structures. These suprastructures have a wide range of often responsive behaviours that take advantage of both the mechanical and morphological support provided by the vesicles and the associated particles with preset functionality. This review includes applications spanning a variety of disciplines, including chemistry, biology, physics and medicine.


Four-wave mixing in a rapidly-spun fiber.
In a previous paper the generalized Schroedinger equation that governs wave propagation in a rapidly-spun fiber was derived. In this paper the aforementioned equation is used to study four-wave mixing (FWM). The properties of FWM associated with a rapidly-spun fiber are described, and contrasted to those associated with constantly-birefringent and randomly-birefringent fibers. FWM driven by perpendicular linearly-polarized pump waves, or counter-rotating circularly-polarized pump waves, provides polarization-independent signal amplification and phase-conjugation, whereas FWM driven by co-rotating circularly-polarized pump waves provides polarization-independent frequency conversion.


Mental health nurses responding to suffering in the 21st century occidental world: accompanying people in their search for meaning.
Much of contemporary health and mental health practice pays little attention to suffering, and when it does, invariably suffering is conflated with pain. Within such views, the health care practitioner ought to be concerned with removing or stopping the suffering as, for many parts of the occidental world at least, suffering is regarded as antagonistic to the pursuit of happiness. However, it has been recognized since ancient times that the experience of suffering can give rise to growth. This view sees suffering as an inevitable aspect of the human condition and experience; as something that might need to be endured, minimized, relieved, explored for meaning and maybe even learned from. The former conceptualization of suffering leaves little, if any, room for the sufferer to be to be proud of his suffering and to consider it ennobling rather than degrading, and such views are highly congruent with the increased pathologizing of 'everyday life' and with that, the inexorable proliferation of pharmacological 'treatment'. Accordingly, we assert that there is a clear need for Psychiatric/Mental Health nurses to re-think their views of suffering and consider how they might help the person discover meaning in the experience; how they might accompany the individual on his/her suffering journey. We therefore identify a range of approaches and interventions that Psychiatric/Mental Health nurses can use when attempting to help those experiencing mental health-related suffering.


A nonviral peptide can replace the entire N terminus of zucchini yellow mosaic potyvirus coat protein and permits viral systemic infection.
Systematic deletion and peptide tagging of the amino-terminal domain (NT, ~43 amino acids) of an attenuated zucchini yellow mosaic potyvirus (ZYMV-AGII) coat protein (CP) were used to elucidate its role in viral systemic infection. Deletion mutants truncated by 8, 13, and 33 amino acid residues from the CP-NT 5' end were systemically infectious and produced symptoms similar to those of the AGII virus. Tagging these deletion mutants with either human c-Myc (Myc) or hexahistidine peptides maintained viral infectivity. Similarly, addition of these peptides to the intact AGII CP-NT did not affect viral life cycle. To determine which parts, if any, of the CP-NT are essential for viral systemic infection, a series of Myc-tagged mutants with 8 to 43 amino acids removed from the CP-NT were constructed. All Myc-tagged CP-NT deletion mutants, including those from which virtually all the viral CP-NT had been eliminated, were able to encapsidate and cause systemic infection. Furthermore, chimeric viruses with deletions of up to 33 amino acids from CP-NT produced symptoms indistinguishable from those caused by the parental AGII virus. In contrast to CP-NT Myc fusion, addition of the foot-and-mouth disease virus (FMDV) immunogenic epitope to AGII CP-NT did not permit systemic infection. However, fusion of the Myc peptide to the N terminus of the FMDV peptide restored the capability of the virus to spread systemically. We have demonstrated that all CP-NT fused peptides were exposed on the virion surface, masking natural CP immunogenic determinants. Our findings demonstrate that CP-NT is not essential for ZYMV spread and that it can be replaced by an appropriate foreign peptide while maintaining systemic infectivity.


Racial differences in neuromyelitis optica spectrum disorder.
We aimed to evaluate racial differences in the clinical features of neuromyelitis optica spectrum disorder. This retrospective review included 603 patients (304 Asian, 207 Caucasian, and 92 Afro-American/Afro-European), who were seropositive for anti-aquaporin-4 antibody, from 6 centers in Denmark, Germany, South Korea, United Kingdom, United States, and Thailand. Median disease duration at last follow-up was 8 years (range 0.3-38.4 years). Asian and Afro-American/Afro-European patients had a younger onset age than Caucasian patients (mean 36, 33, and 44 years, respectively; p < 0.001). During the disease course, Caucasian patients (23%) had a lower incidence of brain/brainstem involvement than Asian (42%) and Afro-American/Afro-European patients (38%) (p < 0.001). Severe attacks (visual acuity ≤0.1 in at least one eye or Expanded Disability Status Scale score ≥6.0 at nadir) at onset occurred more frequently in Afro-American/Afro-European (58%) than in Asian (46%) and Caucasian (38%) patients (p = 0.005). In the multivariable analysis, older age at onset, higher number of attacks before and after immunosuppressive treatment, but not race, were independent predictors of severe motor disabilities at last follow-up. A review of a large international cohort revealed that race affected the clinical phenotype, age at onset, and severity of attacks, but the overall outcome was most dependent on early and effective immunosuppressive treatment.


Enterocyte actin autoantibody detection: a new diagnostic tool in celiac disease diagnosis: results of a multicenter study.
This study describes a new method to detect autoantibodies against actin filaments (AAA) as a serological marker of intestinal villous atrophy (IVA) in celiac disease (CD), and reports the results of an Italian double-blind multicenter study. IgA-AAA were analyzed by immunofluorescence using a newly developed method based on intestinal epithelial cells cultured in presence of colchicine. IgA-AAA were blindly evaluated prospectively in 223 antiendomysial antibody (AEA) and/or antitransglutaminase antibody (TGA) positive subjects and in 78 AEA and TGA negative subjects. IgA-AAA positive patients underwent an intestinal biopsy to confirm the diagnosis. Moreover, IgA-AAA were retrospectively investigated in 84 biopsy-proven CD patients and in 2,000 new consecutively collected serum samples from AEA and TGA negative nonbiopsied subjects. IgA-AAA were positive in 98.2% of the CD patients with flat mucosa, in 89% with subtotal villous atrophy, and in 30% with partial villous atrophy. IgA-AAA were present in none of the AEA and TGA negative nonbiopsied controls. In AEA and/or TGA positive CD patients IgA-AAA positivity significantly correlated with IVA (p < 0.000 in the prospective study, p = 0.005 in the retrospective study). In the prospective study, the values of sensitivity, specificity, the positive predictive value, the negative predictive value, and the efficiency of the IgA-AAA test to identify patients with IVA were, respectively, 83.9%, 95.1%, 97.8%, 69.2%, and 87.0%. Furthermore, a significant correlation (p < 0.0001) was found between the IgA-AAA serum titre and the degree of IVA (rs 0.56). The results of this multicenter study show that the new method for IgA-AAA detection could represent a practical diagnostic tool in AEA and/or TGA positive subjects, which would be especially useful when IVA shows a patchy distribution, when the histological picture is difficult to interpret, or when a biopsy could represent a life-threatening risk.


Survivin' Acute Myeloid Leukaemia-A Personalised Target for inv(16) Patients.
Despite recent advances in therapies including immunotherapy, patients with acute myeloid leukaemia (AML) still experience relatively poor survival rates. The Inhibition of Apoptosis (IAP) family member, survivin, also known by its gene and protein name, Baculoviral IAP Repeat Containing 5 (BIRC5), remains one of the most frequently expressed antigens across AML subtypes. To better understand its potential to act as a target for immunotherapy and a biomarker for AML survival, we examined the protein and pathways that BIRC5 interacts with using the Kyoto Encyclopedia of Genes and Genomes (KEGG), search tool for recurring instances of neighbouring genes (STRING), WEB-based Gene Set Analysis Toolkit, Bloodspot and performed a comprehensive literature review. We then analysed data from gene expression studies. These included 312 AML samples in the Microarray Innovations In Leukemia (MILE) dataset. We found a trend between above median levels of BIRC5 being associated with improved overall survival (OS) but this did not reach statistical significance (p = 0.077, Log-Rank). There was some evidence of a beneficial effect in adjusted analyses where above median levels of BIRC5 were shown to be associated with improved OS (p = 0.001) including in Core Binding Factor (CBF) patients (p = 0.03). Above median levels of BIRC5 transcript were associated with improved relapse free survival (p < 0.0001). Utilisation of a second large cDNA microarray dataset including 306 AML cases, again showed no correlation between BIRC5 levels and OS, but high expression levels of BIRC5 correlated with worse survival in inv(16) patients (p = 0.077) which was highly significant when datasets A and B were combined (p = 0.001). In addition, decreased BIRC5 expression was associated with better clinical outcome (p = 0.004) in AML patients exhibiting CBF mainly due to patients with inv(16) (p = 0.007). This study has shown that BIRC5 expression plays a role in the survival of AML patients, this association is not apparent when we examine CBF patients as a cohort, but when those with inv(16) independently indicating that those patients with inv(16) would provide interesting candidates for immunotherapies that target BIRC5.


[The fight against AIDS among adolescent girls: the impact of the 2003 Carnival campaign by the Brazilian Ministry of Health].
In 2003, the Brazilian Ministry of Health launched a nationwide campaign aimed at promoting condom use by adolescent girls. The "Carnival Campaign" was broadcast on television and radio from February 16 to March 3 and targeted adolescent girls (13-19 years), a group which had shown an increase in the number of cases of AIDS and other sexually transmitted diseases. The MoH hired Kelly Key, a Brazilian pop singer, to star the television and radio ads and deliver the campaign message. One of the objectives was to empower girls and encourage them not to be ashamed of purchasing condoms or of demanding that their partners use them. The article presents the results of a nationwide survey with 1,006 adolescent girls in 86 municipalities, sponsored by the MoH. The results show that campaign materials reached the main target public and were evaluated in a very positive light. Finally, the survey data show that the Carnival Campaign had important effects, stimulating discussions in the adolescent social environment and reinforcing positive attitudes towards condom use.


Assessment of changes in hemostatic markers in Cavalier King Charles Spaniels with myxomatous mitral valve disease.
To evaluate markers of hemostasis and their relationship to the degree of mitral regurgitation (MR) and platelet function in Cavalier King Charles Spaniels (CKCSs) with myxomatous mitral valve disease. 76 clinically healthy CKCSs and 24 control dogs. All dogs underwent echocardiographic examination; various hemostatic, hematologic, and biochemical variables were evaluated in blood. The CKCSs were allocated to 1 of 3 groups on the basis of MR severity. In 8 control dogs and 8 CKCSs, plasma von Willebrand factor (vWF) multimer analysis was performed. Compared with control dogs, plasma fibrinogen concentration was higher in all CKCSs and related to left ventricular end diastolic diameter and left atrial-to-aortic root ratio among all CKCSs. The activated partial thromboplastin times and plasma D-dimer concentration were similar among the 4 groups. Plasma vWF concentration was lower in CKCSs with moderate to severe MR, compared with that of CKCSs with no MR and control dogs. There was a relationship between plasma vWF concentration and platelet function in CKCSs but not in control dogs. In 4 CKCSs with moderate to severe MR and low plasma vWF concentration, amounts of vWF high-molecular-weight multimers (HMWMs) were low. In CKCSs, MR appeared to be associated with a low plasma vWF concentration and likely a loss of vWF HMWMs (possibly through their destruction via shear stress to the blood). The importance of the changes in plasma fibrinogen concentration and the thromboembolic risk in dogs with MR remain to be investigated.


Prostatic stromal sarcoma with neuroectodermal differentiation.
Prostatic stromal sarcoma is a fairly rare tumor that constitutes approximately 0.1-0.2% of all prostatic cancers. Detailed characteristics of the tumor are still unclear due to its rarity.We describe a case of prostatic stromal sarcoma in a 63 year-old man who suffered from urinary obstructive symptoms. Palliative transuterine resection was performed and the preliminary histopathological diagnosis was neuroendocrine carcinoma. After chemotherapy, total pelvic exenteration was performed. Histopathologically, the tumor was composed of monotonously proliferating small to medium-sized round cells, which existed in compact islands with loose or dense fibrovascular networks. Immunohistochemically, the tumor cells were widely positive for vimentin, CD56, CD99 and focally positive for synaptophysin, CD10, progesterone receptor, desmin and CD34, but negative for EMA, cytokeratin, estrogen receptor, S-100 and myoglobin. Most of the previously reported tumors exhibited positive stainability for CD10 and progesterone receptor. In addition to these markers, expressions of CD56, CD99 and synaptophysin were characteristically detected in our case. To the best of our knowledge, we present the first case of prostatic stromal sarcoma with characteristic immunohistochemical staining properties. Although the biological characteristics of this rare tumor have not yet been elucidated, these findings suggest prostatic stromal sarcoma can potentially show neuroectodermal differentiation. The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/7291874028051262.


TEAD mediates YAP-dependent gene induction and growth control.
The YAP transcription coactivator has been implicated as an oncogene and is amplified in human cancers. Recent studies have established that YAP is phosphorylated and inhibited by the Hippo tumor suppressor pathway. Here we demonstrate that the TEAD family transcription factors are essential in mediating YAP-dependent gene expression. TEAD is also required for YAP-induced cell growth, oncogenic transformation, and epithelial-mesenchymal transition. CTGF is identified as a direct YAP target gene important for cell growth. Moreover, the functional relationship between YAP and TEAD is conserved in Drosophila Yki (the YAP homolog) and Scalloped (the TEAD homolog). Our study reveals TEAD as a new component in the Hippo pathway playing essential roles in mediating biological functions of YAP.


Predictors of Inadequate Weight Loss After Laparoscopic Gastric Bypass for Morbid Obesity.
Laparoscopic Roux-en-Y gastric bypass (LRYGB) is an effective treatment for morbid obesity resulting in approx. 70% excess weight loss (EWL) at 1-2 years. The aim of this study was to identify factors predictive of inadequate EWL following primary LRYGB. Data on consecutive patients who underwent primary LRYGB between September 2009 and March 2013 were collected prospectively. The effects of age, gender, baseline body mass index (BMI), preoperative EWL, length of time between initial consultation and surgery (TtS), presence of diabetes mellitus (DM), arthritis, obstructive sleep apnea (OSA) and postoperative length of hospital stay (LOS) on EWL at 12 months were studied. General linear regression models were used to evaluate group differences in EWL and to assess independent associations between baseline variables and EWL at 12 months. Stepwise regression analyses were used to estimate individual contributions of independent variables to the variance in EWL at 12 months. In this study, inadequate EWL was defined as <50% EWL at 12 months. LRYGB was performed in 227 patients with a mean ± SD age and BMI of 48.6 ± 11 years and 53.6 ± 7.1 kg/m2, respectively. Female to male ratio was 3:1. EWL at 12 months had an inverse correlation with age (p = 0.01), baseline BMI (p < 0.001), TtS (p = 0.001), OSA (p = 0.039) and DM (p = 0.039). Conversely, there was a significant positive association between preoperative EWL and that at 12 months (p = 0.009). There was no effect of gender, arthritis or LOS on EWL at 12 months. Multiple regression analysis demonstrated inadequate EWL at 12 months to be predicted by older age (>60 years), patients with diabetes, higher baseline BMI (>60), those who gained weight preoperatively and in patients who waited longer than 18 months for surgery (p = 0.027). Preoperative factors that predict inadequate EWL at 12 months following primary LRYGB include higher initial BMI, older age, presence of DM and preoperative weight gain. Identification of these factors preoperatively should aid in providing intensive support to these at-risk patient groups.


Acidic Residues Control the Dimerization of the N-terminal Domain of Black Widow Spiders' Major Ampullate Spidroin 1.
Dragline silk is the most prominent amongst spider silks and comprises two types of major ampullate spidroins (MaSp) differing in their proline content. In the natural spinning process, the conversion of soluble MaSp into a tough fiber is, amongst other factors, triggered by dimerization and conformational switching of their helical amino-terminal domains (NRN). Both processes are induced by protonation of acidic residues upon acidification along the spinning duct. Here, the structure and monomer-dimer-equilibrium of the domain NRN1 of Latrodectus hesperus MaSp1 and variants thereof have been investigated, and the key residues for both could be identified. Changes in ionic composition and strength within the spinning duct enable electrostatic interactions between the acidic and basic pole of two monomers which prearrange into an antiparallel dimer. Upon naturally occurring acidification this dimer is stabilized by protonation of residue E114. A conformational change is independently triggered by protonation of clustered acidic residues (D39, E76, E81). Such step-by-step mechanism allows a controlled spidroin assembly in a pH- and salt sensitive manner, preventing premature aggregation of spider silk proteins in the gland and at the same time ensuring fast and efficient dimer formation and stabilization on demand in the spinning duct.


Endoscopic Transforaminal and Lateral Recess Decompression After Previous Spinal Surgery.
Leg pain and back pain after lumbar laminectomy and spinal decompression fusion surgery are common and often related to persistent lumbar foraminal or lateral recess stenosis. Although persistent symptoms often stem from incomplete decompression during the primary index surgery, recurrent symptoms may also be the result of intervertebral cage subsidence due to loss of intervertebral and neuroforaminal height. The aim of this study was to investigate the feasibility of using the outpatient transforaminal decompression procedure as an alternative to inpatient open procedure in revision decompression surgery, with the intent of minimizing the incidence of perioperative and postoperative surgical complications while reducing both direct and indirect costs of surgical treatment, shortening time to patient postoperative narcotic independence, and shortening time of patient return to daily activities. A total of 48 patients with conclusive diagnostic imaging and interventional workup underwent endoscopic transforaminal and lateral recess decompression for both persistent or recurrent leg and/or low back pain following previous lumbar laminectomy (22 patients) or decompression fusion surgery (26 patients). In addition to radiographic studies, patients were followed for a minimum of 2 years postoperatively, and clinical outcomes were evaluated with the visual analog scale (VAS), Oswestry Disability Index (ODI), and modified Macnab criteria. At final follow-up, patients with single- and 2-level prior surgeries reported an average ODI reduction following their secondary surgery of 44.6%, with an average final score of 14.8. Less favorable ODI score reductions following secondary surgery (23.8%) were reported by patients who had more than one or a complex prior multilevel surgery. According to the modified Macnab criteria, "excellent" and "good" results were obtained with the secondary surgery in 79.1% (38 of 48) of patients with no more than a single 1- or 2-level prior lumbar surgery. The mean VAS score decreased from 7.7 ± 1.8 preoperatively to 2.3 ± 1.1 at final follow-up (P < .01). Fair and poor results with the secondary surgery were seen in 20.9% (10 of 48) of patients with several prior surgeries or complex multilevel previous lumbar surgeries. The level distribution for secondary surgery was as follows: L4-5 segment (26 levels; 54.1%), L5-S1 (14 levels; 29.2%), L3-4 (7 levels; 14.6%), and the L2-3 level (1 level; 2.1%). Postoperative complications were limited to irritation of the dorsal root ganglion, which occurred in 25% (12 of 48) of patients. There were no wound infections, nerve root injuries, foot drop, or admissions to a hospital for further postoperative care. All patients with "excellent" and "good" outcomes measured by modified Macnab criteria, who were working before and after the primary and secondary surgeries (27 of 38), reported earlier return to work after the endoscopic outpatient surgery (2.6 ± 0.8 weeks) than with the prior inpatient open spinal surgery (8.1 ± 4.5 weeks). Based on the 2012 Medicare fee schedule for professional fees, direct costs were 40.6% and indirect costs were 37.1% lower with the secondary endoscopic surgery compared with primary open surgery. Transforaminal decompression is an effective alternative to open revision lumbar spinal surgery to treat symptomatic spinal stenosis after previous lumbar surgery in patients with persistent or recurrent leg and low back pain. It can be safely done in an outpatient setting, while realizing savings in direct and indirect costs.


First Report of Powdery Mildew Caused by Oidium hortensiae on Mophead Hydrangea in Korea.
Hydrangea macrophylla (Thunb.) Ser., known as mophead hydrangea, is native to Japan and is used as a potted ornamental or is planted for landscaping in gardens worldwide. In May 2011, powdery mildew occurred on potted mophead hydrangea cv. Emerald plants in polyethylene-film-covered greenhouses in Icheon, Korea. Heavily infected plantings were unmarketable, mainly due to purplish red discoloration and crinkling of leaves. Such powdery mildew symptoms on mophead hydrangea in gardens had been often found in Korea since 2001, and the collections (n = 10) were deposited in the Korea University herbarium (KUS). In all cases, there was no trace of chasmothecia formation. Mycelium was effuse on both sides of leaves, young stems, and flower petals. Appressoria were well developed, lobed, and solitary or in opposite pairs. Conidiophores were cylindrical, 70 to 145 × 7.5 to 10 μm, and composed of three to four cells. Foot-cells of conidiophores were straight to sub-straight, cylindric, short, and mostly less than 30 μm long. Conidia produced singly were ellipsoid to oval, 32 to 50 × 14 to 22 μm with a length/width ratio of 1.7 to 2.8, lacked fibrosin bodies, and showed angular/rectangular wrinkling of outer walls. Germ tubes were produced on the perihilar position of conidia. Primary conidia were apically conical, basally rounded to subtruncate, 32 to 42 × 14 to 18 μm, and thus generally smaller than the secondary conidia. The morphological characteristics are consistent with previous descriptions of Oidium hortensiae Jørst. (3,4). To confirm the identification, the complete internal transcribed spacer (ITS) region of rDNA from KUS-F25514 was amplified with primers ITS5 and P3 and directly sequenced. The resulting sequence of 694 bp was deposited in GenBank (Accession No. JQ669944). There was no ITS sequence data known from powdery mildews on Hydrangea. Therefore, this is the first sequence of O. hortensiae submitted to GenBank. Nevertheless, a GenBank BLAST search of this sequence showed >99% similarity with those of Oidium spp. recorded on crassulacean hosts (e.g. GenBank Accession Nos. EU185641 ex Sedum, EU185636 ex Echeveria, and EU185639 ex Dudleya) (2), suggesting their close phylogenetic relationship. Pathogenicity was confirmed through inoculation by gently pressing diseased leaves onto leaves of five healthy potted mophead hydrangea cv. Emerald plants. Five noninoculated plants of the same cultivar served as controls. Plants were maintained in a greenhouse at 22 ± 2°C. Inoculated plants developed signs and symptoms after 6 days, whereas the control plants remained healthy. The fungus present on the inoculated plants was morphologically identical to that originally observed on diseased plants, fulfilling Koch's postulates. Occurrence of powdery mildew disease on mophead hydrangea is circumglobal (1). To our knowledge, this is the first report of powdery mildew disease caused by O. hortensiae on mophead hydrangea in Korea. Powdery mildew infections in Korea pose a serious threat to the continued production of quality potted mophead hydrangea in polyethylene-film-covered greenhouses. References: (1) D. F. Farr and A. Y. Rossman. Fungal Databases, Systematic Mycology and Microbiology Laboratory, ARS, USDA. Retrieved March 19, 2012, from http://nt.ars-grin.gov/fungaldatabases/ . (2) B. Henricot. Plant Pathol. 57:779, 2008. (3) A. Schmidt and M. Scholler. Mycotaxon 115:287, 2011. (4) S. Tanda. J. Agric. Sci. Tokyo Univ. Agric. 43:253, 1999.


Glucose recovery with bare and hydrogel-coated microdialysis probes: experiment and simulation of temporal effects.
In vitro microdialysis glucose sampling was used to test the transient and steady-state suitability of antifouling hydrogel coatings, composed of 2-hydroxyethyl methacrylate, vinylpyrrolidinone, and poly(ethylene glycol). The in vitro glucose diffusion coefficients of bare microdialysis membranes and hydrogel coatings were determined experimentally to be 1.1 x 10-6 and 3.2 x 10-6 cm2/s, respectively. These values were used to numerically simulate the effect of the hydrogel on glucose transport across the microdialysis membrane using a convection-diffusion transport model. The times for dialysate at the exit of the bare and hydrogel-coated microdialysis probes to reach 95% of steady state were calculated to be 20 and 66 s, respectively. However, the experimental data showed that 95% of steady-state glucose recoveries were reached after 4-5 min. Numerical simulations incorporating the Taylor dispersion in the outlet tubing showed the time difference was caused almost completely by convective transport in the outlet tubing with negligible contribution from analyte profile broadening. These data indicated that the hydrogel coatings imposed 44% reduction in glucose permeability and consequently 26% reduction in the percent recovery. The effect of hydrogel coatings on the time to reach the steady-state recovery was insignificant compared with the time required for convection of glucose in the outlet tubing.


[Epidural abscess due to a Mycobacterium tuberculosis strain with primary resistance to isoniazid and ethambutol].
Tuberculosis is primarily characterized by pulmonary involvement, however, one third of the cases exhibit extrapulmonary tuberculosis. In this report, a case of epidural abscess due to Mycobacterium tuberculosis with primary resistance to isoniazid and ethambutol was presented. A 57-year-old male patient was admitted to emergency service with ten days history of weakness in legs, disability of walking and fever. Neurological examination revealed paraplegia of lower extremities, numbness distal to T2 disc level and hyperactivity of deep tendon reflexes indicating transverse myelitis. Laboratory findings were as follows; ESR: 74 mm/hour, CRP: 22 g/L, ALT: 42 IU/L, AST: 45 IU/L and white blood cell count 23.000/mm3 (45% polymorphonuclear leukocyte, 45% lymphocyte, 10% monocyte). Spinal magnetic resonance imaging showed a fusiform abscess localized at anterior epidural space and extending along levels of C5-6 and C6-7. The longitudinal dimension of the abscess was 3 cm. The lesion was hypointense on T1 and hyperintense on T2 weighted MRI images with prominent rim shaped contrast enhancement on contrast-enhanced T1-weighted images. At fourth day of hospitalization the patient underwent neurosurgical management. M.tuberculosis was isolated from the cultures of operation material by Mycobacteria Growth Incubator Tube system (MGIT, BBL; BD, USA) on the 12th day. The isolate was found susceptible to streptomycin and rifampisin, but resistant to isoniazid and ethambutol. The treatment was initiated with rifampicin 600 mg/day, pyrazinamid 2 g/day, ethambutol 1.5 g/day and levofloxacin 500 mg/day. At the end of second month levofloxacin 500 mg/day and rifampisin 600 mg/day combination was sustained and total treatment period was planned as nine months. As far as the national literature was considered, this was the first case of extrapulmonary tuberculosis with primary resistance to isoniazid and ethambutol.