Orientation-selective responses in the mouse lateral geniculate nucleus.
The dorsal lateral geniculate nucleus (dLGN) receives visual information from the retina and transmits it to the cortex. In this study, we made extracellular recordings in the dLGN of both anesthetized and awake mice, and found that a surprisingly high proportion of cells were selective for stimulus orientation. The orientation selectivity of dLGN cells was unchanged after silencing the visual cortex pharmacologically, indicating that it is not due to cortical feedback. The orientation tuning of some dLGN cells correlated with their elongated receptive fields, while in others orientation selectivity was observed despite the fact that their receptive fields were circular, suggesting that their retinal input might already be orientation selective. Consistently, we revealed orientation/axis-selective ganglion cells in the mouse retina using multielectrode arrays in an in vitro preparation. Furthermore, the orientation tuning of dLGN cells was largely maintained at different stimulus contrasts, which could be sufficiently explained by a simple linear feedforward model. We also compared the degree of orientation selectivity in different visual structures under the same recording condition. Compared with the dLGN, orientation selectivity is greatly improved in the visual cortex, but is similar in the superior colliculus, another major retinal target. Together, our results demonstrate prominent orientation selectivity in the mouse dLGN, which may potentially contribute to visual processing in the cortex.


Networking among women snowboarders: a study of participants at an International Woman Snowboard Camp.
The article focuses on women snowboarders' networking and relationships with national snowboard associations and commercial organizers. The study was conducted at an International Women Snowboard Camp, which attracted women snowboarders from five different countries. A qualitative interview was undertaken with participants from each country, eight in total, plus an interview with one of the organizers (a woman). The results indicate that participants from the Nordic countries adopt a more proactive stand to promote snowboarding by organizing specific groups in relation to national associations, particularly the Norwegians and the Finnish. Furthermore, some collaboration across national boarders appeared. The only Swedish participant was associated with several snowboarding communities; whereas the Italian (only one) and the Latvian snowboarders had links with commercial organizers, apparently male dominated in structure. The findings are discussed in the light of Castells' network theory and identity construction in social movements, and gender perspectives. The participants' doing/undoing gender reveals different strategies in negotiating hegemonic masculinity and the power structure in the organizations. Narratives from the Nordic participants reflect undoing gender that impacts on identity constructions in terms of project and/or resistance identity. The Italians and Latvians seemingly do gender while undertaking a subordinate position in the male-dominated structure.


Duration of postlaparoscopic pneumoperitoneum.
Patients who present with abdominal pain after recent laparoscopic surgery present a diagnostic dilemma when pneumoperitoneum is present. Previous studies do not define the duration of postlaparoscopic pneumoperitoneum. In this study, we attempted to define the duration of laparoscopic pneumoperitoneum and to identify factors which affect resolution time. We followed 57 patients who underwent laparoscopic cholecystectomy (34), inguinal herniorraphy (20), or appendectomy (three). Serial abdominal films were taken until all residual gas was resolved. Thirty patients resolved their pneumoperitoneum within 24 h; 16 patients resolved between 24 h and 3 days; nine patients resolved between 3 and 7 days; two patients resolved between 7 and 9 days. Mean resolution time for all patients was 2.6 +/- 2.1 days. There was no apparent difference in resolution time between the three types of procedures; however, the sample size may be insufficient. Duration of the pneumoperitoneum did not correlate with gender, age, weight, initial volume of CO2 used, length of time for the procedure, or postoperative complications. Sixteen patients had bile spillage during cholecystectomy which significantly reduced the duration of postoperative pneumoperitoneum (p < 0.008), resulting in a mean resolution time of 1.3 +/- 0.9 days. While 14 patients reported postoperative shoulder pain, no correlation was found between the presence or duration of shoulder pain and the extent or duration of pneumoperitoneum. We conclude that the residual pneumoperitoneum following laparoscopic surgery resolves within 3 days in 81% of patients and within 7 days in 96% of patients. The resolution time was significantly less in patients sustaining intraoperative bile spillage during cholecystectomy. There was no correlation found between postoperative shoulder pain and the presence or duration of the pneumoperitoneum.


Targeted stimulation of the vagus nerve reduces renal injury in female mice with systemic lupus erythematosus.
Pharmacological stimulation of the vagus nerve has been shown to suppress inflammation and reduce blood pressure in a murine model of systemic lupus erythematosus (SLE) that is characterized by hypertension, inflammation, renal injury and dysautonomia. The present study aims to directly stimulate vagal nerves at the level of the dorsal motor nucleus of the vagus (DMV) using designer receptors exclusively activated by designer drugs (DREADDs) to determine if there is similar protection and confirm mechanism. Female NZBWF1/J (SLE) mice and NZW/LacJ mice (controls, labeled as NZW throughout) received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or control virus into the DMV at 31 weeks of age. After two weeks of recovery and viral transfection, the DREADD agonist clozapine-N-oxide (CNO; 3 mg/kg) was injected subcutaneously for an additional 14 days. At 35 weeks, mean arterial pressure (MAP; mmHg) was increased in SLE mice compared to NZW mice, but selective activation of DMV neurons did not significantly alter MAP in either group. SLE mice had higher indices of renal injury including albumin excretion rate (μg/day), glomerulosclerosis index, interstitial fibrosis, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) compared to NZW mice. Selective DMV neuronal activation reduced albumin excretion rate, glomerulosclerosis, interstitial fibrosis, and NGAL in SLE mice but not NZW mice. Together, these data indicate that selective activation of neurons within the DMV by DREADD protects the kidney suggesting an important role of vagus-mediated pathways in the progression of renal injury in SLE.


Experiences of persons with type II diabetes receiving health coaching: an exploratory qualitative study.
The objective of this exploratory qualitative study was to examine the experience of persons living with type II diabetes who participated in a health coaching intervention. The researchers used a qualitative phenomenological hermeneutic research design to explore the experiences of people undergoing health coaching for self-management of their diabetes. Qualitative data analysis resulted in three themes that best described participants' experience of health coaching for diabetes: (1) "the driving force," which described how health coaches helped clients to find powerful motivators for change; (2) "I'm not a child," which described how people wanted to be treated by the health coaches; and (3) "meeting the inner coach," which described how health coaches helped clients develop their own inner wisdom. The participants' descriptions of coaching challenge a more traditional paradigm of expert-driven and information-laden diabetes education practices. The findings suggest that the process of health coaching may help persons with diabetes become confident self-managers of their diabetes.


The relationship of the ESR1 gene polymorphisms with the presence of coronary artery disease determined by coronary angiography.
Effects of estrogen on the cardiovascular system, mediated mainly by estrogen receptor type alpha (ER alpha), have been well-defined and specific polymorphisms in the ER alpha gene (ESR1) have been associated with several coronary heart diseases including coronary artery disease (CAD) in studies covering different populations. In the present study, we aimed to investigate whether there is an association between two of the known polymorphisms in the ESR1, named c.454-397T>C and c.454-351A>G, and CAD in a Turkish population. One hundred sixty eight patients with CAD and 99 patients without CAD were included in the study. The ESR1 c.454-397T>C and c.454-351A>G polymorphisms were studied by the conventional polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. While no association was found between the c.454-351A>G polymorphism and CAD, the c.454-397T>C genotype distributions were statistically significant independent of known risk factors between CAD-positive (CAD+) and CAD-negative (CAD-) groups (p = 0.001). TT genotype was more frequent in CAD- group than in CAD+ group, 22.2% and 4.8%, respectively. CC genotype was associated with increased risk of CAD (p = 0.001) compared to the TT genotype. When comparing the distribution of CC + TC genotypes to that of TT genotype in CAD+ and CAD- groups, the frequency of CC + TC genotypes showed a significant increase independent of known CAD risk factors in CAD+ subjects (p = 0.001). As a conclusion, a statistically significant relationship between the ESR1 c.454-397T>C polymorphism and CAD were found independent of known CAD risk factors in a Turkish population.


Accuracy of Kvaal's radiographic and translucent dentinal root techniques of extracted teeth in Malay adults for dental age estimation.
The use of teeth to estimate the age of unknown bodies provides much help especially in skeletal remains with no soft tissues left for identification. However, dental age estimation utilizing degenerative changes in teeth like dentinal translucency is often hampered with large margin of error. This study aims to compare the accuracy of Kvaal's radiographic method (intraoral periapical radiograph) with modified Bang-Ramm dentinal root translucency method in estimating dental age in Malay adults. One-hundred teeth of maxillary and mandibular incisors and canine were collected following dental extraction. Date of birth, date of extraction, gender and ethnicity were documented prior to extraction. All teeth were assessed using two methods of dental age estimation: 1) The equation from Kvaal's radiographic method and 2) Formula from modified Bang-Ramm dentinal root translucency method. The results from the age estimation were compared to the chronological age of the persons from whom the teeth were extracted. The average dental age estimated using both methods significantly correlated with the chronological age for both men and women. Overestimation and underestimation with mean absolute error up to 13 years and 15 years was observed in modified Bang-Ramm and Kvaal, respectively. The estimated age calculated from both methods also showed increasing standard deviation as the patient gets older. From the obtained results it is reasonable to conclude that modified Bang-Ramm method gives better accuracy for dental age estimation in Malay adults.


Randomly phased geometrical laser array.
A novel geometrical laser array is presented in which high far-field intensities can be generated without phase control of the laser elements. The array was analyzed by randomly varying the phasing of the elements and calculating the maximum far-field intensity. In the worst possible phasing conditions, the maximum far-field intensity remained high and was nearly constant with regard to the number of array elements. By increasing the geometrical spacing factor, the maximum intensity will approach that of a perfectly phased array.


Purification and characterization of a membrane-associated 48-kilodalton phospholipase A(2) in leaves of broad bean.
Several lines of evidence indicate that phospholipase A(2) (PLA(2)) plays a crucial role in plant cellular responses through production of linolenic acid, the precursor of jasmonic acid, from membrane phospholipids. Here we report the purification and characterization of a 48-kD PLA(2) from the membrane fractions of leaves of broad bean (Vicia faba). The plant PLA(2) was purified to near homogeneity by sequential column chromatographies from the membrane extracts. The purified 48-kD protein migrated as a single band on a SDS-PAGE gel and its density correlated with the PLA(2) activity. It was further confirmed that this 48-kD protein is the PLA(2) enzyme based on immunoprecipitating the activity with a monoclonal antibody against it and purifying the enzyme to homogeneity with the antibody affinity column. The purified plant PLA(2) preferred 2-linolenoyl-sn-glycerol-3-phosphocholine (GPC) to 2-linoleoyl-GPC, 2-palmitoyl-GPC and 2-arachidonyl-GPC as substrates with a pH optimum at pH 7.0 to 8.0. The plant PLA(2) was activated by calmodulin and inhibited by pretreatment of 5,8,11, 14-eicosatetraynoic acid known as an inhibitor of mammalian PLA(2)s. The enzyme was characterized as a Ca(2+)-independent PLA(2) different from mammalian PLA(2)s. This membrane-associated and Ca(2+)-independent PLA(2) is suggested to play an important role in the release of linolenic acid, the precursor of jasmonic acid, through a signal transduction pathway.


Visibility of MRI prostate lesions on B-mode transrectal ultrasound.
Prostate biopsies are usually done with transrectal ultrasound (TRUS) in B-mode (B TRUS) but multiparametric MRI (mpMRI) is the gold imaging standard for the visualization of clinically significant prostate cancer (PCa), since a lowPCa detection rate is reported for B TRUS. The aim of this study was to assess the visibility of MRI lesions on B TRUS and to determine which factors may influence the visibility on B TRUS. 142 men with 148 lesions reported on mpMRI underwent a B TRUS/mpMRI fusion targeted biopsy of the prostate and were included in this retrospective study. During the biopsy, images were obtained and stored in the institution's PACS. These images were reviewed by two radiologists to determine, whether an mpMRI lesion was or was not visible on B TRUS. Overall 92 from 148 mpMRI lesions (62.2%) were visible on B TRUS. The location of the lesion in the prostate, the PIRADS classification of the lesions and the size of the lesion had no significant influence on the visibility on B TRUS. Only the prostate volume had a significant influence on visibility: in smaller prostates significantly more lesions were visible on B TRUS than in large glands (p+0.041; 45.1 ml vs 54 ml). The use of newer high-end ultrasound units as well as experience gained from fusion biopsies enables us to see 62.2 % of all suspicious mpMRI lesions on B TRUS. B TRUS images merit a thorough examination during a conventional biopsy setting.


[Preoperative spontaneous regression of type B3 thymoma;report of a case].
A 65-year-old man experiencing chest oppression was admitted to our hospital. Contrast-enhanced chest computed tomography (CT) showed a 71×52-mm cystic mass with an enhanced wall in the thymus. The CT-guided needle biopsy of the tumor only revealed the presence of necrotic tissue. However, the tumor spontaneously decreased in size significantly to 33×21 mm in 2 months. The patient underwent right hemi-lobectomy of the thymus, which showed necrotic tissue in the center of the mass;the fibrotic cystic wall included several masses of type B3 thymoma cells( so called" well-differentiated thymic carcinoma", Masaoka stage II). Because of avoiding local recurrence, extended thymectomy including lymph node resection was additionally performed. The patient received radiation therapy postoperatively and has shown no sign of recurrence in 3 years of follow-up care.


Evaluation of adhesive bonding of lithium disilicate ceramic material with duel cured resin luting agents.
The purpose of this vitro study was to comparatively evaluate the adhesive bonding of dual cured resin luting agents with lithium disilicate ceramic material. Porcelain laminate veneers were prepared with lithium disilicate ceramic material i.e. IPS Empress II( E-Max Press). These laminates were bonded with RelyX ARC, Panavia F 2.0, Variolink II, Duolink and Nexus NX3.The porcelain laminates were etched with 9.6% hydrofluoric acid (Pulpdent Corporation) for one minute, washed for 15 sec with three way syringe and dried for 15 sec with air syringe. The silane (Ultradent) was applied with the help of applicator tip in a single coat and kept undisturbed for one minute. The prepared surfaces of the premolars were treated with 37% phosphoric acid (Prime dent) for 15 sec, thoroughly rinsed and dried as per manufactures instructions. The shear bond test was carried out on all samples with the Universal testing machine (Instron U.S.A.) The scanning electron microscopic study was performed at the fractured interface of representative samples from each group of luting agents. In this study, the highest value of shear bond strength was obtained for NEXUS NX3 and the lowest for VARIOLINK II. The difference in bond strength can be interpreted as the difference in fracture resistance of luting agents, to which shearing load was applied during the shear bond strength test. It is inferred from this study that the composition of the luting agent determines the adhesive characteristics in addition to surface treatment and bonding surface area.


Bilateral abdominal cryptorchidism in males: autotransplantation of the testis.
5 patients with bilateral abdominal cryptorchidism are reported. Orthotopic autotransplantation of the right testis was performed in 4 cases and both testes in 1 case. Testicular vessels were anastomosed end-to-end with the inferior epigastric vessels. The ischemic testes were cooled to 20 degrees C. The vas was mobilized intact. We discuss the expediency of this organ-preserving operation, the type of vascular anastomosis and the use of local hypothermia.


IFN-λ4: the paradoxical new member of the interferon lambda family.
Interferons (IFNs) are generally considered antiviral cytokines, yet the newly discovered IFN-λ4 is linked with the failure to clear hepatitis C virus (HCV) infection either spontaneously or in response to treatment. IFN-λ4 can be generated only by individuals who carry the IFNL4-ΔG allele (rs368234815), which is the strongest known host factor for predicting clearance of HCV. The ancestral IFNL4-ΔG allele is the major variant in Africans while the minor variant in Asians, suggesting very strong negative genetic selection for this allele-most likely driven by an infectious agent other than HCV. IFN-λ4 most closely resembles IFN-λ3, but these proteins share only 29% amino-acid identity, and, in contrast to IFN-λ3, IFN-λ4 is only weakly secreted. Nevertheless, IFN-λ4 signals through the IFN-λ receptor complex and induces expression of IFN-stimulated genes via the Janus kinase-signal transducer and activator of transcription signaling pathway. Although the IFNL4-ΔG variant is strongly associated with the failure to clear HCV infection, HCV-infected patients who carry this allele have lower baseline HCV RNA levels in the absence of treatment. Resolving the paradoxical functions of IFN-λ4, which appears to induce antiviral activity yet impair effective clearance of HCV, may yield critical new insights into the immunologic response to HCV infection and IFN biology.


Continuing Medical Education Speakers with High Evaluation Scores Use more Image-based Slides.
Although continuing medical education (CME) presentations are common across health professions, it is unknown whether slide design is independently associated with audience evaluations of the speaker. Based on the conceptual framework of Mayer's theory of multimedia learning, this study aimed to determine whether image use and text density in presentation slides are associated with overall speaker evaluations. This retrospective analysis of six sequential CME conferences (two annual emergency medicine conferences over a three-year period) used a mixed linear regression model to assess whether post-conference speaker evaluations were associated with image fraction (percentage of image-based slides per presentation) and text density (number of words per slide). A total of 105 unique lectures were given by 49 faculty members, and 1,222 evaluations (70.1% response rate) were available for analysis. On average, 47.4% (SD=25.36) of slides had at least one educationally-relevant image (image fraction). Image fraction significantly predicted overall higher evaluation scores [F(1, 100.676)=6.158, p=0.015] in the mixed linear regression model. The mean (SD) text density was 25.61 (8.14) words/slide but was not a significant predictor [F(1, 86.293)=0.55, p=0.815]. Of note, the individual speaker [χ2(1)=2.952, p=0.003] and speaker seniority [F(3, 59.713)=4.083, p=0.011] significantly predicted higher scores. This is the first published study to date assessing the linkage between slide design and CME speaker evaluations by an audience of practicing clinicians. The incorporation of images was associated with higher evaluation scores, in alignment with Mayer's theory of multimedia learning. Contrary to this theory, however, text density showed no significant association, suggesting that these scores may be multifactorial. Professional development efforts should focus on teaching best practices in both slide design and presentation skills.


The neurogenesis of P1 and N1: A concurrent EEG/LFP study.
It is generally recognised that event related potentials (ERPs) of electroencephalogram (EEG) primarily reflect summed post-synaptic activity of the local pyramidal neural population(s). However, it is still not understood how the positive and negative deflections (e.g. P1, N1 etc) observed in ERP recordings are related to the underlying excitatory and inhibitory post-synaptic activity. We investigated the neurogenesis of P1 and N1 in ERPs by pharmacologically manipulating inhibitory post-synaptic activity in the somatosensory cortex of rodent, and concurrently recording EEG and local field potentials (LFPs). We found that the P1 wave in the ERP and LFP of the supragranular layers is determined solely by the excitatory post-synaptic activity of the local pyramidal neural population, as is the initial segment of the N1 wave across cortical depth. The later part of the N1 wave was modulated by inhibitory post-synaptic activity, with its peak and the pulse width increasing as inhibition was reduced. These findings suggest that the temporal delay of inhibition with respect to excitation observed in intracellular recordings is also reflected in extracellular field potentials (FPs), resulting in a temporal window during which only excitatory post-synaptic activity and leak channel activity are recorded in the ERP and evoked LFP time series. Based on these findings, we provide clarification on the interpretation of P1 and N1 in terms of the excitatory and inhibitory post-synaptic activities of the local pyramidal neural population(s).


Gaussian quadrature as a numerical integration method for estimating area under the curve.
This paper presents a numerical integration method for estimating the area under the curve (AUC) over the infinite time interval. This method is based on the Gauss-Laguerre quadrature and produces AUC estimates over the infinite time interval without extrapolation in a usual sense. By contrast, in traditional schemes, piecewise interpolation is used to obtain the area up to the final sampling point, and the remaining portion is extrapolated using nonlinear regression. In this case, there is no theoretical consistency between the quadrature and extrapolation. The inconsistency may cause certain problems. For example, the optimal sampling criterion for the former is not necessarily optimal for the latter. Such inconsistency does not arise in the method of this work. The sampling points are placed near the zeros of Laguerre polynomials so as to directly estimate the AUC over the infinite time interval. The sampling design requires no particular prior information. This is also advantageous over the previous strategy, which worked by minimizing the variance of estimated AUC under the assumptions of particular pharmacokinetic and variance functions. The original Gaussian quadrature is believed to be inappropriate for numerical integration of data because of several restrictions. In this paper, it is shown that, using a simple strategy for managing errors due to these restrictions, the method produces an estimate of AUC with practically sufficient precision. The efficacy of this method is finally shown by numerical simulations in which the bias and variance of its estimate were compared with those of the previous methods such as the trapezoidal, log-trapezoidal, Lagrange, and parabolas-through-the-origin methods.


Active anionic zero-valent palladium catalysts: characterization by density functional calculations.
This works uses DFT (B3LYP/LACVP*(+)//B3LYP/LACVP* level) to ascertain the existence of the tricoordinate, anionic zero-valent palladium complexes that were postulated as the active species in the catalytic cycles of Pd-catalyzed Heck and cross-coupling reactions. The variety of complexes studied (1 and 2), include [Pd(PR(3))(2)X](-) species, in which R=H, Me, vinyl, and phenyl, and X=Cl, Br, I, AcO, and TFA, as well as bidentate complexes, [Pd[Ph(2)P(CH(2))(n)Ph(2)P]X](-), in which X=Cl, AcO and n=3-6. The study shows that these complexes exist as distinct minima in the gas phase as well as in THF. In addition, it provides geometric features and Pd--X(-) dissociation energies for all these complexes as well as some NMR and IR data, which show a clear distinction in these features between the tri- and dicoordinate Pd(0) species. An orbital interaction model and perturbation theory arguments account for the bonding mechanism and rationalize all the trends in the stability of the Pd--X bond. These trends include the effects of variation of X, R, and the length of the linker in the bidentate ligands.


Volumetric determination of placental and uterine growth relationships from B-mode ultrasound by serial area-volume determinations.
Serial area-volume determinations may be made from B-mode ultrasonography. Multiple sonographic sections are taken through a structure of interest. The area of the structure of interest is determined on each sonographic section by a form of planimetry and multiplied by the step-interval to obtain the volume of the structure of interest between sonographic sections. The total volume of the structure of interest is the sum of the individual volumes. The volume is computed from both transverse and longitudinal images and an average obtained for improved accuracy. Total intrauterine volume and placental volume were determined by the serial area-volume method in 63 normal patients and the results were analyzed. Placental and total intrauterine volumes were also determined for five cases of intrauterine growth retardation. Although there is some error in the serial area-volume method, the initial evaluation of five cases with intrauterine growth retardation suggests a greater precision and accuracy than volume estimates based on prolate ellipsoid geometry. Placental volume may provide an acceptable parameter to screen for intrauterine growth retardation.


The accessory function of murine intercellular adhesion molecule-1 in T lymphocyte activation. Contributions of adhesion and co-activation.
These studies demonstrate that the murine intercellular adhesion molecule-1 (ICAM-1) performs at least two roles in enhancing T cell activation. These two roles are evident in both of our experimental systems: with ICAM-1 expressed on the surface of transfected fibroblast cells, and with purified ICAM-1 immobilized on plastic. First, as has been documented by many investigators, ICAM-1 mediates adhesion between ICAM-1- and lymphocyte function-associated Ag-1 (LFA-1)-bearing cells. This adhesive interaction occurs even in the absence of T cell stimulation, although it is increased by addition of phorbol ester and calcium ionophore. Although ICAM-1 expression does markedly increase intercellular adhesion, the increase is significantly less than the improvement ICAM-1 expression makes in the Ag-presenting ability of MHC class II-transfected fibroblast cells. We have investigated whether this difference is due to LFA-1-mediated signaling, and we present data that demonstrates that although ICAM-1 does not deliver costimulatory signals required for T cell activation, the interaction of LFA-1 with ICAM-1 does synergize with TCR-transduced signals. This synergy is observed for ICAM-1 on live and on chemically fixed accessory cells, and for purified ICAM-1 molecules, but in all cases occurs only when the ICAM-1 and the TCR ligands are on the same surface. Finally, when the ICAM-1 is present on the surface of accessory cells, it enhances T cell activation by changing the Ag dose-dependence of the T cell, but when ICAM-1 and CD3 mAb are co-immobilized, ICAM-1 increases the peak response of the T cell without affecting the dose dependence of the response.


Endomyocardial biopsy-integrating electrode at the bioptome tip.
The addition of electroanatomic mapping to a standard echo-guided endomyocardial biopsy could identify areas of abnormal pathology and increase the diagnostic yield of the procedure. In this demonstration of a novel technique, a 45-year-old woman with clinical suspicion for cardiac sarcoidosis underwent right ventricular bipolar electroanatomical mapping with identification of areas of signal fractionation and low voltage. A bioptome, configured to record an electrogram from the tip, was then visualized on the three-dimensional electroanatomic mapping (3DEAM) system, and directed to these areas. The biopsy was assisted by the use of a steerable introducer sheath, and by recording unipolar and extended bipolar signals from the bioptome tip. A prominent change in the signal was detected by the electrode at the bioptome tip when the jaws closed on the endomyocardial tissue. Patient tolerated the procedure without complications, and the biopsied samples were appropriate for pathological analysis. Using existing technology, the 3DEAM, which integrates unipolar and bipolar signal from the bioptome tip, is feasible, and can be safely added to a standard echocardiographically guided endomyocardial biopsy. Future studies should investigate whether such a technique could increase the safety and diagnostic yield of endomyocardial biopsies in patients with suspected cardiomyopathies.


Severe acute respiratory syndrome coronavirus pathogenesis, disease and vaccines: an update.
A novel coronavirus has recently been identified as the cause of severe acute respiratory syndrome (SARS-CoV). The ability of this family of positive strand RNA viruses to move between species and cause severe disease in humans, with the potential for pandemic spread, has been confirmed. An understanding of the disease and its pathogenesis and the genetics of coronavirus infections, as well as strategies to treat or prevent coronavirus infections, are essential. The history of coronavirus vaccines and the occurrence of laboratory-associated SARS-CoV infections underscore the need for stably attenuated strains of SARS-CoV and other coronaviruses. Rapid progress has been made in understanding the clinical disease of SARS in adults and children. In adults, systemic infection with clinical and biochemical abnormalities, as well as respiratory infection, may be the rule. SARS is much milder in children younger than 12 years old than it is in adolescents and adults. In children age 12 years and younger, symptoms are generally nonspecific and cold-like. Numerous approaches to the development of SARS-CoV vaccines have been undertaken, and there is evidence that antibodies to the spike protein may be protective from replication and pathology in animal models. The availability of reverse genetic systems has made it possible to engineer and recover coronavirus variants that contain multiple genetically stable mutations that grow well in culture but are attenuated for replication, virulence or both. Such variants will be platforms for the safe growth of SARS-CoV and candidates for live attenuated vaccines.


Self-assembled capsules based on tetrafunctionalized calix[4]resorcinarene cavitands.
Calix[4]resorcinarene-based cavitands with a bowl-shaped aromatic cavity are widely used as scaffolds for covalently bound and self-assembled capsules. There are two main categories of calix[4]resorcinarene-based cavitands that are tetrafunctionalized at the upper (wider) rim: one category includes derivatives that have functionalized bridges between pairs of hydroxy groups of the calix[4]resorcinarene, and the second category includes derivatives with functional groups at the 2-position on the resorcinol ring and the methylene bridge between pairs of hydroxy groups. This review describes capsular self-assemblies of the latter type of methylene-bridge cavitands, which are formed through hydrogen bonds, metal-coordination bonds, and dynamic covalent bonds.


Subcellular localization and purification of a p-hydroxyphenylpyruvate dioxygenase from cultured carrot cells and characterization of the corresponding cDNA.
p-Hydroxyphenylpyruvate dioxygenase catalyses the transformation of p-hydroxyphenylpyruvate into homogentisate. In plants this enzyme has a crucial role because homogentisate is the aromatic precursor of all prenylquinones. Furthermore this enzyme was recently identified as the molecular target for new families of potent herbicides. In this study we examine precisely the localization of p-hydroxyphenylpyruvate dioxygenase activity within carrot cells. Our results provide evidence that, in cultured carrot cells, p-hydroxyphenylpyruvate dioxygenase is associated with the cytosol. Purification and SDS/PAGE analysis of this enzyme revealed that its activity is associated with a polypeptide of 45-46 kDa. This protein specifically cross-reacts with an antiserum raised against the p-hydroxyphenylpyruvate dioxygenase of Pseudomonas fluorescens. Gel-filtration chromatography indicates that the enzyme behaves as a homodimer. We also report the isolation and nucleotide sequence of a cDNA encoding a carrot p-hydroxyphenylpyruvate dioxygenase. The nucleotide sequence (1684 bp) encodes a protein of 442 amino acid residues with a molecular mass of 48094 Da and shows specific C-terminal regions of similarity with other p-hydroxyphenylpyruvate dioxygenases. This cDNA encodes a functional p-hydroxyphenylpyruvate dioxygenase, as evidenced by expression studies with transformed Escherichia coli cells. Comparison of the N-terminal sequence of the 45-46 kDa polypeptide purified from carrot cells with the deduced peptide sequence of the cDNA confirms that this polypeptide supports p-hydroxyphenylpyruvate dioxygenase activity. Immunodetection studies of the native enzyme in carrot cellular extracts reveal that N-terminal proteolysis occurs during the process of purification. This proteolysis explains the difference in molecular masses between the purified protein and the deduced polypeptide.


Effects of thermal denaturation on the solid-state structure and molecular mobility of glycinin.
The effects of moisture and thermal denaturation on the solid-state structure and molecular mobility of soy glycinin powder were investigated using multiple techniques that probe over a range of length and time scales. In native glycinin, increased moisture resulted in a decrease in both the glass transition temperature and the denaturation temperature. The sensitivity of the glass transition temperature to moisture is shown to follow the Gordon-Taylor equation, while the sensitivity of the denaturation temperature to moisture is modeled using Flory's melting point depression theory. While denaturation resulted in a loss of long-range order, the principal conformational structures as detected by infrared are maintained. The temperature range over which the glass to rubber transition occurred was extended on the high temperature side, leading to an increase in the midpoint glass transition temperature and suggesting that the amorphous regions of the newly disordered protein are less mobile. (13)C NMR results supported this hypothesis.


Discoidin I and discoidin II are localized differently in developing Dictyostelium discoideum.
The distribution of discoidin I and discoidin II, developmentally regulated lectins in Dictyostelium discoideum, was determined immunohistochemically at various stages of development. Discoidin I was first prominent as focal clumps in aggregating cells, then accumulated on the surface of aggregates and around them. Discoidin II became prominent later and ultimately localized in what appear to be prespore vesicles. The results indicate that discoidin I and discoidin II have different and possibly multiple functions.


Efficacy of interferon-gamma in patients with refractory bullous pemphigoid.
Bullous pemphigoid (BP) usually responds well to conventional therapies, although some severe cases show less response to various therapies or develop side-effects due to long-term drug administration using high doses. Most BP patients are elderly and are thus prone to systemic deterioration or unfavorable outcome. In the present study, we investigated the efficacy of interferon-gamma on severe BP patients resistant to conventional therapies. Interferon-gamma was administered to 10 severe BP patients at a dose of 2 million Japan reference units (JRU) once a day for 7 consecutive days by i.v. infusion in addition to oral corticosteroids. The degree of improvement in the clinical symptoms, serum interleukin (IL)-4, IL-5, and plasma RANTES concentrations, as well as the results of indirect immunofluorescence and BP180 enzyme-linked immunosorbent assay index values, were compared before and after the 7-day drug administration. Among the nine patients whose clinical symptoms were evaluated, an improvement was observed in all patients. Except for one patient, the serum IL-4 concentrations decreased and similar results were observed for the serum IL-5 concentration. All five patients in whom the plasma RANTES concentration was measured showed decreased levels. The indirect immunofluorescence titers decreased in only four patients. However, in seven patients in whom index values of BP180 enzyme-linked immunosorbent assay were evaluated, all patients showed significant decrease of the index values. These results suggest that, in severe BP patients refractory to conventional therapies, interferon-gamma in addition to oral corticosteroids is effective and thus should be considered for further clinical use.


Prevalence and phylogenetic analysis of human enteric emerging viruses in porcine stool samples in the Republic of Korea.
Emerging infectious diseases (EID) in humans and animals are proving to be a serious health concern. This study investigated the prevalence of emerging or re-emerging human enteric viruses in porcine stools and swabs. Eleven enteric EID viruses were selected as target viruses for the current study and ranked based on their impact on public health and food safety: enterovirus (EV), hepatitis E virus, norovirus GI and GII, sapovirus (SaV), adenovirus (AdV), astrovirus, rotavirus, hepatitis A virus, aichivirus, and bocavirus. Using real-time RT-PCR or real-time PCR, EID viruses were detected in 129 (86.0%) of 150 samples. The most prevalent virus was EV, which was detected in 68.0% of samples, followed by AdV with a detection rate of 38.0%. In following sequencing and phylogenetic analyses, 33.0% (58/176) of the detected viruses were associated with human enteric EID viruses, including AdV-41, coxsackievirus-A2, echovirus-24, and SaV. Our results show that porcine stools frequently contain human enteric viruses, and that few porcine enteric viruses are genetically related to human enteric viruses. These findings suggest that enteric re-emerging or EID viruses could be zoonoses, and that continuous monitoring and further studies are needed to ensure an integrated "One Health" approach that aims to balance and optimize the health of humans, animals, and ecosystems.


Selectivity and plasticity in a sound-evoked male-male interaction in Drosophila.
During courtship, many animals, including insects, birds, fish, and mammals, utilize acoustic signals to transmit information about species identity. Although auditory communication is crucial across phyla, the neuronal and physiologic processes are poorly understood. Sound-evoked chaining behavior, a display of homosexual courtship behavior in Drosophila males, has long been used as an excellent model for analyzing auditory behavior responses, outcomes of acoustic perception and higher-order brain functions. Here we developed a new method, termed ChaIN (Chain Index Numerator), in which we use a computer-based auto detection system for chaining behavior. The ChaIN system can systematically detect the chaining behavior induced by a series of modified courtship song playbacks. Two evolutionarily related Drosophila species, Drosophila melanogaster and Drosophila simulans, exhibited dramatic selective increases in chaining behavior when exposed to specific auditory cues, suggesting that auditory discrimination processes are involved in the acceleration of chaining behavior. Prolonged monotonous pulse sounds containing courtship song components also induced high intense chaining behavior. Interestingly, the chaining behavior was gradually suppressed over time when song playback continued. This behavioral change is likely to be a plastic behavior and not a simple sensory adaptation or fatigue, because the suppression was released by applying a different pulse pattern. This behavioral plasticity is not a form of habituation because different modality stimuli did not recover the behavioral suppression. Intriguingly, this plastic behavior partially depended on the cAMP signaling pathway controlled by the rutabaga adenylyl cyclase gene that is important for learning and memory. Taken together, this study demonstrates the selectivity and behavioral kinetics of the sound-induced interacting behavior of Drosophila males, and provides a basis for the systematic analysis of genes and neural circuits underlying complex acoustic behavior.


Increased fructose intake as a risk factor for dementia.
The transition in the world age demographic toward older age is associated with an increased risk of neurodegenerative diseases, such as Alzheimer's disease. Risk profiles for dementia may also be changing. Obesity and type 2 diabetes have increased in prevalence in the last half-century and have been associated with increased dementia risk. Specific changes in nutrition may also represent a direct risk. A diet transition in the United States has occurred in the intake of refined sugar, particularly high-fructose corn syrup (HFCS) from a yearly estimate of 8.1 kg/person at the beginning of the XIX century to a current estimate of 65 kg/person. This article considers the association between refined sugar intake, markers of cardiovascular disease risk, and the possible promotion of the development of dementia.


Offshore multi-purpose platforms for a Blue Growth: A technological, environmental and socio-economic review.
"Blue Growth" and "Blue Economy" is defined by the World Bank as: "the sustainable use of ocean resources for economic growth, improved livelihoods and jobs, while preserving the health of ocean ecosystem". Multi-purpose platforms (MPPs) can be defined as offshore platforms serving the needs of multiple offshore industries (energy and aquaculture), aim at exploiting the synergies and managing the tensions arising when closely co-locating systems from these industries. Despite a number of previous projects aimed at assessing, from a multidisciplinary point of view, the feasibility of multipurpose platforms, it is here shown that the state-of-the-art has focused mainly on single-purpose devices, and adopting a single discipline (either economic, or social, or technological, or environmental) approach. Therefore, the aim of the present study is to provide a multidisciplinary state of the art review on, whenever possible, multi-purpose platforms, complementing it with single-purpose and/or single discipline literature reviews when not possible. Synoptic tables are provided, giving an overview of the multi-purpose platform concepts investigated, the numerical approaches adopted, and a comprehensive snapshot classifying the references discussed by industry (offshore renewables, aquaculture, both) and by aspect (technological, environmental, socio-economic). The majority of the multi-purpose platform concepts proposed are integrating only multiple offshore renewable energy devices (e.g. hybrid wind-wave), with only few integrating also aquaculture systems. MPPs have significant potential in economizing CAPEX and operational costs for the offshore energy and aquaculture industry by means of concerted spatial planning and sharing of infrastructure.


Multistate licensure: a new regulatory concept.
With the transformation of the health care delivery system, the traditional and time-honored method of state-by-state licensure may be in need of modification. Revising the current licensure system involves some risk and many challenges to licensing boards, which are charged by state legislatures to protect the public welfare and safety through enforcement of practice acts. What components of the current licensure system will be maintained and how will the system adapt in response to the increasing pressure from employers and licensees to create a more flexible, expedient and responsive system?


Oligonucleotide probes complementary to variable regions of ribosomal RNA discriminate between Mycoplasma species.
On the basis of information from computer-assisted sequence comparison of the Mycoplasma pneumoniae 16S ribosomal RNA (rRNA) sequences with sequences from various other mycoplasmal and bacterial species, we constructed M. pneumoniae-specific oligonucleotide probes complementary to variable regions in the 16S rRNA molecule. Using a DNA/RNA dot blot hybridization procedure, it was possible to detect less than 1 X 10(3) mycoplasmas. This test is a most sensitive assay for species-specific detection of bacteria. It can easily be adapted for detection and identification of other bacterial species and may have wide medical and industrial application.


Remote ischaemic conditioning and ischaemic heart disease.
As clinical evidence builds regarding the efficacy of remote ischaemic conditioning's ability to attenuate myocardial injury arising from acute coronary syndromes and cardiac surgery, this article describes the conditioning phenomenon, current clinical evidence and how ischaemic conditioning may be used in future clinical practice.


Tooth-implant connection in removable denture.
When the patient cannot be rehabilitated with a fixed denture, or when he does not succeed in adapting to a traditional removable denture, a possible alternative solution consists in the use of a limited number of implants, placed in strategic positions in the arches of the patient, and subsequently connected to their residual teeth. The aim of this review is to evaluate the progress made on connections between teeth and implants in removable denture, to analyze their advantages and disadvantages and to compare the survival rate, both of the teeth and of the implants used as abutments, present in the various studies taken into examination, with the aim of being able to evaluate the effectiveness of this rehabilitative option. The concept of preserving residual teeth, even if these are unfavorably distributed, and inserting a minimum number of implants in strategic positions, thanks to which an area of favorable support for the denture can be created, seems reasonable; this will guarantee a better adaptation of the patient to the denture, as well as an improvement in the quality of life. The study of articles present in literature suggests that the survival rate of the implants in removable dentures, supported by teeth and implants through traditional systems of anchorage, appears to be quite high. However, further studies with a higher level of evidence, more representative test subjects and a longer follow-up period are necessary, in order to confirm the validity of this rehabilitative solution.


The Mechanism of Action of Nanomaterials Loaded with Clarithromycin after Sinusitis Surgery under the Guidance of Dynamic Enhanced Scanning.
This study was to explore the mechanism of action of nanomaterial-loaded clarithromycin (CLA) after sinusitis surgery. Under the guidance of dynamic enhanced scanning (DES). 120 patients with sinusitis admitted to the First Affiliated Hospital of China Medical University from July 2019 to March 2020 were selected and divided into a control group and an observation group according to the random number table method, with 60 cases in each group. Then, the CLA-containing nano-polylactic acid material was prepared, observed with the scanning electron microscope (SEM), and its drug release ability was tested. All patients underwent endoscopic sinus surgery under general anesthesia. After the surgery was completed, patients in the control group were given only CLA capsules, and patients in the observation group were given freshly prepared nanomaterial-loaded CLA, and both groups of patients were continuously observed for two weeks. After that, the patients were examined using the dynamic enhancement computed tomography (CT). The clinical efficacy, serum interleukin-4 (IL-4), interleukin-8 (IL-8), and tumor necrosis factor α (TNF-α) levels of the two groups of patients were observed. The secretions of the patients' sinuses were performed with microbial bacterial culture, and the results were observed and recorded. Results showed that the characterization and analysis of the nano drug-carrying preparation suggested that the polylactic acid nanomembrane showed linear fiber morphology, relatively dense distribution, not greatly different fiber diameter, and small porosity. Characterization under a field of view (FOV) of 500 um showed that the fiber surface was smooth and rich in content. The release of CLA showed a gradual and steady upward trend. On the 25th day, nearly 50% of the dose had been released, and it had reached more than 90% of the total release on the 55th day. According to the statistics on the clinical efficacy of patients, it was found that the number of cured and effective patients in the observation group was higher than that of the control group, while the number of ineffective cases was much lower than that of the control group. The dynamic enhanced CT examination results of the patients in the control group after treatment showed that the soft tissue mass on the posterior right side of the nasopharynx was reduced, but the pharyngeal suture still existed; while those in the observation group showed that the plain scan density was uniform, and the mastoid air cells were clear on both sides. The number of cases with Staphylococcus aureus (S. aureus), Staphylococcus saprophyticus (S. saprophyticus), and Pasteurella multocida infections in the observation group were observably lower than those of the control group (P< 0.05), and it was the same case for the levels of serum IL-4, IL-8, and TNF-α. Conclusion: after dynamic enhanced CT scanning, it can be found that the nanomaterial-loaded CLA increased the utilization rate of the drug, showing good clinical efficacy, and effectively improved the clinical symptoms of patients, achieving the therapeutic effect.


Osmolytes Modulate Photoactivation of Phytochrome: Probing Protein Hydration.
Phytochromes are bistable red/far-red light-responsive photoreceptor proteins found in plants, fungi, and bacteria. Light-activation of the prototypical phytochrome Cph1 from the cyanobacterium Synechocystis sp. PCC 6803 allows photoisomerization of the bilin chromophore in the photosensory module and a subsequent series of intermediate states leading from the red absorbing Pr to the far-red-absorbing Pfr state. We show here via osmotic and hydrostatic pressure-based measurements that hydration of the photoreceptor modulates the photoconversion kinetics in a controlled manner. While small osmolytes like sucrose accelerate Pfr formation, large polymer osmolytes like PEG 4000 delay the formation of Pfr. Thus, we hypothesize that an influx of mobile water into the photosensory domain is necessary for proceeding to the Pfr state. We suggest that protein hydration changes are a molecular event that occurs during photoconversion to Pfr, in addition to light activation, ultrafast electric field changes, photoisomerization, proton release and uptake, and the major conformational change leading to signal transmission, or simultaneously with one of these events. Moreover, we discuss this finding in light of the use of Cph1-PGP as a hydration sensor, e.g., for the characterization of novel hydrogel biomaterials.


Short-term pain for long-term gain: the role of experiential avoidance in the relation between anxiety sensitivity and emotional distress.
Research has provided evidence of an interactive effect between anxiety sensitivity (AS) and experiential avoidance (EA) in predicting both anxiety and posttraumatic stress (PTS) symptomatology. Additionally, theory suggests that EA alleviates distress in the short-term, but exacerbates it in the long-term. The present cross-sectional study was developed to replicate the noted findings and examine the interaction (EA × AS) in the context of an emotionally evocative task. It was predicted that, among high AS participants, high EA would (a) reduce the likelihood of experiencing short-term increases in negative affect following the task, and (b) increase the likelihood of anxiety and PTS symptomatology. Undergraduate participants (N=199) completed a battery of self-report questionnaires and an emotionally evocative task. As predicted, positive associations were observed between AS and both anxiety and PTS symptoms, but only among high EA participants. Additionally, AS only predicted increases in negative affect following the emotionally evocative task for those with lower levels of EA, thus providing empirical evidence of the affect regulatory function of EA among those who fear anxiety-related bodily sensations. These findings help to elucidate the motives for the use of avoidance among those high in AS. Conceptual and clinical implications are discussed.


Job satisfaction, engagement, and burnout in the population of orthopedic surgeon and neurosurgeon trainees in mainland China.
In China, orthopedics and neurosurgery are among the most desired majors for medical students. However, little is known about the working and living status of specialists in these two fields. This study was aimed at evaluating job satisfaction, engagement, and burnout in the population of Chinese orthopedist and neurosurgeon trainees. A nationwide online survey was administered in mainland China. Questionnaires were answered anonymously. Job satisfaction, engagement, and burnout were assessed using the Job Descriptive Index, the Utrecht Work Engagement Scale, and the Maslach Burnout Inventory, respectively. Data were collected from 643 orthopedist trainees and 690 neurosurgeon trainees. Orthopedists and neurosurgeons showed no statistical difference in terms of age, sex, job titles, and preference for working in tertiary hospitals. Orthopedists had a higher marriage rate (p < 0.01), a lower divorce rate (p = 0.017), relatively shorter working hours (p < 0.01), and a higher annual income (p = 0.023) than neurosurgeons. Approximately 40% of respondents experienced workplace violence in the last 5 years. Less than 10% of respondents were satisfied with their pay, and over 70% would not encourage their offspring to become a doctor. Orthopedists were more satisfied with their careers than neurosurgeons (p < 0.01) and had a higher level of work engagement (p < 0.01). In addition, a higher proportion of orthopedists were burnt out (p < 0.01) than neurosurgeons, though the difference between the two groups was not significant (p = 0.088). Multivariate regressions suggested that younger age (≤ 25 years old), being a senior trainee, getting divorced, working in a regional hospital, long working hours (≥ 71 hrs/wk), a low annual income (<¥100,000), sleeping < 6 hrs/day, and experience with workplace violence were significantly related to burnout for both groups. Chinese orthopedic surgical and neurosurgical trainees are under significant stress. Orthopedic surgeons showed relatively optimistic data in their assessments of job satisfaction, engagement, and burnout. This study may provide valuable information for orthopedic and neurosurgical candidates considering either specialty as a career.


Multiplex CARS for simultaneous measurement of temperature and CO(2) and H(2) concentrations in a combustion environment.
Simultaneous temperature and CO(2) concentration measurements with multiplex coherent anti-Stokes Raman scattering (CARS) spectra of CO(2) were performed. CARS spectra of pure CO(2) and various mixtures of CO(2) and N(2) in a furnace were recorded at various temperatures to test the computer code that simulates CO(2) CARS spectra using recent spectroscopic constants. The temperatures obtained from the CO(2) CARS spectra were in good agreement with thermocouple temperature measurements. However, the CO(2) concentrations cannot be accurately extracted from these spectra. It is believed by the authors that the cross-coherent effect, which has not been included in the present model, and the difficulty of accurately accounting for the background are two important factors affecting the CO(2) concentration measurements. H(2) pure rotational lines S(4) and S(5) were found in the CO(2) CARS spectra of a hydrocarbon flame. These assignments were confirmed from intensity ratio measurements of S(4) and S(5) lines at different temperatures. A theoretical study shows that the H(2) concentration measurement from the S(5) line should be more sensitive than that of the S(4) and S(9) lines at the flame temperature. CARS spectra of preanalyzed mixtures of N(2), CO(2), and H(2) in a furnace were recorded to investigate the feasibility of inferring the H(2) concentration from these spectra. Simultaneous CO(2) and H(2) multiplex CARS spectra were also recorded in a CH(4)/O(2) diffusion flame and in the MSU/DIAL test stand to observe the high temperature spectra. The results of these measurements are presented.


Overview of the signaling pathways involved in metastasis: An intriguing story-tale of the metastatic journey of ovarian cancer cells.
Wealth of information has revolutionized our understanding related to the genetics and functional genomics of this heterogeneous disease. Keeping in view the heterogeneity of ovarian cancer, long-term survival might be achieved by translation of recently emerging mechanistic insights at the cellular and molecular levels to personalize individual strategies for treatment and to identify biomarkers for early detection. Importantly, the motility and invasive properties of ovarian cancer cells are driven by a repertoire of signaling cascades, many components of which have been experimentally verified as therapeutic targets in preclinical models as well as in clinical trials. Scientific evidence garnered over decades of research has deconvoluted the highly intricate intertwined network of intracellular signaling pathways which played fundamental role in carcinogenesis and metastasis. In this review we have provided a compendium of myriad of signaling cascades which have been documented to play critical role in the progression and metastasis of ovarian cancer. We have partitioned this multi-component review into different sections to individually discuss and summarize the roles of TGF/SMAD, JAK/STAT, Wnt/β-Catenin, NOTCH, SHH/GLI, mTORC1/mTORC2, VEGFR and Hippo/YAP pathways in ovarian cancer metastasis.


[Blood rheology in peripheral occlusive disease. Effects of hemodilution and pentoxifylline].
The understanding of rheological relations in peripheral chronic arterial occlusive disease gained in the past two decades allows the conclusion that an efficient conservative therapy may be realized by rheological measures even in advanced states of this vascular disease. The points of therapeutic approach are the flow properties or the fluidity of the blood. The therapeutic objective consists in the improvement of the microcirculation by restoring perfusion reserves for the formation of collaterals. Employment of hemodilution and administration of the rheologically active drug pentoxifylline are quoted as exemplary possibilities for a promising treatment. The therapeutic procedures must also include consequent elimination of risk factors and should bear in mind correction of hypercoagulation in order to counteract the progression of the disease.


An indigenous spacer device for drug delivery in severely dyspnoeic patients.
Bronchodilator aerosols are commonly delivered through nebulizers or metered dose inhalers (MDI) to treat bronchospasm. Although the clinical results obtained with both these devices are comparable, the use of MDI offers several advantages like lower drug dose, reduced risk of complications, reliability of dosing, ease of administration, less personnel time and reduced cost. However, in non-intubated, spontaneously breathing patients, the amount of drug inhaled depends on the coordination of the inspiratory phase and delivery of the drug. In severely dyspnoeic or disoriented patients in the casualty department or intensive care settings, this is often not possible. Valved spacers and breath-actuated inhalers may not be easily available in such situations. Also, the spacer devices cannot be connected to the anatomical facemask and the need to discontinue oxygenation for aerosol delivery further limits their use.


Diabetic retinopathy (treatment).
Diabetic retinopathy is the most common cause of blindness in the UK, with older people and those with worse diabetes control, hypertension, and hyperlipidaemia being most at risk. Diabetic retinopathy can cause microaneurysms, haemorrhages, exudates, changes to blood vessels, and retinal thickening. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with diabetic retinopathy? What are the effects of treatments for vitreous haemorrhage? We searched: Medline, Embase, The Cochrane Library, and other important databases up to June 2010 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 58 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. In this systematic review we present information relating to the effectiveness and safety of the following interventions: peripheral retinal laser photocoagulation, focal and grid laser photocoagulation for maculopathy, corticosteroids for macular oedema, vascular endothelial growth factor inhibitors, and vitrectomy for vitreous haemorrhage.


Pathobiology of germ cell tumors - applying the gossip test!
Residual mature teratoma, a frequent finding in clinical pathology since the introduction of cisplatin-based chemotherapy, put Wolter Oosterhuis on the track of germ cell tumors (GCTs). These neoplasms in the borderland between developmental biology and oncology have fascinated him ever since. He tells the story on how GCTs brought him in contact with leading investigators in the field like Ivan Damjanov, Peter Andrews, and Niels Skakkebaek. His fruitful line of research was made possible through a longstanding collaboration with Bauke de Jong and, to this day, Leendert Looijenga who joined his group as a student in 1988. Probably their most important contribution to the field of GCTs is an integrated approach to GCTs, combining epidemiology, pathology, (cyto)genetics and molecular biology, that has resulted in a pathobiology-based classification of GCTs in five types. It has clinical relevance and stimulates further research on these intriguing neoplasms and their corresponding animal models.


Non-cystic fibrosis bronchiectasis: a retrospective review of clinical, radiological, microbiological and lung function profile at a tertiary care center of low-middle income country.
Non-cystic fibrosis (non-CF) bronchiectasis has emerged as a significant respiratory disease in developing countries. Given the variation in causes and clinical characteristics across different regions, it is necessary to conduct studies in regions with limited data such as low-middle income countries (LMIC). The aim of the study was to investigate the underlying causes, clinical presentation, etiology, lung function and imaging in patients with bronchiectasis who sought treatment at a tertiary care hospital in a LMIC. We conducted retrospective observational study at the Aga Khan University, Pakistan. Adult patients diagnosed with non-CF bronchiectasis on high-resolution computed tomography scan between 2000 and 2020 were included. We evaluated the etiology, clinical characteristics, microbiology, radiology and spirometric pattern of these patients. A total of 340 patients were included with 56.5% being female and 44.7% aged over 60 years. Among them, 157 (46.2%) had experienced symptoms for 1-5 years. The most common spirometric pattern observed was obstructive impairment (58.1%). Previous tuberculosis (TB) (52.94%) was the most common etiology followed by allergic bronchopulmonary aspergillosis (7.64%). Bilateral lung involvement on HRCT scan was found in 63.2% of patients. Pseudomonas aeruginosa was the most frequently identified organism (38.75%) among 240 patients with available specimens. Patients with P. aeruginosa infections had a significantly higher number of exacerbations (p=0.016). There was a significant difference (p<0.001) in P. aeruginosa growth among different etiologies. In conclusion, post-TB bronchiectasis was the most common cause of non-CF bronchiectasis in our study population. P. aeruginosa was the predominant organism, and 63.2% of the patients exhibited bilateral lung involvement. Since P. aeruginosa growth and extensive lung involvement have been associated with poor prognosis and increased mortality risk, we recommend close follow ups of these patients to improve quality of life and survival in developing countries like Pakistan.


HTLV-1-associated myelopathy in Spain.
HTLV-1 infection is a neglected disease. Over 10 million people are infected worldwide, with hot spots of high endemicity across all continents. Roughly 5% of HTLV-1 carriers develop HTLV-1-associated myelopathy (HAM), a progressive subacute neurological disabling disease. We report the main features of patients diagnosed with HAM up to date in Spain, a non-endemic country with a relatively high migrant flow from Latin America and Equatorial Africa, where HTLV-1 is endemic. A total of 451 cases of HTLV-1 had been recorded in Spain until the end of year 2022. HAM had been diagnosed in 58 (12.9%). The current incidence is of 2-3 new cases per year. Women represent 76%. Mean age at diagnosis is 49 years-old. Nearly 60% are Latin Americans. Although sexual transmission is the most likely route of HTLV-1 acquisition, up to 6 individuals had been infected following solid organ transplantation. Rapid onset myelopathy developed in all but one of these transplant recipients from three HTLV-1-positive donors. HTLV-1 subtype 1a transcontinental was the only variant recognized in HAM patients. HTLV-1 proviral load was significantly greater in HAM patients than in asymptomatic HTLV-1 carriers (677 vs 104 HTLV-1 DNA copies/104 PBMC; p = 0.012). Symptom relief medications and physiotherapy have been the only treatment providing some benefit to HAM patients. Neither significant clinical nor virological efficacy was noticed using antiretrovirals in at least 9 HAM patients. Two thirds of HAM patients ended up in a wheelchair and with urinary/fecal sphincter incontinence. HAM is the most frequent clinical manifestation of HTLV-1 infection in Spain, a non-endemic country. Middle aged women migrants from Latin America are the most frequently affected. Two thirds end up in a wheelchair despite using antiretroviral therapy.


A laboratory score at presentation to rule-out serious cardiac outcomes or death in patients presenting with symptoms suggestive of acute coronary syndrome.
We evaluated whether a low high-sensitivity cardiac troponin (hs-cTn) cutoff combined with glucose, red cell distribution width (RDW), and the estimated glomerular filtration rate (eGFR) can be used to rule-out a serious cardiac outcome or death in patients presenting with symptoms suggestive of acute coronary syndrome (ACS). This was a prospective observational emergency department (ED) study enrolling consecutive patients presenting with symptoms suggestive of ACS (ClinicalTrials.gov: NCT01994577). The primary outcome was a 7-day composite of myocardial infarction, unstable angina, decompensated congestive heart failure, serious ventricular cardiac arrhythmia, or death. A laboratory score combining glucose, RDW, eGFR with hs-cTnT (Roche) or hs-cTnI (Abbott) was compared to hs-cTn alone using the limit of detection (LoD; hs-cTnT<5ng/l/hs-cTnI<2ng/l) as the cutoff. A benchmark of >99% sensitivity was used to assess the laboratory panel with hs-cTn versus the LoD alone to identify low-risk patients suitable for discharge. A total of 1095 patients (n=267 composite-outcomes) had measurements of glucose, RDW, eGFR, hs-cTnT, and hs-cTnI at presentation. Applying the hs-cTn LoD alone as the cutoff missed 5 composite-outcomes (sensitivity=98.1%), however the addition of the laboratory panel to the hs-cTn LoD increased the sensitivity to >99% with approximately 10% of the population identified as low-risk. The percentage of low-risk patients was increased to 15% (1 composite-outcome missed) when employing a low measurable hs-cTnI cutoff with the laboratory panel (laboratory score<2 points). A laboratory score with hs-cTn may identify low-risk patients suitable for ED discharge at presentation.


Racial/Ethnic Disparities in Failure to Initiate HIV Care: Role of HIV Testing Site, Individual Factors, and Neighborhood Factors, Florida, 2014-2015.
Delayed initiation of human immunodeficiency virus (HIV) care affects disease progression. To determine the role of HIV testing site and neighborhood- and individual-level factors in racial/ethnic disparities in initiation of care, we examined Florida population-based HIV/AIDS surveillance system records. We performed multilevel Poisson regression to calculate adjusted prevalence ratios (APR) for non-initiation of care by race/ethnicity adjusting for HIV testing site type and individual- and neighborhood-level characteristics. Of 8,913 people diagnosed with HIV during 2014-2015 in the final dataset, 18.3% were not in care within three months of diagnosis. The APR for non-initiation of care for non-Hispanic Blacks relative to non-Hispanic Whites was 1.57 (95% confidence interval [CI] 1.38-1.78) and for those tested in plasma/donation centers relative to outpatient clinics was 2.45 (95% CI 2.19-2.74). Testing site and individual variables contribute to racial/ethnic disparities in non-initiation of HIV care. Linkage procedures, particularly at plasma/blood donation centers, warrant improvement.


The value of service dogs for people with severe ambulatory disabilities. A randomized controlled trial.
To assess the value of service dogs for people with ambulatory disabilities. Randomized, controlled clinical trial. Environments of study participants. Forty-eight individuals with severe and chronic ambulatory disabilities requiring use of wheelchairs who were recruited from advocacy and support groups for persons with muscular dystrophy, multiple sclerosis, traumatic brain injury, and spinal cord injury. Participants were matched on age, sex, marital status, race, and the nature and severity of the disability in order to create 24 pairs. Within each pair, participants were randomly assigned to either the experimental group or a wait-list control group. Experimental group members received trained service dogs 1 month after the study began, and subjects in the wait-list control group received dogs in month 13 of the study. Dependent variables evaluated were self-reported assessments of psychological well-being, internal locus of control, community integration, school attendance, part-time work status, self-esteem, marital status, living arrangements, and number of biweekly paid and unpaid assistance hours. Data collection occurred every 6 months over a 2-year period, resulting in five data collection points for all subjects. Significant positive changes in all but two dependent measures were associated with the presence of a service dog both between and within groups (P<.001). Psychologically, all participants showed substantial improvements in self-esteem, internal locus of control, and psychological well-being within 6 months after receiving their service dog. Socially, all participants showed similar improvements in community integration. Demographically, all participants showed increases in school attendance and/or part-time employment. Economically, all participants showed dramatic decreases in the number of both paid and unpaid assistance hours. Trained service dogs can be highly beneficial and potentially cost-effective components of independent living for people with physical disabilities.


Copterus tyloloricatus (Ciliophora, Suctorea), a new suctorian genus and species.
We present the description of the new suctorian genus Copterus gen. n. with type species Copterus tyloloricatus sp. n. from the family Acinetidae, inhabiting the prosomes and urosomes of calanoid copepods from the northern North Pacific Ocean. The new taxon is characterized by (i) an ellipsoidal to triangular, asymmetric, dorsoventrally flattened cell body, which lies horizontally on the lorica surface; (ii) an unflattened lorica; and (iii) the presence of three to five radially arranged bundles of tentacles positioned at the edge of the body or on actinophores.


Treatment of accommodative dysfunction in children: results from a randomized clinical trial.
To report the effectiveness of various forms of vision therapy/orthoptics in improving accommodative amplitude and facility in children with symptomatic convergence insufficiency (CI) and co-existing accommodative dysfunction. In a randomized clinical trial, 221 children aged 9 to 17 years with symptomatic CI were assigned to one of four treatments. Of the enrolled children, 164 (74%) had accommodative dysfunction; 63 (29%) had a decreased amplitude of accommodation with respect to age, 43 (19%) had decreased accommodative facility, and 58 (26%) had both. Analysis of variance models were used to compare mean accommodative amplitude and accommodative facility for each treatment group after 4, 8, and 12 weeks of treatment. After 12 weeks of treatment, the increases in amplitude of accommodation [office-based vergence/accommodative therapy with home reinforcement group (OBVAT) 9.9 D, home-based computer vergence/accommodative therapy group (HBCVAT+) 6.7 D, and home-based pencil push-up therapy group (HBPP) 5.8 D] were significantly greater than in the office-based placebo therapy (OBPT) group (2.2 D) (p-values ≤0.010). Significant increases in accommodative facility were found in all groups (OBVAT: 9 cpm, HBCVAT+: 7 cpm, HBPP: 5 cpm, OBPT: 5.5 cpm); only the improvement in the OBVAT group was significantly greater than that found in the OBPT group (p = 0.016). One year after completion of therapy, reoccurrence of decreased accommodative amplitude was present in only 12.5% and accommodative facility in only 11%. Vision therapy/orthoptics is effective in improving accommodative amplitude and accommodative facility in school-aged children with symptomatic CI and accommodative dysfunction.


Transitioning from pediatric to adult health care with familial hypercholesterolemia: Listening to young adult and parent voices.
Young adults with familial hypercholesterolemia (FH) are at a critical period for establishing behaviors to promote future cardiovascular health. To examine challenges transitioning to adult care for young adults with FH and parents of FH-affected young adults in the context of 2 developmental tasks, transitioning from childhood to early adulthood and assuming responsibility for self-management of a chronic disorder. Semistructured, qualitative interviews were conducted with 12 young adults with FH and 12 parents of affected young adults from a pediatric subspecialty preventive cardiology program in a northeastern academic medical center. Analyses were conducted using a modified grounded theory framework. Respondents identified 5 challenges: (1) recognizing oneself as a decision maker, (2) navigating emerging independence, (3) prioritizing treatment for a chronic disorder with limited signs and symptoms, (4) managing social implications of FH, and (5) finding credible resources for guidance. Both young adults and parents proposed similar recommendations for addressing these challenges, including the need for family and peer involvement to establish and maintain diet and exercise routines and to provide medication reminders. Systems-level recommendations included early engagement of adolescents in shared decision-making with health care team; providing credible, educational resources regarding FH; and using blood tests to track treatment efficacy. Young adults with FH transitioning to adult care may benefit from explicit interventions to address challenges to establishing healthy lifestyle behaviors and medication adherence as they move toward being responsible for their medical care. Further research should explore the efficacy of recommended interventions.


Does crew resource management training work? An update, an extension, and some critical needs.
This review provides the state of crew resource management (CRM) training evaluations since the E. Salas, C. S. Burke, C. A. Bowers, and K. A. Wilson (2001) review and extends it to areas beyond aviation cockpits. Some critical evaluation needs in CRM training are also covered. Because of the purported success of CRM training in aviation, other high-consequence domains have begun to implement CRM training for their workforces. However, the true impact of CRM training in aviation and these other domains has yet to be determined. Using D. L. Kirkpatrick's (1976) framework for evaluating training (i.e., reactions, learning, behavior, and organizational impact), we reviewed 28 published accounts of CRM training to determine its effectiveness within aviation, medicine, offshore oil production and maintenance, shipping/maritime, and nuclear power domains. Findings indicate that CRM training generally produced positive reactions from trainees; however, the impact of training on learning and behavioral changes suggest mixed results across and within domains. Furthermore, and as was found by Salas, Burke, et al. in 2001, we cannot ascertain whether CRM has had an impact on the organization's bottom line (i.e., safety). Based on the results, there are several critical needs that the CRM training community must address before CRM training can have the desired impact on safety: a mandate, access to data, and resources. As CRM training expands to organizations beyond aviation, it is critical that its impact be understood such that it can be improved and achieve the intended results.


Foreign Bodies in the Abdominal Area: Review of the Literature.
The aim of this paper is to update and summarize the relevant literature on the anatomical localization, incidence, and diagnostic and therapeutic approaches to abdominal foreign bodies. A comprehensive review was carried out on recorded cases related to the presence of foreign bodies in the abdominal area throughout the literature. Moreover, the phenomenon was discussed in relation to different patient categories associated with childhood, mental or neurological illness, incarceration, and drug trafficking as well as sexual accident or abuse. Particular importance is ascribed to the underlying psychopathology and motivation of foreign body ingestion in each category of patients. The surgical, psychiatric and legal implications of the issue are discussed in detail.


Evidence-based concepts for prevention of knee and ACL injuries. 2017 guidelines of the ligament committee of the German Knee Society (DKG).
Knee injuries and especially anterior cruciate ligament (ACL) tears are frequent in athletes. Therefore, primary and secondary prevention of sports-related lower limb injuries is an ongoing topic of interest. The aim of present study was to establish guidelines for the prevention of knee and ACL injuries on the basis of evidence-based concepts represented in current literature. A comprehensive literature review regarding prevention programs for knee and ACL injuries was conducted. Several modifiable and non-modifiable risk factors for knee injuries in athletes have been reported in literature. Referring to the ACL, specific injury mechanisms have been identified and are well understood. In particular, it has been demonstrated that dynamic valgus is one of the most important modifiable risk factors. Simple tests like the drop jump test have shown their efficacy in screening and detecting athletes at risk. There is only few evidence for the preventive effect on knee and ACL injuries by single exercises. However, in order to prevent or correct endangering movement patterns including dynamic valgus, several complex prevention programs have been developed in the past. These prevention programs are included in standard warm-up exercises and are focusing on muscle strength, balance, and proprioception, as well as running and flexibility. It is reported that these training programs can reduce the incidence of knee injuries by up to 27% and ACL injuries by up to 51%. Screening, identification, and correction of endangering movement patterns like the dynamic valgus are the first crucial steps in order to prevent knee and ACL injuries in athletes. Furthermore, jumping, running and flexibility exercises as well as balance and strength training are proven to reduce the incidence of these injuries and should, therefore, be integrated into the regular warm up program. Appropriate complete prevention programs are freely accessible via the Internet and should be adapted to the specific sport disciplines.


Molecular basis of Lewis blood type in Taiwanese.
The Lewis (Le) histo-blood group system comprises two major antigens, Le(a) and Le(b) which are determined by alpha (1,2)-fucosyltransferase (FUT2) and alpha (1,3/1,4)-fucosyltransferase (FUT3). In this study, we analyzed the mutations of FUT2 and FUT3 genes in 101 Taiwanese by molecular biology method and compared them with their serologic phenotypes to explore their relationship. There is at least one wild allele of FUT2 and FUT3 genes in phenotype of Le (a-b+). The phenotypes of Le (a+b-) and Le (a+b+) are caused by mutations of both alleles of FUT2 gene and at least one wild allele of FUT3 gene. The genotypes of Le (a+b-) and Le (a+b+) are the same. Twenty cases are phenotype of Le (a-b-), which are caused by mutations of both alleles of FUT 2 gene and/or FUT 3 gene. Twelve cases were caused by both alleles mutations of FUT 3 gene only, while three cases were caused by mutations of both alleles of FUT2 gene and the rest of the cases were caused by mutations of both alleles of FUT2 and FUT3 genes. Our findings confirm that the Le histo-blood group is determined by the interaction of FUT 2 and FUT 3 genes. Our report is the first study of FUT 2 gene and FUT 3 gene in a Taiwanese population. We suggest that the genetic analysis of Le blood group should include FUT 2 and FUT 3 genes together.


Computerized tomography (CT) semeiotics in the presurgical evaluation of gynaecological neoplasias.
Computerized tomography has been introduced in studies concerning neoplastic pathology of the pelvis. In this study, we have attempted to define a series of radiological signs, resulting from CT tests of pelvis or abdomen in patients with gynaecological tumors, each of which corresponds to a particular anatomopathologic situation. For each gynaecologic tumor, there is a set of more frequently found signs, the presence of which, in the single case, depends on the stage of evolution of the disease. In the staging of cervical or endometrial carcinoma, the evaluation of the relation to the bladder and rectum is very important, just like vaginal, parametrial and ureteral infiltration. In the presurgical staging of ovarian carcinoma the CT can reveal the size and shape of mono- or bilateral ovarian tumour masses and the relation that they have established with the pelvic organs and with the intestine. In spite of inevitable limitations the CT plays an essential role in gynaecologic oncologic diagnostics.


Response to febuxostat according to clinical subtypes of hyperuricemia: a prospective cohort study in primary gout.
While xanthine oxidase inhibitors target uric acid production, renal urate underexcretion is the predominant subtypes in gout. This study was to compare treatment response to the XOI febuxostat in a gout cohort according to clinical subtypes of hyperuricemia. A prospective cohort study was conducted to compare the efficacy and safety of febuxostat (initially 20 mg daily, escalating to 40 mg daily if not at target) in 644 gout patients with the three major clinical subtypes for 12 weeks. Hyperuricemia was defined as the renal overload subtype, the renal underexcretion subtype, or the combined subtype based on UUE > or ≤ 600 mg/d/1.73 m2 and FEUA < or ≥ 5.5%. The primary endpoint was the rate of achieving serum urate (SU) < 6 mg/dL at week 12. Fewer participants with combined subtype achieved the SU target, 45.5% compared with 64.8% with overload subtype (P = 0.007), and 56.6% with underexcretion subtype (P = 0.022). More participants with combined subtype (82%) had febuxostat escalated to 40 mg than those with overload (62%, P = 0.001) or underexcretion subtype (68%, P = 0.001). In all participants, combined subtype hyperuricemia (OR = 0.64, 95%CI 0.41-0.99, P = 0.048) and baseline SU (OR = 0.74, 95%CI 0.62-0.89, P = 0.001) were independently associated with lower rates of achieving SU target. People with combined subtype have a lower response to febuxostat, compared to those with either overload or underexcretion subtype. Assessment of hyperuricemia subtype may provide useful clinical data in predicting febuxostat response.


Use of larvae of the wax moth Galleria mellonella as an in vivo model to study the virulence of Helicobacter pylori.
Helicobacter pylori is the first bacterium formally recognized as a carcinogen and is one of the most successful human pathogens, as over half of the world's population is colonized by the bacterium. H. pylori-induced gastroduodenal disease depends on the inflammatory response of the host and on the production of specific bacterial virulence factors. The study of Helicobacter pylori pathogenic action would greatly benefit by easy-to-use models of infection. In the present study, we examined the effectiveness of the larvae of the wax moth Galleria mellonella as a new model for H. pylori infection. G. mellonella larvae were inoculated with bacterial suspensions or broth culture filtrates from either different wild-type H. pylori strains or their mutants defective in specific virulence determinants, such as VacA, CagA, CagE, the whole pathogenicity island (PAI) cag, urease, and gamma-glutamyl transpeptidase (GGT). We also tested purified VacA cytotoxin. Survival curves were plotted using the Kaplan-Meier method and LD50 lethal doses were calculated. Viable bacteria in the hemocoel were counted at different time points post-infection, while apoptosis in larval hemocytes was evaluated by annexin V staining. We found that wild-type and mutant H. pylori strains were able to survive and replicate in G. mellonella larvae which underwent death rapidly after infection. H. pylori mutant strains defective in either VacA, or CagA, or CagE, or cag PAI, or urease, but not GGT-defective mutants, were less virulent than the respective parental strain. Broth culture filtrates from wild-type strains G27 and 60190 and their mutants replicated the effects observed using their respective bacterial suspension. Also, purified VacA cytotoxin was able to kill the larvae. The killing of larvae always correlated with the induction of apoptosis in hemocytes. G. mellonella larvae are susceptible to H. pylori infection and may represent an easy to use in vivo model to identify virulence factors and pathogenic mechanisms of H. pylori. The experimental model described can be useful to screen a large number of clinical H. pylori strain and to correlate virulence of H. pylori strains with patients' disease status.


Overexpression of microRNA-130a predicts adverse prognosis of primary gastrointestinal diffuse large B-cell lymphoma.
Primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) is a highly heterogeneous type of non-Hodgkin lymphoma. A number of studies have demonstrated that microRNA-130a (miR-130a) serves a role in the tumorigenesis and prognosis of numerous human tumors. However, to the best of our knowledge, the prognostic significance of miR-130a in PGI-DLBCL remains unknown. The present study explored the association between miR-130a and the clinical outcomes of PGI-DLBCL. Relative miR-130a expression was assessed by reverse transcription-quantitative PCR. Immunohistochemistry was used to detect expression levels of BCL-2, c-MYC, neprilysin, B-cell lymphoma 6 protein, PWWP domain-containing DNA repair factor 3A and proliferation marker protein Ki-67. A receiver operating characteristic curve was constructed to analyze the specificity and sensitivity of microRNA levels in the diagnosis of PGI-DLBCL. Survival curves were constructed using the Kaplan-Meier method. In the present study, miR-130a expression was notably higher in patients with PGI-DLBCL compared with in the controls (P<0.0001). miR-130a overexpression was closely associated with a high International Prognostic Index score (3-5) and drug resistance (P=0.017 and P=0.044, respectively). No significant difference in other clinical features was observed. Patients with increased expression levels of miR-130a had lower overall survival [hazard ratio (HR), 2.998; 95% CI, 1.347-6.673; P=0.007] and progression-free survival (HR, 3.325; 95% CI, 1.488-7.429; P=0.003) compared with patients who had lower expression levels of miR-130a. Furthermore, multivariate Cox regression analysis suggested that miR-130a was a negative prognostic parameter in PGI-DLBCL. Therefore, upregulation of miR-130a could become a potential prognostic marker for PGI-DLBCL. Additionally, further study of these results may have important guiding significance for the prognosis of patients with PGI-DLBCL in the clinical setting.


Development and pharmacological characterization of conformationally constrained urotensin II-related peptide agonists.
Urotensin II (UII) and its paralog peptide, urotensin II-related peptide (URP), exert not only common but also divergent actions through the activation of UT, a specific membrane-bound receptor that belongs to the 1A G protein-coupled receptor subclass. In this study, we have designed and synthesized new URP analogues in which the intracyclic Trp residue was replaced with natural, unnatural, and constrained amino acids to determine important physicochemical features for receptor binding and activation. The biological data, highlighting the potent agonistic behavior of [Tiq(4)]URP and [Tpi(4)]URP, also suggest that the Trp residue, and more specifically the indole ring, is not critical for receptor interaction and could in fact be involved in the intramolecular stabilization of the bioactive conformation of URP. Finally, these analogues, which are intracyclic constrained URP-based agonists, could represent useful pharmacological tools for the study of the urotensinergic system.


Computing Cellulase Kinetics with a Two-Domain Linear Interaction Energy Approach.
While heterogeneous enzyme reactions play an essential role in both nature and green industries, computational predictions of their catalytic properties remain scarce. Recent experimental work demonstrated the applicability of the Sabatier principle for heterogeneous biocatalysis. This provides a simple relationship between binding strength and the catalytic rate and potentially opens a new way for inexpensive computational determination of kinetic parameters. However, broader implementation of this approach will require fast and reliable prediction of binding free energies of complex two-phase systems, and computational procedures for this are still elusive. Here, we propose a new framework for the assessment of the binding strengths of multidomain proteins, in general, and interfacial enzymes, in particular, based on an extended linear interaction energy (LIE) method. This two-domain LIE (2D-LIE) approach was successfully applied to predict binding and activation free energies of a diverse set of cellulases and resulted in robust models with high accuracy. Overall, our method provides a fast computational screening tool for cellulases that have not been experimentally characterized, and we posit that it may also be applicable to other heterogeneously acting biocatalysts.


Hypersensitivity pneumonitis in man. Light- and electron-microscopic studies of 18 lung biopsies.
Light- and electron-microscopic changes produced by hypersensitivity pneumonitis were analyzed in open lung biopsies taken from 18 patients with chronic forms of the disease. The main changes observed were: alveolitis (both luminal and mural), granulomas, intraalveolar buds, and interstitial fibrosis. The cells infiltrating the alveolar walls were mainly lymphocytes. Occasionally these lymphocytes presented irregularities in the contours of the nuclear membranes and resembled Sézary cells. In one patient, a few lymphocytes were found that resembled "hand-mirror" cells. Intraalveolar macrophages often had a foamy appearance. Granulomas, present in two-thirds of the patients, differed in several respects from those in sarcoidosis: they were smaller, more loosely arranged, and poorly limited; they had a higher content of lymphocytes; and they were located more frequently in alveolar tissue than in the vicinity of bronchioles and vessels. Intraalveolar buds, also present in about two thirds of the patients, were composed mainly of fibroblasts, myofibroblasts, and macrophages in a loose connective tissue that was rich in proteoglycan material. Capillaries and epithelial cells were rarely seen in buds. Alveolar buds appear to develop by a process of disruption of the epithelial lining layer, due to alveolitis, followed by intraalveolar exudation and by subsequent intraalveolar migration of connective tissue cells interacting with macrophages. Severe fibrotic and alveolar epithelial changes were observed in four patients; milder changes were frequent in most other patients. It is concluded that hypersensitivity pneumonitis usually has distinctive morphologic features; these may help to distinguish the resultant pulmonary fibrosis from that due to other causes.


Altering Escherichia coli envelope integrity by mimicking the lipoprotein RcsF.
Escherichia coli cell envelope is crucial for stress sensing and signal transduction, mediated by numerous protein-protein interactions to enable adaptation and survival. Interfering with these interactions might affect envelope integrity leading to bacterial death. The outer membrane lipoprotein (RcsF) is the stress sensor of the regulator of capsule synthesis (Rcs) phosphorelay that senses envelope threats. RcsF interacts with two essential proteins, IgaA (repressing the Rcs system) and BamA (inserting β-barrel proteins in the outer membrane). Disturbing RcsF interactions may alter Rcs signaling and/or membrane integrity thus affecting bacterial survival. Here, we derived the sequence of a peptide mimicking RcsF (RcsFmim), based on the in silico docking of RcsF with IgaA. Expression of rcsFmim caused 3-to-4-fold activation of the Rcs system and perturbation of the outer membrane. Both effects result in decreased E. coli growth rate. We anticipate that RcsFmim present a candidate for future antibacterial peptide development.


Use of Illumina sequencing to identify transposon insertions underlying mutant phenotypes in high-copy Mutator lines of maize.
High-copy transposons have been effectively exploited as mutagens in a variety of organisms. However, their utility for phenotype-driven forward genetics has been hampered by the difficulty of identifying the specific insertions responsible for phenotypes of interest. We describe a new method that can substantially increase the throughput of linking a disrupted gene to a known phenotype in high-copy Mutator (Mu) transposon lines in maize. The approach uses the Illumina platform to obtain sequences flanking Mu elements in pooled, bar-coded DNA samples. Insertion sites are compared among individuals of suitable genotype to identify those that are linked to the mutation of interest. DNA is prepared for sequencing by mechanical shearing, adapter ligation, and selection of DNA fragments harboring Mu flanking sequences by hybridization to a biotinylated oligonucleotide corresponding to the Mu terminal inverted repeat. This method yields dense clusters of sequence reads that tile approximately 400 bp flanking each side of each heritable insertion. The utility of the approach is demonstrated by identifying the causal insertions in four genes whose disruption blocks chloroplast biogenesis at various steps: thylakoid protein targeting (cpSecE), chloroplast gene expression (polynucleotide phosphorylase and PTAC12), and prosthetic group attachment (HCF208/CCB2). This method adds to the tools available for phenotype-driven Mu tagging in maize, and could be adapted for use with other high-copy transposons. A by-product of the approach is the identification of numerous heritable insertions that are unrelated to the targeted phenotype, which can contribute to community insertion resources.