Alkaloids from the root of Isatis indigotica.
Seventeen new alkaloids (1-17) and 14 known analogues have been isolated from an aqueous extract of the root of Isatis indigotica. The structures and absolute configurations of these compounds were determined by extensive spectroscopic data analysis, including 2D NMR, single-crystal X-ray crystallography using anomalous scattering of Cu Kα radiation, and electronic circular dichroism spectra calculations based on the quantum-mechanical time-dependent density functional theory. Compounds 1, 2, and 3 are the first examples of natural products with unique linkages between a molecule of 2-(4-methoxy-1H-indol-3-yl)acetonitrile and 2-(1H-indol-3-yl)acetonitrile, 2-(4-methoxy-1H-indol-3-yl)acetonitrile, and 4-hydroxyphenylethane, respectively. Compounds (-)-4 and (+)-4 represent the first natural products with the pyrrolo[2,3-b]indolo[5,5a,6-b,a]quinazoline skeleton. Some structural assignments for the new alkaloids suggest that the assignments made for certain previously reported alkaloids require revision. Compounds 1-3 and arvelexin (18) show antiviral activity against the influenza virus A/Hanfang/359/95 (H3N2), with IC(50) values of 3.70-12.35 μM, and 17 inhibits Coxsackie virus B3 replication with an IC(50) of 6.87 μM.


Questionable accuracy of home blood pressure measurements in the obese population - Validation of the Microlife WatchBP O3® and Omron RS6® devices according to the European Society of Hypertension-International Protocol.
Two oscillometric devices, the Microlife WatchBP O3® and the Omron RS6®, designed for self-blood pressure measurement were evaluated according to the European Society of Hypertension (ESH)-International Protocol (IP) Revision 2010 in the obese population. The Microlife WatchBP O3 measures blood pressure (BP) at the brachial level and the Omron RS6 measures BP at the wrist level. The ESH-IP revision 2010 includes a total of 33 subjects. The difference between observers' and device BP values was calculated for each measure. A total of 99 pairs of BP differences were classified into three categories (≤5, ≤10, and ≤15 mmHg). The protocol procedures were followed precisely in each of the two studies. Microlife WatchBP O3 and Omron RS6 failed to fulfill the criteria of the ESH-IP. The mean differences between the device and the mercury readings were: 0.3±7.8 mmHg and -1.9±6.4 mmHg for systolic BP and diastolic BP, respectively, for Microlife WatchBP O3, and 2.7±9.9 mmHg for SBP and 3.5±11.1 mmHg for diastolic BP for Omron RS6. Microlife WatchBP O3 and Omron RS6 readings differing from the mercury standard by more than 5, 10, and 15 mmHg failed to fulfill the ESH-IP revision 2010 requirements in obese subjects. Therefore, the two devices cannot be recommended for use in obese subjects.


Deep venous thrombosis after emergency gastrointestinal operations: a pilot study.
In a prospective pilot study, 30 patients over 50 years of age undergoing major emergency gastrointestinal surgery were examined with the 125I-fibrinogen uptake test for postoperative deep venous thrombosis (DVT). Prophylaxis against thrombosis was at that time not used routinely for the emergency patients. The surgeon decided for each patient whether and when prophylaxis with low-dose heparin, 5,000 units twice daily, should be given. DVT was diagnosed in 11 patients (37%; 95% confidence interval 20 to 56%), in five of them bilaterally. No thrombi occurred within seven days in the patients who received low-dose heparin from the day of surgery. Major emergency gastrointestinal surgery carries a high risk of postoperative DVT.


Patterns of Care in Adjuvant Therapy for Resected Oral Cavity Squamous Cell Cancer in Elderly Patients.
To characterize the patterns of care and potential barriers to access to care for elderly patients with oral cavity cancer in the adjuvant setting. We performed a retrospective cohort study using the National Cancer Data Base and identified patients with resected oral cavity squamous cell carcinoma diagnosed between 2004 and 2012, who survived for ≥3 months after surgery. We used logistic regression models to assess the association between age (<70, 70-79, and ≥80 years) and the receipt of adjuvant therapy within 3 months of surgery. We additionally assessed the association between patient and tumor characteristics and the receipt of adjuvant therapy among those aged ≥70 years. A total of 25,829 patients were included in the study. Compared with those aged <70 years, older patients were more likely to have no neck dissection or have fewer lymph nodes dissected and were less likely to receive adjuvant therapy than younger patients. Among our cohort, 11,361 patients (44%) had pathologic T3-T4 disease or N2-N3 disease, and 4185 patients (16%) had extracapsular nodal extension or positive surgical margins. In multivariate analyses controlling for comorbidity and demographic characteristics, older age was independently associated with lower odds of receiving adjuvant radiation therapy in the subgroup with T3 or T4 disease or N2 or N3 disease and adjuvant chemoradiation therapy in the positive extracapsular nodal extension or positive surgical margin subgroup. Among elderly patients, both greater patient distance from reporting facility and older age were associated with lower odds of receiving both adjuvant radiation therapy (odds ratio 0.66; 95% confidence interval, 0.55-0.81) and chemoradiation therapy (odds ratio 0.56; 95% confidence interval, 0.40-0.79). In a national hospital-based cohort of patients with oral cavity cancer, elderly patients were less likely to receive adjuvant radiation or chemoradiation therapy. Greater patient distance from reporting facility, in addition to older age, was associated with lower odds of receiving both adjuvant radiation therapy and adjuvant chemoradiation therapy.


Effects of aging on adipose resistance artery vasoconstriction: possible implications for orthostatic blood pressure regulation.
The purpose of this investigation was to determine mean arterial pressure (MAP) and regional vascular conductance responses in young and aged Fisher-344 rats during orthostatic stress, i.e., 70 degrees head-up tilt (HUT). Both groups demonstrated directionally different changes in MAP during HUT (young, 7% increase; aged, 7% decrease). Vascular conductance during HUT in young rats decreased in most tissues but largely remained unchanged in the aged animals. Based on the higher vascular conductance of white adipose tissue from aged rats during HUT, resistance arteries from white visceral fat were isolated and studied in vitro. There was diminished maximal vasoconstriction to phenylephrine and norepinephrine (NE: young, 42 +/- 5%; old, 18 +/- 6%) in adipose resistance arteries from aged rats. These results demonstrate that aging reduces the ability to maintain MAP during orthostatic stress, and this is associated with a diminished vasoconstriction of adipose resistance arteries.


[Bronchial carcinoma. Epidemiology, diagnosis and therapy].
Bronchial carcinoma still has a dark prognosis and therapeutic progress remains painfully slow: the 5-year survival rate raised in the last 20 years from 11 to 15%. There are no early symptoms by the tumor and detection by screening is not effective. Worldwide incidence is raising, the falling rates in men in the western world have been compensated by a steep increase in eastern Europe an Asia. Cigarette smoking is in 85% the main cause of this epidemic. Better understanding of genetic predisposition may identify patients at higher risk. Tumor in stage IA-IIB of non small cell carcinoma could gain by neoadjuvant chemotherapy, what is more probable for stage IIA and IIIB. Radiation therapy in combination with chemotherapy improves survival in inoperable stage IIIB. In stage IV disease palliative chemotherapy is superior to best supportive care.


A technique for extending the precision and the range of temperature programmed desorption toward extremely low coverages.
In this paper, an improvement of the temperature programmed desorption (TPD) technique is introduced, which facilitates fully automated sampling of TPD spectra with excellent reproducibility, especially useful for extremely low coverages. By averaging many sampled TPD spectra, the range of the TPD technique can be extended toward lower coverages, as well as the quality of the spectra can be improved. This allows for easy extraction of information about the adsorbate-surface bond. A state of the art TPD apparatus with a two chamber setup and a high quality quadrupole mass spectrometer was extended by automated components. These are an automated gas dosing system, ensuring precise dosing of gas, combined with a motor driven sample manipulation unit and a liquid nitrogen cryostat with automatic refilling. In addition all components were controlled by a computer. A large number of TPD cycles could be sampled without the need of interaction of an operator. Here, it is shown for up to more than 400 TPD cycles. This opens a wide range of new interesting applications for the TPD technique, especially in the limit of zero coverage. Here, basic experiments on well known adsorbate systems are shown to view the ability and limit of this approach.


Immune escape mechanism: defective resting and stimulated leukocyte-endothelium interaction in hepatocellular carcinoma of the rat.
Hepatocellular carcinoma represents an increasing therapeutic challenge due to its high incidence and early metastasis. Numerous studies have demonstrated the influence of the vascular system on tumor growth and development. In addition, the role of leukocyte-endothelium interaction in tumor vessels is of particular significance with regard to immunological tumor therapy. In this study we used an experimental in vivo animal model that allows a quantitative analysis on vessel morphology, microcirculation, and leukocyte-endothelium interaction. The vessel architecture in tumor tissue was found to be extremely heterogeneous, with a consecutively variable blood flow velocity. Following superfusion with chemotactic factors (fMLP, LB4), the leukocyte-endothelium interaction in tumor tissue with respect to leukocyte sticking was significantly reduced in comparison to healthy liver tissue. In conclusion, one of the main mechanisms for the reduced leukocyte-endothelium interaction in tumor tissue seems to be a decreased expression of adhesion molecules such as ICAM-1, indicating an effective immune escape mechanism for this tumor.


Apoptotic effects of signal transduction inhibitors on human tumor cells with different PTEN expression.
An important mechanism of antitumoral targeted therapies is the induction of apoptosis in tumor cells. Tamoxifen and trastuzumab (Herceptin), respectively, are able to trigger apoptosis in human breast cancer cells. But, frequently altered apoptotic signal cascades, for instance through PTEN mutations, help tumor cells to escape antitumoral therapy. We studied to what extent the apoptotic effect of signal-transduction inhibitors is dependent on PTEN expression. PTEN expression was analysed by Western blot analysis in tumor cell lines of the breast (BT-474, MCF-7, MDA-MB-231), ovary (BG-1, SK-OV-3) and endometrium (Ishikawa, HEC-1A). Apoptotic effects of tamoxifen, trastuzumab, ZD1839 (Iressa) and different mitogen-activated protein kinase (MAP) inhibitors were measured after 24 h of treatment. Cellular apoptosis was determined by the detection of cytoplasmic histone-DNA complexes. The tested tumor cell lines exhibited a different PTEN expression, ranging from a high expression (ovarian cancer cell line BG-1 and BT-474 breast cancer cells) to a total absence of PTEN expression (endometrial Ishikawa cells). The apoptotic effect of receptor-targeting drugs (tamoxifen, trastuzumab, ZD1839) was dependent both on receptor expression and PTEN expression. When cells were treated with MAPK inhibitors, no correlation between PTEN expression and the apoptosis rate was observed. Our data underline the importance of PTEN expression regarding the induction of apoptosis through various targeted therapies.


An unconventional myosin required for cell polarization and chemotaxis.
MyTH/FERM (myosin tail homology 4/band 4.1, ezrin, radixin, and moesin) myosins have roles in cellular adhesion, extension of actin-filled projections such as filopodia and stereocilia, and directional migration. The amoeba Dictyostelium discoideum expresses a simple complement of MyTH/FERM myosins, a class VII (M7) myosin required for cell-substrate adhesion and a unique myosin named MyoG. Mutants lacking MyoG exhibit a wide range of normal actin-based behaviors, including chemotaxis to folic acid, but have a striking defect in polarization and chemotaxis to cAMP. Although the myoG mutants respond to cAMP stimulation by increasing persistence and weakly increasing levels of cortical F-actin, they do not polarize; instead, they maintain a round shape and move slowly and randomly when exposed to a chemotactic gradient. The mutants also fail to activate and localize PI3K to the membrane closest to the source of chemoattractant. These data reveal a role for a MyTH/FERM myosin in mediating early chemotactic signaling and suggest that MyTH/FERM proteins have conserved roles in signaling and the generation of cell polarity.


Immunohistochemical study on gastrointestinal endocrine cells of four reptiles.
To clarify the types, regional distributions and distribution densities as well as morphological features of gastrointestinal (GI) endocrine cells in various parts of the gastrointestinal track (GIT) of four reptiles, Gekko japonicus, Eumeces chinensis, Sphenomorphus indicus and Eumeces elegans. Paraffin-embedded sections (5 mum) of seven parts (cardia, fundus, pylorus, duodenum, jejunum, ileum, rectum) of GIT dissected from the four reptiles were prepared. GI endocrine cells were revealed by using immunohistochemical techniques of streptavidin-peroxidase (S-P) method. Seven types of antisera against 5-hydroxy-tryptamine (5-HT), somatostatin (SS), gastrin (GAS), glucagon (GLU), substance P (SP), insulin and pancreatic polypeptide were identified and then GI endocrine cells were photomicrographed and counted. The GI endocrine system of four reptiles was a complex structure containing many endocrine cell types similar in morphology to those found in higher vertebrates. Five types of GI endocrine cells, namely 5-HT, SS, GAS, SP and GLU immunoreactive (IR) cells were identified in the GIT of G. japonicus, E. chinensis and S. indicus; while in the GIT of E. elegans only the former three types of endocrine cells were observed. No PP- and INS- IR cells were found in all four reptiles. 5-HT-IR cells, which were most commonly found in the pylorus or duodenum, distributed throughout the whole GIT of four reptiles. However, their distribution patterns varied from each other. SS-IR cells, which were mainly found in the stomach especially in the pylorus and/or fundus, were demonstrated in the whole GIT of E. chinensis, only showed restricted distribution in the other three species. GAS-IR cells, with a much restricted distribution, were mainly demonstrated in the pylorus and/or the proximal small intestine of four reptiles. GLU-IR cells exhibited a limited and species-dependent variant distribution in the GIT of four reptiles. SP-IR cells were found throughout the GIT except for jejunum in E. elegans and showed a restricted distribution in the GIT of G. japonicus and S. indicus. In the GIT of four reptiles the region with the highest degree of cell type heterogeneity was pylorus and most types of GI endocrine cells along the GIT showed the peak density in pylorus as well. Some common and unique features of the distribution and morphology of different types of GI endocrine cells are found in four reptiles. This common trait may reflect the similarity in digestive physiology of various vertebrates.


Bacillus subtilis RecO nucleates RecA onto SsbA-coated single-stranded DNA.
Subsaturating amounts of Bacillus subtilis SsbA, independently of the order of addition, partially inhibit the single-stranded DNA-dependent dATPase activity of RecA. This negative effect is fully overcome when a substoichiometric amount of RecO is added. SsbA added prior to RecA does not stimulate the dATP-dependent DNA strand exchange activity; however, added after RecA it enhances the extent of strand exchange. The addition of RecO stimulates RecA-mediated joint molecule formation, although it limits the accumulation of final recombination products. Thus we suggest that RecO has a dual activity: RecO acts as a RecA mediator enabling RecA to utilize SsbA-coated single-stranded DNA as a polymerization substrate and controls RecA-mediated DNA strand exchange by limiting its extent. We herein discuss the possible mechanisms of RecO involvement in the regulation of double strand break repair and genetic transformation.


Scale-free networks with tunable degree-distribution exponents.
We propose and study a model of scale-free growing networks that gives a degree distribution dominated by a power-law behavior with a model-dependent, hence tunable, exponent. The model represents a hybrid of the growing networks based on popularity-driven and fitness-driven preferential attachments. As the network grows, a newly added node establishes m new links to existing nodes with a probability p based on popularity of the existing nodes and a probability 1-p based on fitness of the existing nodes. An explicit form of the degree distribution P(p,k) is derived within a mean field approach. For reasonably large k, P(p,k) approximately k(-gamma(p)) F(k,p), where the function F is dominated by the behavior of 1/ln (k/m) for small values of p and becomes k independent as p-->1, and gamma(p) is a model-dependent exponent. The degree distribution and the exponent gamma(p) are found to be in good agreement with results obtained by extensive numerical simulations.


False-positive rates in two-point parametric linkage analysis.
Two-point linkage analyses of whole genome sequence data are a promising approach to identify rare variants that segregate with complex diseases in large pedigrees because, in theory, the causal variants have been genotyped. We used whole genome sequence data and simulated traits provided by Genetic Analysis Workshop 18 to evaluate the proportion of false-positive findings in a binary trait using classic two-point parametric linkage analysis. False-positive genome-wide significant log of odds (LOD) scores were identified in more than 80% of 50 replicates for a binary phenotype generated by dichotomizing a quantitative trait that was simulated with a polygenic component (that was not based on any of the provided whole genome sequence genotypes). In contrast, when the trait was truly nongenetic (created by randomly assigning affected-unaffected status), the number of false-positive results was well controlled. These results suggest that when using two-point linkage analyses on whole genome sequence data, one should carefully examine regions yielding significant two-point LOD scores with multipoint analysis and that a more stringent significance threshold may be needed.


Acidification improves cryotolerance of Lactobacillus delbrueckii subsp. bulgaricus CFL1.
The effect of acidification of the fermented broth at the end of the culture was examined on the growth and the cryotolerance of Lactobacillus bulgaricus CFL1, as a new means to better preserve lactic acid bacteria. Cryotolerance was investigated by evaluating the loss of specific acidification activity during freezing and frozen storage. An experimental design made it possible to determine optimal acidification conditions that improved cryotolerance, such as pH 5.15 for 30min. These conditions were also conducive to high biomass productivity. By considering the type of acid used, H(2)SO(4) enabled us to obtain cells with better cryotolerance, as compared to HCl. It was also observed that increasing the pH after acidification slightly minimised the acid shock, thus improving cryotolerance. Moreover, it was concluded that this improvement was related to a physiological adaptation of L. bulgaricus CFL1 during the 30-min acidification at pH 5.15.


Tuning multidomain hemodynamic simulations to match physiological measurements.
In recent years, considerable progress has been made in creating more realistic models of the cardiovascular system, often based on patient-specific anatomic data, whereas comparatively little progress has been made on incorporating measured physiological data. We have developed a method to systematically adjust the parameters of three-element windkessel outlet boundary conditions of three-dimensional blood flow models such that desired features of pressure and flow waveforms are achieved. This tuning method was formulated as the solution of a nonlinear system of equations and employed a quasi-Newton method that was informed by a reduced-order model. The three-dimensional hemodynamic models were solved using a stabilized finite-element method incorporating deformable vessel walls. The tuning method was applied to an idealized common carotid artery, an idealized iliac arterial bifurcation, and a patient-specific abdominal aorta. The objectives for the abdominal aortic model were values of the maximum and minimum of the pressure waveform, an indicator of the pressure waveform's shape, and the mean, amplitude, and diastolic mean of the flow waveform for an infrarenal measurement plane. The hemodynamic models were automatically generated and tuned by custom software with minimal user input. This approach enables efficient development of cardiovascular models for applications including detailed evaluation of cardiovascular mechanics, simulation-based design of medical devices, and patient-specific treatment planning.


Structural and magnetic properties of CoGe(n)- (n=2-11) clusters: photoelectron spectroscopy and density functional calculations.
A series of cobalt-doped germanium clusters, CoGe(n)(-/0) (n=2-11), are investigated by using anion photoelectron spectroscopy combined with density functional theory calculations. For both anionic and neutral CoGe(n) (n=2-11) clusters, the critical size of the transition from exo- to endohedral structures is n=9. Natural population analysis shows that there is electron transfer from the Ge(n) framework to the Co atom at n=7-11 for both anionic and neutral CoGe(n) clusters. The magnetic moments of the anionic and neutral CoGe(n) clusters decrease to the lowest values at n=10 and 11. The transfer of electrons from the Gen framework to the Co atom and the minimization of the magnetic moments are related to the evolution of CoGe(n) structures from exo- to endohedral.


[The effects of iodine/selenium on the function of antigen presentation of peritoneal macrophages in rats].
To observe the effects of iodine/selenium on the function of antigen presentation of peritoneal macrophages in rats and explore the immunological mechanisms of iodine/ selenium's role in pathogenesis of autoimmune thyroid diseases (AITD). Female Lewis rats were randomly divided into four groups including (1) low selenium and normal iodine group (L(sE)N(I)) (2) low selenium and high iodine group (L(Se)H(I)) (3) normal selenium and normal iodine group (N(Se)N(I) ) (4) normal selenium and high iodine group (N(Se)H(I)). All rats were fed by a special diet with lower selenium and iodine in it and drunk ion-free water containing different levels of iodine and selenium for 3 months. Peritoneal macrophages of each group and OVA allergized T cells were prepared and cultured together. Then the function of antigen presentation were estimated by detecting the levels of IL-2 in the culture supernatant. The levels of the expression of co-stimulator CD86 in the spleen of each group were determined by RT-PCR. The level of IL-2 in the supernatant in N(Se)H(I) (43.22 +/- 3.27) pg/ml was much stronger than N(Se)N(I) [the level of IL-2 was (25.74 +/- 2.45) pg/ml, P < 0.05]. The level of IL-2 in L(Se)N(I) (15.79 +/- 2.13) pg/ml was significantly lower than N(Se)N(I) (P < 0.05). The expression of CD86 mRNA in N(Se)H(I) (CD86/beta-actin: 0.52 +/- 0.10) were higher than N(Se)N(I) (CD86/beta-actin: 0.35 +/- 0.04), P < 0.05. High iodine could promote the presentation function of macrophages to a higher state than normal. Therefore, high iodine intake might become an importantly inducing factor in thyroid autoimmunity. Low selenium could weaken the ability of recognizing and presenting OVA antigen of peritoneal macrophages which might destroy immunological homeostasis and thus the low selenium intake might also become an inducer of AITD.


Composite grafts in the treatment of osteosarcoma of the proximal humerus.
Treatment of osteosarcoma (OSA) of the proximal humerus poses many difficulties and challenges to the treating team. Between 1993 and 2000, we treated 11 patients (three women, eight men; age range, 17-74 years) suffering from OSA of the proximal humerus by 'composite': massive allografts and long humeral prosthesis. At presentation, 10 patients were at stage 2-B and one at stage 3-B of OSA. One patient presented with a pathologic fracture. All patients except patient No. 6, received preoperative chemotherapy followed by limb salvage surgery and postoperative chemotherapy.Surgical margins were graded as wide in all patients. Postoperative complications included non-union at the allograft/host junction (which united after auto grafting) and superficial wound infections that resolved after antibiotic therapy. All surgical procedures were performed by a team headed by an orthopedic oncologist and shoulder surgeon. At latest follow-up (December 2001) all patients, with the exception of one (who was at stage 3-B at presentation) were alive, and had good function of the upper limb. It is our opinion that the team approach comprising an orthopedic oncologist and shoulder surgeon greatly contributed to the good surgical outcome, and hence the good survival and functional results of the patients. Bone allograft offers a modular malleable durable solution to the resected bone segment.


Oncologic Safety of Robot Thyroid Surgery for Papillary Thyroid Carcinoma: A Comparative Study of Robot versus Open Thyroid Surgery Using Inverse Probability of Treatment Weighting.
The aim of this study was to evaluate the oncologic safety of robot thyroid surgery compared to open thyroid surgery for papillary thyroid carcinoma (PTC). We enrolled 722 patients with PTC who underwent a total thyroidectomy with central compartment node dissection (CCND) from January 2009 to December 2010. These patients were classified into open thyroid surgery (n = 610) or robot thyroid surgery (n = 112) groups. We verified the impact of robot thyroid surgery on clinical recurrence and ablation/control-stimulated thyroglobulin (sTg) levels predictive of non-recurrence using weighted logistic regression models with inverse probability of treatment weighting (IPTW). Age, sex, thyroid weight, extent of CCND, and TNM were significantly different between the two groups (p < 0.05); however, there was no significant difference in recurrence between the open and robot groups (1.5% vs. 2.7%; p = 0.608). The proportion of patients with ablation sTg < 10.0 ng/mL and control sTg < 1.0 ng/mL was comparable between the two groups (p > 0.05). Logistic regression with IPTW using the propensity scores estimated by adjusting all of the parameters demonstrated that robot thyroid surgery did not influence the clinical recurrence (OR; 0.784, 95% CI; 0.150-3.403, p = 0.750), ablation sTg (OR; 0.950, 95% CI; 0.361-2.399, p = 0.914), and control sTg levels (OR; 0.498, 95% CI; 0.190-1.189, p = 0.130). Robot thyroid surgery is comparable to open thyroid surgery with regard to oncologic safety in PTC patients.


AAEE minimonograph #30: electrophysiologic studies of myoclonus.
Definition as well as classification of myoclonus and electrophysiologic methods for investigating myoclonus were reviewed. Among the electrophysiologic techniques currently available in most laboratories, the EEG-EMG polygraph is the most essential one and can provide us with the most important information. Jerk-locked averaging and evoked potential studies are useful for further investigating the pathophysiology of myoclonus and can be performed by using the same recording electrodes as those used for the polygraph. Jerk-locked evoked potentials and double-stimulation evoked potentials can be employed only for further investigating how cerebral cortex is involved in the generation of certain myoclonia. All these techniques can be used in proper combinations depending on the clinical features of the myoclonus in question, the purpose of the study, and the facilities available in each laboratory. These techniques also will be useful for following the clinical course during the treatment with antimyoclonus agents.


Retention and sustained viral suppression in HIV patients transferred to community refill centres in Kinshasa, DRC.
In 2010, Médecins Sans Frontières set up decentralised community antiretroviral therapy (ART) refill centres ("poste de distribution communautaire", PODI) for the follow-up of stable human immunodeficiency virus (HIV) patients. To assess retention in care and sustained viral suppression after transfer to three main PODI in Kinshasa, Democratic Republic of Congo (DRC) (PODI Barumbu/Central, PODI Binza Ozone/West and PODI Masina I/East). Retrospective cohort study using routine programme data for adult HIV patients transferred from Kabinda Hospital to PODIs between January 2015 and June 2017. A total of 337 patients were transferred to PODIs: 306 (91%) were on ART for at least 12 months; 118 (39%) had a routine "12-month" viral load (VL) done, 93% (n = 110) of whom had a suppressed VL <1000 copies/ml. Median time from enrolment into PODI to 12-month routine VL was 14.6 months (IQR 12.2-20.8). Kaplan-Meier estimates of retention in care at 6, 12 and 18 months after enrolment into PODIs were respectively 96%, 92% and 88%. Retention in care and viral suppression among patients in PODI with VL results were better than patients in clinic care and national outcomes.


Metasurface-Assisted Terahertz Sensing.
Terahertz (THz) waves, which fall between microwaves and infrared bands, possess intriguing electromagnetic properties of non-ionizing radiation, low photon energy, being highly sensitive to weak resonances, and non-polar material penetrability. Therefore, THz waves are extremely suitable for sensing and detecting chemical, pharmaceutical, and biological molecules. However, the relatively long wavelength of THz waves (30~3000 μm) compared to the size of analytes (1~100 nm for biomolecules, <10 μm for microorganisms) constrains the development of THz-based sensors. To circumvent this problem, metasurface technology, by engineering subwavelength periodic resonators, has gained a great deal of attention to enhance the resonance response of THz waves. Those metasurface-based THz sensors exhibit high sensitivity for label-free sensing, making them appealing for a variety of applications in security, medical applications, and detection. The performance of metasurface-based THz sensors is controlled by geometric structure and material parameters. The operating mechanism is divided into two main categories, passive and active. To have a profound understanding of these metasurface-assisted THz sensing technologies, we review and categorize those THz sensors, based on their operating mechanisms, including resonators for frequency shift sensing, nanogaps for enhanced field confinement, chirality for handedness detection, and active elements (such as graphene and MEMS) for advanced tunable sensing. This comprehensive review can serve as a guideline for future metasurfaces design to assist THz sensing and detection.


Patients' attitudes and preferences toward delayed disease progression in the absence of improved survival.
Cancer patients' attitudes toward progression-free survival (PFS) gains offered by treatment are not well understood, particularly in the absence of overall survival (OS) gains. The objectives were to describe patients' willingness to accept treatment that offers PFS gains without OS gains, to compare these findings with treatments offering OS gains, and to qualitatively summarize patients' reasons for their preferences. A multicenter, cross-sectional, convergent mixed-methods study design recruited patients who had received at least 3 months of systemic therapy for incurable solid tumors. A treatment trade-off exercise determined the gains in imaging PFS that patients require to prefer additional systemic treatment for a scenario of a newly diagnosed, asymptomatic, incurable abdominal tumor. A qualitative, descriptive, thematic analysis explored factors influencing patients' decisions, and a narrative method integrated the quantitative and qualitative findings. In total, 100 patients participated (63% were older than 60 years of age). If additional treatment with added toxicity offered no OS advantage, 17% would prefer it for no PFS benefit; 26% for some PFS benefit (range, 3-9 months), whereas 51% would decline it regardless of PFS benefit. Similarly, 71% preferred additional treatment offering a 6-month OS advantage dependent on described toxicity levels (P = .03). A spectrum of reasons for these preferences reflected the complexity of participants' attitudes and values. Prolongation of time to progression was not universally valued. Most patients did not prefer treatments that negatively affect quality of life for PFS gains alone. Implications for individual decision making, policy, and trials research are discussed.


Fermi-level shift, electron separation, and plasmon resonance change in Ag nanoparticle-decorated TiO2 under UV light illumination.
Noble metal nanoparticles are widely used as co-catalysts for storing and separating electrons in semiconductor photocatalysis. Thus, evaluating this ability is important and meaningful to understand the photocatalytic mechanism. Employing Ag nanoparticles, the present study combined in situ photoconductance and theoretical analysis to evaluate the Fermi-level (EF) shift in a UV-illuminated Ag/TiO2 system under gaseous conditions. Based on this, the role of the Ag nanoparticles in storing and separating electrons was discussed. It was found that the EF of Ag/TiO2 is located deeper in the gap and a variation in temperature has less effect on the EF of Ag/TiO2 compared to the undecorated TiO2. The analysis showed that ∼46 electrons can be stored in 10 nm Ag nanoparticles under our experimental conditions, which does not change with temperature. The electron traps in TiO2 can affect the electron distribution in the TiO2 and Ag nanoparticles. It was observed that the localized surface plasmon resonance (LSPR) of the Ag nanoparticles exhibited a blue-shift under UV light illumination, which is generally ascribed to the electron storage in the Ag nanoparticles. However, we showed that the blue-shift is not related to the electron storage in the Ag nanoparticles, and thus it cannot be used as an indicator for evaluating their electron-storage ability. The in situ XPS analysis also does not support that the LSPR blue shift is associated with the reduction in the Ag2O layer and TiO2.


Twenty-four-hour preservation of the duct-ligated canine pancreatic allograft.
Twenty previously pancreatectomized dogs received a duct-ligated pancreatic allograft; 16 of the grafts were preserved for 24 h, 9 with continuous hypothermic albumin perfusion, 7 with simple hypothermic storage; 4 glands were transplanted immediately and served as controls. The outcome of preservation was assessed by studying the early endocrine function of the glands. Excluding five early failures due to bleeding, all grafts showed endocrine activity after transplantation and the glucose values were on a normal level. An initial hyperglucemia caused by pancreatectomy disappeared within 24h. In the two groups with 24h preservation, no differences in graft function were found. In the control group, there was a hypoglucemic tendency the first days after transplantation and a prolonged hyperinsulinemia during glucose load. It could be concluded that duct-ligated, isolated canine pancreas well tolerated 24h of preservation both by continuous hypothermic albumin perfusion and by simple hypothermic storage in an extracellular type of fluid.


P105 as a prognostic indicator in patients irradiated for locally advanced head-and-neck cancer: a clinical/laboratory correlative analysis of RTOG-9003.
In a previous retrospective study, p105 AD, a proliferation-associated nuclear antigen density (AD), was found to be an independent prognostic factor for patients irradiated for locally advanced head-and-neck cancer. We sought to confirm this finding by analyzing patients entered on RTOG 9003, a Phase III randomized trial of altered fractionation radiotherapy. Paraffin blocks of pretreatment biopsies of the primary tumor of patients with Stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, or supraglottic larynx, or Stage II squamous cell carcinoma of the hypopharynx or base of tongue entered on RTOG 9003 were prospectively collected at patient entry. From these paraffin blocks, areas of tumor were selected based on histologic examinations and sectioned. Nuclear suspensions were then prepared and processed for p105 antibody and DNA staining. Flow cytometric quantification of p105 labeling indices and DNA content were then performed for correlation with local-regional control and survival. Paraffin blocks of tumor biopsies from 457 of 1073 patients entered were available for p105 determination. There was no significant difference in pretreatment characteristics between patients who had paraffin blocks available or not available. The median (range) of p105 labeling index (LI-C), p105 labeling index of cells in S phase (p105 LI-S), and p105 AD were 56 (range: 6-99), 8.255 (range: 0.913-23), and 67 (range: 5-364), respectively. Multivariate analysis of prognostic factors showed that T stage, N stage, Karnofsky performance status, and fractionation schedule were significant for local-regional control (p < 0.0001, 0.0011, <0.0001, and 0.007, respectively) and T stage, N stage, Karnofsky performance status, and tumor grade were significant for survival (p = 0.018, 0.002, <0.0001, and 0.0058, respectively). Neither p105 LI-C nor p105 LI-S nor p105 AD nor DNA ploidy was significant for local-regional control or survival. p105 labeling indices, antigen density, and DNA ploidy do not predict the outcome of patients irradiated for advanced squamous cell carcinomas of the head and neck.


Real-world assessment of immunogenicity in immunocompromised individuals following SARS-CoV-2 mRNA vaccination: a one-year follow-up of the prospective clinical trial COVAXID.
Immunocompromised patients have varying responses to SARS-CoV-2 mRNA vaccination. However, there is limited information available from prospective clinical trial cohorts with respect to long-term immunogenicity-related responses in these patient groups following three or four vaccine doses, and in applicable cases infection. In a real-world setting, we assessed the long-term immunogenicity-related responses in patients with primary and secondary immunodeficiencies from the prospective open-label clinical trial COVAXID. The original clinical trial protocol included two vaccine doses given on days 0 and 21, with antibody titres measured at six different timepoints over six months. The study cohort has subsequently been followed for one year with antibody responses evaluated in relation to the third and fourth vaccine dose, and in applicable cases SARS-CoV-2 infection. In total 356/539 patients were included in the extended cohort. Blood samples were analysed for binding antibody titres and neutralisation against the Spike protein for all SARS-CoV-2 variants prevailing during the study period, including Omicron subvariants. SARS-CoV-2 infections that did not require hospital care were recorded through quarterly in-person, or phone-, interviews and assessment of IgG antibody titres against SARS-CoV-2 Nucleocapsid. The original clinical trial was registered in EudraCT (2021-000175-37) and clinicaltrials.gov (NCT04780659). The third vaccine dose significantly increased Spike IgG titres against all the SARS-CoV-2 variants analysed in all immunocompromised patient groups. Similarly, neutralisation also increased against all variants studied, except for Omicron. Omicron-specific neutralisation, however, increased after a fourth dose as well as after three doses and infection in many of the patient subgroups. Noteworthy, however, while many patient groups mounted strong serological responses after three and four vaccine doses, comparably weak responders were found among patient subgroups with specific primary immunodeficiencies and subgroups with immunosuppressive medication. The study identifies particularly affected patient groups in terms of development of long-term immunity among a larger group of immunocompromised patients. In particular, the results highlight poor vaccine-elicited neutralising responses towards Omicron subvariants in specific subgroups. The results provide additional knowledge of relevance for future vaccination strategies. The present studies were supported by grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, and Karolinska Institutet.


The influence of host blood on infection rates in Glossina morsitans sspp. infected with Trypanosoma congolense, T. brucei and T. simiae.
Trypanosoma congolense, T. brucei and T. simiae isolated from wild-caught Glossina pallidipes were fed to laboratory-reared G. morsitans centralis and G.m. morsitans to determine the effect of host blood at the time of the infective feed on infection rates. Bloodstream forms of trypanosomes were membrane-fed to flies either neat, or mixed with blood from cows, goats, pigs, buffalo, eland, waterbuck and oryx. The use of different bloods for the infective feed resulted in differences in infection rates that were repeatable for both tsetse subspecies and most parasite stocks. Goat, and to a lesser extent, pig blood facilitated infection, producing high infection rates at low parasitaemias. Blood from cows and the wildlife species produced low infection rates, with eland blood producing the lowest. Addition of D(+)-glucosamine (an inhibitor of tsetse midgut lectin) increased infection rates in most cases. These results indicate the presence of species-specific factors in blood that affect trypanosome survival in tsetse. In certain hosts, factors actually appear to promote infection. The nature of these factors and how they might interact with midgut lectins and proteases are discussed.


Macrophage migration inhibitory factor: a neuroendocrine modulator of chronic inflammation.
The diverse actions of macrophage migration inhibitory factor (MIF) within the immuno-neuroendocrine system are yet to be fully understood, but it is clear that MIF plays a pivotal role in the regulation of both the innate and adaptive immune response. An emerging body of data presently indicates that MIF's position within the cytokine cascade is to act in concert with glucocorticoids to control the 'set point' and magnitude of the immune and inflammatory response. In this article we will review the actions of MIF within the immune system and discuss the overlapping and contrasting aspects of MIF and glucocorticoid biology. In particular we will focus on the role of MIF within the immuno-neuroendocrine interface and suggest molecular mechanisms by which MIF may counter-regulate glucocorticoid function. Finally we will discuss emerging evidence that functional MIF gene-promoter polymorphisms render one susceptible to elevated MIF expression, and the development of an exaggerated immune/inflammatory response that potentiates the progression to chronic inflammatory disease.


How does the timing of antiretroviral therapy initiation in acute infection affect HIV reservoirs?
The long-lived viral reservoir is a major obstacle to achieving a cure for HIV. Therapeutic strategies, such as early antiretroviral therapy (ART), may be a prerequisite to achieving long-term control of viral replication upon ART withdrawal. HIV persistence is established early in acute HIV infection (AHI) with infection in long-lived memory CD4⁺ T cells. Studies conducted in nonhuman primates have suggested that this could occur as early as 3 days postinfection; however, the timing in humans is uncertain. ART during AHI significantly restricts the HIV reservoirs as compared with later treatment. Early ART, particularly prior to the detection of HIV immunoglobulin M, may also reduce the contribution of the long-lived central memory CD4⁺ T cells to the total HIV reservoir, a profile observed in individuals who naturally control HIV without ART. It is clear that early ART has a greater impact in limiting the HIV reservoirs than later treatment. However, latently infected long-lived memory CD4⁺ T cells persist in most early treated individuals. Therefore, additional interventions will likely be required to eliminate all cells capable of producing replication-competent virus but treatment in AHI may be the critical first step in containing the HIV reservoirs.


In silico prediction of the effects of mutations in the human triose phosphate isomerase gene: Towards a predictive framework for TPI deficiency.
Triose phosphate isomerase (TPI) deficiency is a rare, but highly debilitating, inherited metabolic disease. Almost all patients suffer severe neurological effects and the most severely affected are unlikely to live beyond early childhood. Here, we describe an in silico study into well-characterised variants which are associated with the disease alongside an investigation into 79 currently uncharacterised TPI variants which are known to occur in the human population. The majority of the disease-associated mutations affected amino acid residues close to the dimer interface or the active site. However, the location of the altered amino acid residue did not predict the severity of the resulting disease. Prediction of the effect on protein stability using a range of different programs suggested a relationship between the degree of instability caused by the sequence variation and the severity of the resulting disease. Disease-associated variations tended to affect well-conserved residues in the protein's sequence. However, the degree of conservation of the residue was not predictive of disease severity. The majority of the 79 uncharacterised variants are potentially associated with disease since they were predicted to destabilise the protein and often occur in well-conserved residues. We predict that individuals homozygous for the corresponding mutations would be likely to suffer from TPI deficiency.


Markers of tissue response to thyroid hormones in patients with hyperthyroidism or hypothyroidism.
Changes in serum cholesterol and aminoterminal type III procollagen propeptide (PIIIPN) were compared in 33 patients with hyperthyroidism, 16 patients with hypothyroidism, and 23 healthy individuals. An increase in PIIIPN was found in patients with hyperthyroidism and an increase in serum cholesterol level was associated with hypothyroidism. There was no correlation between investigated indices. It is suggested that PIIIPN changes were a result of altered connective tissue metabolism, while serum cholesterol was related to the intensity of body metabolism.


2-Aminopurine abolishes epidermal growth factor-stimulated phosphorylation of complexed and chromatin-associated forms of a 33 kDa phosphoprotein.
We have recently reported that several purified polypeptide mitogens such as epidermal growth factor, embryonal carcinoma-derived growth factor, basic fibroblast growth factor and Bombesin induce the rapid appearance of a 33 kDa chromatin-associated phosphoprotein in the nuclei of murine fibroblasts. We show here that in both mouse and human cell lines, a second form of the 33 kDa phosphoprotein exists in a detergent-extractable complexed form which may be pelleted by ultracentrifugation. When quiescent [32P]-labelled cells are treated with EGF, both complexed and chromatin-associated forms of the labelled phosphoprotein are detectable within 10 min, the response peaking at about 1 h and being substantially over 3 h after EGF stimulation. By chymotryptic and cyanogen bromide phosphopeptide mapping studies, the two forms of the 33 kDa phosphoprotein are indistinguishable, as are the mouse and human forms of the protein. The protein kinase inhibitor 2-aminopurine, which has recently been shown to block growth factor-stimulated c-fos and c-myc induction, specifically abolishes the mitogen-stimulated appearance of both forms of the 33 kDa phosphoprotein without affecting the phosphorylation of other cellular proteins. The 33 kDa protein has been purified from Hela cells by a combination of sucrose density gradient centrifugation, preparative electrophoresis and reverse-phase HPLC during which the protein is resolved into two closely-eluting peaks which differ markedly in their specific activity. These results are discussed in relation to the possible role of these events in coupling growth factor-receptor interaction at the cell surface to the early responses of transcriptional activation in the nucleus.


Use of Mesenchymal Stem Cells in Experimental Ovarian Damage.
Bisphenol-A (BPA) has a well-proven deleterious effect on the hypothalamic-pituitary-gonadal axis. The current study investigated the therapeutic potentials of mesenchymal stem cells (MSCs) in a murine model of BPA-induced ovarian damage. Fifty adult female rats were divided into: Group 1; control group, Group IIa, IIb: rats were given oral gavage of BPA (25 and 50 mg/Kg body weight respectively) on a daily basis for 15 days, and Group IIIa, IIIb; rats were intravenously treated with of MSCs (106 cells) after receiving the last dose of BPA as in group II. Plasma and ovarian tissue levels of Malondialdehyde (MDA) and gonadal axis hormones were assessed. Apoptosis was evaluated by TUNNEL assay and by apoptosis markers (FAS, FASL, Caspase 3, SLTM). A histological examination of ovarian tissue was also conducted. BPA resulted in a significant elevation in plasma levels of LH, FSH, and ovarian tissue levels of MDA and a significant decrease in estradiol and progesterone. All genetic and protein markers of apoptosis were elevated in BPA treated group with decreased oestrogen receptor expression in the ovarian tissue. Increased apoptotic cells were confirmed by TUNEL assay. A high dose of BPA was able to increase the number of atretic follicles in the ovarian tissue whereas the numbers of primordial, primary, secondary and Graafian follicles were decreased. All the laboratory and histological abnormalities were ameliorated by treatment with MSCs. The antioxidant and anti-apoptotic effects of MSCs could possibly explain the ability of this therapeutic modality to ameliorate BPA-induced-ovarian damage.


Predisposing, Enabling, and Reinforcing Factors Associated with Mammography Referrals in U.S. Primary Care Practices.
OBJECTIVE: We examined how predisposing, enabling and reinforcing factors influence mammography referrals by primary care physicians (PCPs). METHODS: Using the 2001-2003 National Ambulatory Medical Care and National Hospital Ambulatory Medical Care Surveys, we identified visits to office (n=8,756) and outpatient (n=17,067) PCPs by women≥40 without breast symptoms or breast cancer. We examined mammography referrals by predisposing (age, race, ethnicity, education, chronic problem), enabling (income, payer, visits within 12 months, time with physician), and reinforcing factors (physician age, gender, specialty/clinic, PCP status, region, MSA, solo/group practice). Gender, specialty, physician age, time with physician and solo/group were only in NAMCS. Clinic type was only in NHAMCS. We fitted logistic regression models adjusted for all factors and year. RESULTS: Office-based referrals were more likely during visits: for preventive or chronic care; with private payer vs self/uninsured; by women with no visit within 12 months vs≥3; lasting≥15 minutes; to female PCPs; to PCPs aged ≥45; to gynecologists. Outpatient referrals were more likely during visits: by Hispanics; for preventive or chronic care; by women with no visit within 12 months; to one's own PCP; to gynecologic clinics; in the Northeast or Midwest. CONCLUSIONS: Reinforcing factors, in addition to predisposing and enabling factors, are associated with mammography referral. Interventions to increase referrals should consider provider factors and aspects of the healthcare environment, and recognize differences between settings. Efforts to facilitate referrals during chronic care visits or outpatient visits to non-PCP providers may provide opportunities to increase screening. Efforts are needed to ensure that uninsured women are receiving appropriate referrals.


Determinants of Dropout and Nonadherence in a Dementia Prevention Randomized Controlled Trial: The Prevention of Dementia by Intensive Vascular Care Trial.
To explore and compare sociodemographic, clinical, and neuropsychiatric determinants of dropout and nonadherence in older people participating in an open-label cluster-randomized controlled trial-the Prevention of Dementia by Intensive Vascular care (preDIVA) trial-over 6 years. Secondary analysis. One hundred sixteen general practices in the Netherlands. Community-dwelling individuals aged 70 to 78 (N = 2,994). Nurse-led multidomain intervention targeting cardiovascular risk factors to prevent dementia. The associations between participant baseline sociodemographic (age, sex, education), clinical (medical history, disability, cardiovascular risk), neuropsychiatric (depressive symptoms (Geriatric Depression Scale-15), and cognitive (Mini-Mental State Examination)) characteristics and dropout from the trial and nonadherence to the trial intervention were explored using multilevel logistic regression models. Older age, poorer cognitive function, more symptoms of depression, and greater disability were the most important determinants of dropout of older people. The presence of cardiovascular risk factors was not associated with dropout but was associated with nonadherence. Being overweight was a risk factor for nonadherence, whereas people with high blood pressure or a low level of physical exercise adhered better to the intervention. The association between poorer cognitive function and symptoms of depression and dropout was stronger in the control group than in the intervention group, and vice versa for increased disability. In a large dementia prevention trial with 6-year follow-up, dropout was associated with older age, poorer cognitive function, symptoms of depression, and disability at baseline. These findings can help to guide the design of future dementia prevention trials in older adults. The associations found between cardiovascular risk factors and nonadherence need to be confirmed in other older populations receiving cardiovascular prevention interventions.


Age-related changes in the regulation of transcription factor NF-kappa B in rat brain.
Aging process involves an increase in stress at cellular level. We studied whether aging affects the regulation of stress responsive transcription factor NF-kappa B in brain samples of Wistar rats. Hippocampus, cerebellum, and temporal and frontal lobes of cortex were studied. We observed a significant up-regulation in the constitutive, nucleus-located NF-kappa B binding activity in 30-month-old Wistar rats compared to young and 18-month-old rats. The increase was most prominent in cerebellum and in frontal cortex, but age-related changes did not occur in hippocampus. Inducible, cytoplasmic NF-kappa B binding activity was not affected by aging in any of the samples studied. Western blot assays did not show any age-related changes in the nuclear level of p50, p52, and p65 protein components of NF-kappa B complex. Cytoplasmic level of inhibitory I kappa B-alpha was also unaffected. The increase in nuclear constitutive NF-kappa B binding activity during aging may be related to the NF-kappa B driven cellular response to adapt neurons against apoptotic pressure, as observed recently in several apoptotic conditions.


Biophysical analysis of Arabidopsis protein-only RNase P alone and in complex with tRNA provides a refined model of tRNA binding.
RNase P is a universal enzyme that removes 5' leader sequences from tRNA precursors. The enzyme is therefore essential for maturation of functional tRNAs and mRNA translation. RNase P represents a unique example of an enzyme that can occur either as ribonucleoprotein or as protein alone. The latter form of the enzyme, called protein-only RNase P (PRORP), is widespread in eukaryotes in which it can provide organellar or nuclear RNase P activities. Here, we have focused on Arabidopsis nuclear PRORP2 and its interaction with tRNA substrates. Affinity measurements helped assess the respective importance of individual pentatricopeptide repeat motifs in PRORP2 for RNA binding. We characterized the PRORP2 structure by X-ray crystallography and by small-angle X-ray scattering in solution as well as that of its complex with a tRNA precursor by small-angle X-ray scattering. Of note, our study reports the first structural data of a PRORP-tRNA complex. Combined with complementary biochemical and biophysical analyses, our structural data suggest that PRORP2 undergoes conformational changes to accommodate its substrate. In particular, the catalytic domain and the RNA-binding domain can move around a central hinge. Altogether, this work provides a refined model of the PRORP-tRNA complex that illustrates how protein-only RNase P enzymes specifically bind tRNA and highlights the contribution of protein dynamics to achieve this specific interaction.


Patterns of vascular sprouting in the postnatal development of the cerebral cortex of the rat.
Light microscopic histochemistry for alkaline phosphatase was employed in a study of the development of vascular sprouting, with respect to time and distribution, inthe rat cerebral cortex. Sprouts were counted in the full thickness of the cerebral cortex at each day from birth to 21 days of age. Several distinct bursts of sprouting activity were observed at specific times and levels of cortex. From birth to 4 days of age, sprouting was intense in the superficial third of the cortex. At 7 to 8 days, a burst of sprouting was found which was greatest in the middle third. Additional bursts of sprouting appeared at 10 and 14 days. Developing vessels with characteristics of arteries, capillaries, or sprouts were alkaline-phosphatase positive, while veins were not. It is concluded that alkaline phosphatase is a useful marker for identification of both mature and immature vasculature, as it reveals patent and nonpatent vessels, and the sprouts which are precursors of the mature vascular bed. New vessels developing in the cortex arise mainly from blind sprouts of capillaries, evidently in response to the metabolic demands imposed by the maturational process. At birth, the majority of intracortical vessels are capillaries. By 10 days of age, most perforating vessels from the surface have taken on arterial or venous characteristics. The findings are discussed in connection with morphological and biochemical differentiation and the pattern of vascularization in the mature cerebral cortex.


RNA Analysis as a Tool to Determine Clinically Relevant Gene Fusions and Splice Variants.
- Technologic advances have contributed to the increasing relevance of RNA analysis in clinical oncology practice. The different genetic aberrations that can be screened with RNA include gene fusions and splice variants. Validated methods of identifying these alterations include fluorescence in situ hybridization, immunohistochemistry, reverse transcription-polymerase chain reaction, and next-generation sequencing, which can provide physicians valuable information on disease and treatment of cancer patients. - To discuss the standard techniques available and new approaches for the identification of gene fusions and splice variants in cancer, focusing on RNA analysis and how analytic methods have evolved in both tissue and liquid biopsies. - This is a narrative review based on PubMed searches and the authors' own experiences. - Reliable RNA-based testing in tissue and liquid biopsies can inform the diagnostic process and guide physicians toward the best treatment options. Next-generation sequencing methodologies permit simultaneous assessment of molecular alterations and increase the number of treatment options available for cancer patients.


Yaws in Polynesia's Wallis and Futuna Islands: a seroprevalence survey.
We carried out a serological and clinical survey to determine the prevalence and clinical presentation of yaws on two twin islands in Polynesia: Wallis and Futuna. A total of 264 serum samples were tested for specific Treponema pallidum haemagglutinations assay and non-specific rapid plasma reagin: 52 were positive for one or both tests; only one young adult had skin lesion consistent with yaws; and there were no observed cases of secondary or tertiary yaws. Our results contrast with findings in neighbouring islands, such as Vanuatu, where yaws has been reported to resurge. This difference might be explained by better availability and accessibility of healthcare on Wallis and Futuna, thus allowing widespread use of antibiotics for other bacterial diseases.


Pharmacokinetics, pharmacodynamics, and safety of the 5-HT(1B/1D) agonist eletriptan following intravenous and oral administration.
Four separate studies were conducted to examine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of eletriptan, a 5-HT(1B/1D) receptor agonist being developed for the treatment of migraines, after oral and intravenous administration. Fifty-five males received oral (1.5-30 mg or 30-120 mg) or intravenous (1.67-50 microg/kg or 50-102 microg/kg) eletriptan in four double- and single-blind, placebo-controlled, ascending-dose crossover studies. The maximum plasma concentration (Cmax) and area under the concentration curve (AUC) appeared linear over all dose ranges, with an apparent terminal half-life of 4 to 5 hours. Clearance and volume of distribution remained constant with dose. The time to first occurrence of Cmax (tmax) for oral eletriptan was approximately 1 hour and was unaffected by dose. Comparison of AUC values suggested an absolute bioavailability of approximately 50%. A linear PK/PD model, fitted to the data, predicted small, transient elevations in diastolic blood pressure following eletriptan doses > or = 60 mg. These effects were considered unlikely to be clinically significant. Eletriptan was well tolerated, and treatment-related adverse events were mild to moderate and transient. These PK properties should result in eletriptan having a rapid onset and sustained duration of action in terms of migraine efficacy.


Treatment outcomes of retrograde intrarenal surgery for renal stones and predictive factors of stone-free.
The aim of this study was to evaluate the efficacy and safety of retrograde intrarenal surgery (RIRS) for the treatment of renal stones and to analyze the predictive factors for stone-free. We retrospectively reviewed the records of patients who underwent RIRS for renal stones from January 2000 to July 2009. We identified 66 RIRSs (63 patients with 3 bilateral renal stones) and collected data. Stone-free and success were respectively defined as no visible stones and clinically insignificant residual stones less than 3 mm on postoperative imaging; predictive factors for stone-free were evaluated. Of the 66 renal stones, 18 stones (27.3%) were located in the upper pole or midpole or renal pelvis and 48 (72.7%) in the lower pole with or without others, respectively. The mean cumulative stone burden was 168.9±392.5 mm(2). The immediate postoperative stone-free rate was 69.7%, and it increased to 72.7% at 1 month after surgery. The success rate was 80.3% both immediately after the operation and 1 month later. In the multivariate analysis, stone location except at the lower pole (p=0.049) and small cumulative stone burden (p=0.002) were significantly favorable predictive factors for the immediate postoperative stone-free rate. The overall complication rate was 6%. RIRS is a safe and effective treatment for renal stones. The stone-free rate of RIRS was particularly high for renal stones with a small burden, except for those located in the lower pole. RIRS could be considered in selective patients with renal stones.


Intra-articular placebo effect in the treatment of knee osteoarthritis: a survey of the current clinical evidence.
Knee osteoarthritis (KOA) is a debilitating disease characterized by chronic pain, stiffness, and decreased mobility. Intra-articular injectable therapies show good clinical efficacy in improving symptoms; however, these therapies and their comparators (intra-articular saline) have been associated with a large underlying placebo effect. We aimed to describe the existing evidence on the challenges, hypotheses, and potential solutions to mitigate the intra-articular placebo effect in clinical trials in KOA. A targeted literature review was conducted by searching Embase, MEDLINE®, and CENTRAL using predefined study selection criteria. All eligible studies identified were extracted for relevant data, and results were narratively summarized. Forty-three studies were included following screening. Challenges associated with the intra-articular placebo effect included its ability to mask the comparative efficacy of active treatments in trials (n = 7 studies), long-lasting effects (up to 6 months; n = 3), and substantial variation of placebo effect sizes across populations (n = 3). Hypotheses for the mechanism of the placebo effect included aspiration of synovial fluid during administration (n = 6) and dilution of inflammatory mediators (n = 2). Factors affecting the placebo effect size were more invasive routes of administration (e.g., injection versus oral; n = 4) and patient expectations (n = 2). Proposed solutions included the suggestion for readers to weigh the relevance of clinical trial evidence against the presence of large underlying placebo effects (n = 9), discontinuation of intra-articular saline as an appropriate placebo (n = 5), and inclusion of 'no treatment' or sham injection as a control (n = 4). The intra-articular placebo effect is a well-documented occurrence in KOA clinical trials, and it is suggested that it be accounted for when designing randomized controlled trials. Awareness and understanding of the intra-articular placebo effect in KOA are required for fair interpretation of clinical trial evidence.


High BMI is associated with low ALS risk: A population-based study.
To investigate the temporal relationship among prediagnostic body mass index (BMI), weight change, and risk of amyotrophic lateral sclerosis (ALS). From the compulsory Norwegian tuberculosis screening program, we collected objectively measured BMI from 85% of all citizens (near 1.5 million) between 20 and 70 years of age living in 18 of 19 Norwegian counties between 1963 and 1975. For those who participated in later health surveys, we collected further information on weight change, lifestyle, and health. We identified ALS cases until September 2017 through national registries of diagnoses at death and at encounters with the specialist health service. Both Cox hazard models and flexible parametric survival models were fitted to address our research question. We identified 2,968 ALS cases during a mean of 33 (maximum 54) years follow-up. High prediagnostic BMI was associated with low subsequent ALS risk across the typical ALS ages in both sexes. Overall, hazard ratio (HR) for ALS per 5-unit increase in prediagnostic BMI was 0.83 (95% confidence interval [CI] 0.79-0.88). After an initial increase during the first 10 years, it decreased almost linearly throughout the observation period and was 0.69 (95% CI 0.62-0.77) after 50 years. Those in the quartile with highest weight gain had lower ALS risk than those in the lowest quartile (HR 0.63, 95% CI 0.44-0.89). High BMI and weight gain are associated with low ALS risk several decades later. The strength of the association between BMI and ALS risk increases up to 50 years after BMI measurement.


The Downside of Greater Lexical Influences: Selectively Poorer Speech Perception in Noise.
Although lexical information influences phoneme perception, the extent to which reliance on lexical information enhances speech processing in challenging listening environments is unclear. We examined the extent to which individual differences in lexical influences on phonemic processing impact speech processing in maskers containing varying degrees of linguistic information (2-talker babble or pink noise). Twenty-nine monolingual English speakers were instructed to ignore the lexical status of spoken syllables (e.g., gift vs. kift) and to only categorize the initial phonemes (/g/ vs. /k/). The same participants then performed speech recognition tasks in the presence of 2-talker babble or pink noise in audio-only and audiovisual conditions. Individuals who demonstrated greater lexical influences on phonemic processing experienced greater speech processing difficulties in 2-talker babble than in pink noise. These selective difficulties were present across audio-only and audiovisual conditions. Individuals with greater reliance on lexical processes during speech perception exhibit impaired speech recognition in listening conditions in which competing talkers introduce audible linguistic interferences. Future studies should examine the locus of lexical influences/interferences on phonemic processing and speech-in-speech processing.


[Survival analysis of gastric cancer patients during 2005-2010 in Zhejiang Province, China].
To conduct a survival analysis of gastric cancer patients according to the data of population-based cancer registry during 2005-2010 in Zhejiang Province in order to provide information for prognosis assessment and control of this disease. The deadline of the last follow-up of 26, 536 patients was December 31st, 2012. Cumulative observed survival rate (OSR) and expected survival rate were calculated by life table and Hakulinen method. the 1-, 3-, and 5-year OSR were 58.51%, 39.07%, and 33.08%, and the 1-, 3-, and 5-year relative survival rates (RSR) were 60.24%, 42.90%, and 39.03%, respectively. The 1-, 3-, and 5-year relative survival rates of males vs. females were 60.49% vs. 59.65%, 42.88% vs. 42.96%, and 38.76% vs. 39.64%, respectively, statistically with non-significant differences (χ(2) = 0.13, P > 0.05) between them. The 5-year OSR and RSR of urban patients were 39.15% and 46.30%, and the 5-year OSR and RSR of rural patients were 30.81% and 36.32%, with statistically significant differences between them (P < 0.05). The 15-44 age group had a better relative survival rate. The survival rate of gastric cancer patients in Zhejiang Province is low. Work of cancer prevention and control should be strengthened. The wide variation in gastric cancer survival rates between urban and rural patients indicates that priority should be given to rural areas in allocating medical and public health resources.


A Bayesian evolutionary model towards understanding wildlife contribution to F4-family Mycobacterium bovis transmission in the South-West of France.
In two "départements" in the South-West of France, bovine tuberculosis (bTB) outbreaks due to Mycobacterium bovis spoligotype SB0821 have been identified in cattle since 2002 and in wildlife since 2013. Using whole genome sequencing, the aim of our study was to clarify badger contribution to bTB transmission in this area. We used a Bayesian evolutionary model, to infer phylogenetic trees and migration rates between two pathogen populations defined by their host-species. In order to account for sampling bias, sub-population structure was inferred using the marginal approximation of the structured coalescent (Mascot) implemented in BEAST2. We included 167 SB0821 strains (21 isolated from badgers and 146 from cattle) and identified 171 single nucleotide polymorphisms. We selected a HKY model and a strict molecular clock. We estimated a badger-to-cattle transition rate (median: 2.2 transitions/lineage/year) 52 times superior to the cattle-to-badger rate (median: 0.042 transitions/lineage/year). Using the maximum clade credibility tree, we identified that over 75% of the lineages from 1989 to 2000 were present in badgers. In addition, we calculated a median of 64 transition events from badger-to-cattle (IQR: 10-91) and a median of zero transition event from cattle-to-badger (IQR: 0-3). Our model enabled us to infer inter-species transitions but not intra-population transmission as in previous epidemiological studies, where relevant units were farms and badger social groups. Thus, while we could not confirm badgers as possible intermediaries in farm-to-farm transmission, badger-to-cattle transition rate was high and we confirmed long-term presence of M. bovis in the badger population in the South-West of France.


Chronic vulvovaginitis in children due to Shigella flexneri.
Although previous reports have implicated Shigella flexneri in resistant or chronic cases of vulvovaginitis in children, no authors have described the clinical findings of this condition. The report presents four cases of persistent vulvovaginitis in prepubertal Indian girls from different reservation communities in Arizona. S. flexneri was isolated in pure culture from the vaginal discharge of each patient. All four cases were characterized by a prolonged vaginitis with a bloody, purulent discharge which responded poorly or not at all to various topical modes of therapy for nonspecific vaginitis. Three cases cleared completely when treated with orally given ampicillin for one week. The striking similarity of these cases suggests that chronic Shigella vulvovaginitis is a recognizable clinical entity and should be considered in the differential diagnosis of persistent vaginitis in children, especially in those from communities where Shigella is endemic.


Topical topic: value of fine needle aspiration biopsy in childhood rhabdomyosarcoma: twenty-six years of experience in Slovenia.
Chemotherapy (Cht) for rhabdomyosarcoma (RMS) given before local treatment can prevent mutilating surgery and high-dose irradiation (RT). Fine needle aspiration biopsy (FNAB) can confirm the diagnosis and neoadjuvant treatment can start without delay. The purpose of our study was to assess the role of FNAB in the management of childhood RMS in Slovenia. A total of 78 children and young adults were included. FNAB provided the pre-treatment diagnosis in 37 and surgical biopsy in 41 patients. In 61 cases recurrent/metastatic disease was aspirated. Cytological diagnoses were compared to the original histological diagnoses. All case histories, cytological and histological material were reviewed and immunocytochemical staining performed when necessary. FNAB provided a correct diagnosis of malignancy in all 37 primary tumours, a specific diagnosis of RMS was given in 29 (78%). With the use of immunocytochemistry during the last 15 years, the accuracy has risen to 87%. FNAB provided the diagnosis of recurrence/metastasis in 57/61 cases. No complications of FNAB were noted. Review of histology reclassified five original diagnoses of RMS into one malignant rhabdoid tumour and four sarcomas NOS. In review of cytology we were able to sub classify 80% of RMS. FNAB is a safe method, which enables us to establish the pre-treatment diagnosis of RMS, and to some extent even its type, without delay. In our study, FNAB successfully replaced surgical biopsy in 87% of RMS patients during the last 15 years. Neoadjuvant Cht was started immediately, surgery was delayed and more conservative. Consequently, the risk for treatment sequelae was considerably reduced.


Cellular automaton model of damage.
We investigate the role of equilibrium methods and stress transfer range in describing the process of damage. We find that equilibrium approaches are not applicable to the description of damage and the catastrophic failure mechanism if the stress transfer is short ranged. In the long-range limit, equilibrium methods apply only if the healing mechanism associated with ruptured elements is instantaneous. Furthermore we find that the nature of the catastrophic failure depends strongly on the stress transfer range. Long-range transfer systems have a failure mechanism that resembles nucleation. In short-range stress transfer systems, the catastrophic failure is a continuous process that, in some respects, resembles a critical point.


On Exploring Multiplicity of Primitives and Attributes for Texture Recognition in the Wild.
Texture recognition is a challenging visual task since its multiple primitives or attributes can be perceived from the texture image under different spatial contexts. Existing approaches predominantly built upon CNN incorporate rich local descriptors with orderless aggregation to capture invariance to the spatial layout. However, these methods ignore the inherent structure relation organized by primitives and the semantic concept described by attributes, which are critical cues for texture representation. In this paper, we propose a novel Multiple Primitives and Attributes Perception network (MPAP) that extracts features by modeling the relation of bottom-up structure and top-down attribute in a multi-branch unified framework. A bottom-up process is first proposed to capture the inherent relation of various primitive structures by leveraging structure dependency and spatial order information. Then, a top-down process is introduced to model the latent relation of multiple attributes by transferring attribute-related features between adjacent branches. Moreover, an augmentation module is devised to bridge the gap between high-level attributes and low-level structure features. MPAP can learn representation through jointing bottom-up and top-down processes in a mutually reinforced manner. Experimental results on six challenging texture datasets demonstrate the superiority of MPAP over state-of-the-art methods in terms of accuracy, robustness, and efficiency.


NMR spectroscopy of RNA.
NMR spectroscopy is a powerful tool for studying proteins and nucleic acids in solution. This is illustrated by the fact that nearly half of all current RNA structures were determined by using NMR techniques. Information about the structure, dynamics, and interactions with other RNA molecules, proteins, ions, and small ligands can be obtained for RNA molecules up to 100 nucleotides. This review provides insight into the resonance assignment methods that are the first and crucial step of all NMR studies, into the determination of base-pair geometry, into the examination of local and global RNA conformation, and into the detection of interaction sites of RNA. Examples of NMR investigations of RNA are given by using several different RNA molecules to illustrate the information content obtainable by NMR spectroscopy and the applicability of NMR techniques to a wide range of biologically interesting RNA molecules.


A high-resolution morphogenetic map of the second-leg basitarsus inDrosophila melanogaster.
The lineages of cells on the second-leg basitarsus ofDrosophila melanogaster were analyzed by examining gynandromorphs andMinute mosaics. Bracts lie proximal to bristles on the adult basitarsus, yet bract precursor cells were found to originate lateral to bristle precursor cells. In 6 of the 8 longitudinal rows of bristles on this segment, the bract cells arise ventral to the bristle cells; in the others they arise dorsally. The lateral cell origins are interpreted as reflecting a pattern of lateral cell movements associated with evagination of the leg disc. An unusual discrepancy was observed in the relative frequencies of male vs. female bracts and bristles in gynandromorphs. The discrepancy suggests that there is a cell-autonomous sexual difference in either the time at which cells begin moving during evagination or the speed with which they move.On the basis of the results, it is reasoned that the bristle pattern of the basitarsus does not originate in its final form. Prior to evagination, the bristle cells of each row are apparently closer together than in the final pattern, and the rows are farther apart. Evidence is presented which suggests that the bristle cells of each row may originally be arranged in a jagged line which is later straightened by cell movements.The two locations where the anterior/posterior compartment boundary of the second leg passes through the basitarsus were found to vary relative to the bristle pattern. If this boundary is assumed to be a fixed line of positional values, then the extent of the observed variability - which is estimated to be ± 1 or 2 cell diameters - provides a measure of the precision of patterning around the circumference.


Behavior in term, small for gestational age preschoolers.
To evaluate whether being born small for gestational age (SGA) was associated with an increased frequency of preschool behavioral problems. Follow-up study at 5 years of age. A population based cohort of 318 term infants who were SGA, defined as having a birthweight less than the 15th percentile for gestational age, and without major handicap such as cerebral palsy or mental retardation, and a random control sample of 307 appropriate for gestational age (AGA) infants. The Personality Inventory for Children and the Yale Children's Inventory (completed by the mothers), and child behavior during psychometric testing. Behavior problems was not more common among the SGA children. The results were not confounded by a wide range of parental demographic and child rearing factors, including maternal non-verbal problem solving abilities, child rearing style, and maternal psychological distress. However, the parental factors explained 13% of the variance in a summary score of child behavior compared to 1% explained by SGA vs. AGA status. The SGA children were not more sensitive to the negative impacts of parental risk factors than AGA controls. The study does not address the outcome of severely growth-retarded SGA infants. Being born moderately SGA is not a significant risk factor for preschool behavior problems.


Secondary-Structure-Driven Self-Assembly of Reactive Polypept(o)ides: Controlling Size, Shape, and Function of Core Cross-Linked Nanostructures.
Achieving precise control over the morphology and function of polymeric nanostructures during self-assembly remains a challenge in materials as well as biomedical science, especially when independent control over particle properties is desired. Herein, we report on nanostructures derived from amphiphilic block copolypept(o)ides by secondary-structure-directed self-assembly, presenting a strategy to adjust core polarity and function separately from particle preparation in a bioreversible manner. The peptide-inherent process of secondary-structure formation allows for the synthesis of spherical and worm-like core-cross-linked architectures from the same block copolymer, introducing a simple yet powerful approach to versatile peptide-based core-shell nanostructures.


Selective localization of histamine to electron dense granules in antigen-challenged sensitized rat mast cells and to similar granules isolated from sonicated mast cells. An electron microscope autoradiographic study.
The subcellular localization of histamine was studied in sensitized rat mast cells following antigen challenge and in granules obtained from sonicated cells, using an electron microscope autoradiographic technique. The mast cells were furnished with labelled histamine by incubation in 3-H-histidine. The silver grain distribution (reflecting the radioactive histamine) was highly non-random. The highest silver grain densities occured over homogeneous, electron dense (normal) granules and moderately electron dense granules. Swollen, less electron dense ("changed") granules with a reticular appearance and devoid of a limiting membrane had the lowest density of all subcellular structures studied and were therefore probably almost free of histamine. There was a good correlation between the percentage of electron dense granules, the histamine content and the silver grain density insaline-washed granule fractions isolated after sonication of mast cells for different times. These results support the hypothesis that histamine release occurs during the sequential exocytosis of storage granules, and during the sonication of mast cells, probably as a cation exchange between the amine, which is ionically bound to the heparin-protein complex of the granule matrix, and cations from the extracellular fluid. The exchanges will occur as soon as the perigranular membrane becomes premeable to water and cations.


Disordered interdomain region of Gins is important for functional tetramer formation to stimulate MCM helicase in Thermoplasma acidophilum.
The eukaryotic MCM is activated by forming the CMG complex with Cdc45 and GINS to work as a replicative helicase. The eukaryotic GINS consists of four different proteins to form tetrameric complex. In contrast, the TaGins51 protein from the thermophilic archaeon, Thermoplasma acidophilum forms a homotetramer (TaGINS), and interacts with the cognate MCM (TaMCM) to stimulate the DNA-binding, ATPase, and helicase activities of TaMCM. All Gins proteins from Archaea and Eukarya contain α-helical A- and β-stranded B-domains. Here, we found that TaGins51 forms the tetramer without the B-domain. However, the A-domain without the linker region between the A- and B-domains could not form a stable tetramer, and furthermore, the A-domain by itself could not stimulate the TaMCM activity. These results suggest that the formation of the Gins51 tetramer is necessary for MCM activation, and the disordered linker region between the two domains is critical for the functional complex formation.


Malignant giant-cell tumours of bone. Clinico-pathological types and prognosis: a review of 29 cases.
Twenty-nine patients with malignant giant-cell tumours of bone (GCT) were followed-up for between 6 months and 18 years. Seventeen of the tumours were primary and 12 were due to malignant degeneration of initially benign lesions. The clinical features did not differ from those of benign GCT, except for a higher incidence in the distal tibia and sacrum. Anaplastic GCTs were included in the study because their clinical and radiographic features and prognosis were no different from those of the GCT grade III of Jaffe. Eighteen of the tumours were grade III, and 11 were anaplastic. This retrospective study was intended to assess the effects of chemotherapy and surgery for malignant GCT. Three treatment groups were selected, in which treatment was either by surgery alone, surgery plus chemotherapy, or radiotherapy alone.--The prognosis was poor and the 5 year tumour-free survival rate in the series was 50%. The prognosis was the same for primary as for secondarily malignant tumours. There was no statistical difference in survival between malignant grade III and anaplastic malignant tumours. The one-year survival rate for patients treated by chemotherapy and surgery was statistically higher (chi2 test) than for persons treated by surgery alone. However, the five-year survival rate and the actuarial survival curves were not statistically different in the two groups (log rank test).--Chemotherapy appears to be of some value in the treatment of these malignant tumours but a larger series is required to confirm the efficacy of this approach.


[Sick building syndrome or fungal allergy? When houses cause illness].
In modern societies, the sick building syndrome (SBS) is a very common building-related complex of unspecific symptoms affecting groups of persons. Most frequently, complains include irritation of the eyes and respiratory tract that are believed to be related to negative ambient factors at the workplace. The etiology is multifactorial. In persons showing typical anxiety about the environment, SBS may also be considered a variant of a somatoform disorder. SBS must be clearly differentiated from building-related illness. Diagnostic measures and therapeutic implications are discussed.


Concurrent Hospice Healthcare Utilization in the Hematology/Oncology Veteran's Affairs Patient Population.
Objectives: Concurrent care is a unique care delivery system that allows patients to receive disease modifying treatments and other supportive interventions while also receiving the traditional benefits of hospice care. The objectives of our observational study were to examine health care utilization, use of cancer-directed therapies and palliative interventions, and location of death in patients enrolled in concurrent care. Methods: 72 hematology-oncology patients at the Hines Veteran's Affairs Medical Center (VAMC) who enrolled in concurrent care from 12/2018-4/2021 were reviewed. Data were summarized with descriptive statistics including medians and percentages. Results: A minority of patients received cytotoxic chemotherapy (27.8%), immunotherapy (20.8%), palliative radiation (20.9%), blood products (11.1%), or invasive pain procedures (4.2%). Patients also used fewer cancer-directed treatments as they approached end of life (24.4% within 30 days of death compared to 13.3% within 14 days of death). Most patients died at home (62.9%) or in inpatient hospice (12.9%) as opposed to the hospital (2.9%). Conclusions: A minority of concurrent care patients received cancer-directed therapies or additional types of health care interventions despite the option to do so. Cancer-directed treatment utilization also decreased as patients approached end of life. Patients enrolled in concurrent care were able to appreciate its benefits for longer, as the average length of stay on concurrent care was nearly 3 months.


Identification of functional differences in metabolic networks using comparative genomics and constraint-based models.
Genome-scale network reconstructions are useful tools for understanding cellular metabolism, and comparisons of such reconstructions can provide insight into metabolic differences between organisms. Recent efforts toward comparing genome-scale models have focused primarily on aligning metabolic networks at the reaction level and then looking at differences and similarities in reaction and gene content. However, these reaction comparison approaches are time-consuming and do not identify the effect network differences have on the functional states of the network. We have developed a bilevel mixed-integer programming approach, CONGA, to identify functional differences between metabolic networks by comparing network reconstructions aligned at the gene level. We first identify orthologous genes across two reconstructions and then use CONGA to identify conditions under which differences in gene content give rise to differences in metabolic capabilities. By seeking genes whose deletion in one or both models disproportionately changes flux through a selected reaction (e.g., growth or by-product secretion) in one model over another, we are able to identify structural metabolic network differences enabling unique metabolic capabilities. Using CONGA, we explore functional differences between two metabolic reconstructions of Escherichia coli and identify a set of reactions responsible for chemical production differences between the two models. We also use this approach to aid in the development of a genome-scale model of Synechococcus sp. PCC 7002. Finally, we propose potential antimicrobial targets in Mycobacterium tuberculosis and Staphylococcus aureus based on differences in their metabolic capabilities. Through these examples, we demonstrate that a gene-centric approach to comparing metabolic networks allows for a rapid comparison of metabolic models at a functional level. Using CONGA, we can identify differences in reaction and gene content which give rise to different functional predictions. Because CONGA provides a general framework, it can be applied to find functional differences across models and biological systems beyond those presented here.


Development of a protective immunity against Ostertagia leptospicularis in trickle-infected sheep and parallel changes of serum gastrin, pepsinogen and antibody levels.
Nine lambs, approximately 9 months of age were allocated to three groups (A, B, C), with three animals in each. Sheep in Groups A and B were trickle-infected with doses of 1000 third-stage larvae (L3) of Ostertagia leptospicularis (five times per week) over periods of 7.5 and 10.5 weeks, respectively, and were subsequently treated with fenbendazole (7.5 mg/kg). Approximately 3 weeks after anthelmintic treatment, all sheep were challenged with a single dose of 100,000 L3, whereas sheep of Group C received the same dose as a primary infection. Sheep of Groups A and B were almost completely refractory against the challenge infection, as indicated by negative faecal egg counts and adult worm burdens. A relatively high infection level was present in the sheep of Group C. The results indicate that a comparatively short immunization period of 7.5 weeks is sufficient to protect lambs against subsequent larval challenge. During immunization, the pepsinogen-, gastrin- and IgA-responses were similar in the individual sheep. In contrast to parasite-specific IgG1 and IgG2 levels, IgA decreased rapidly after cessation of trickle infection and parallel anthelmintic treatment, and may therefore indicate current exposure to parasite antigen. After challenge, the majority of the immunized sheep exhibited immediate and short-term responses of pepsinogen, gastrin and IgA in the serum. The time course and the level of each of these responses were very similar in the individual sheep, suggesting that the release of pepsinogen, gastrin and IgA into the circulation was influenced by related mechanisms.


Organic food retailing: to what extent are foods processed and do they contain markers of ultra-processing?
In France, around 70% of conventional industrial foods are ultra-processed, with no data for organic foods. The objectives of this study were to evaluate the percentage of ultra-processed foods (UPFs) in industrially packaged organic (n = 8554) and conventional (n = 45,791) foods, and to describe their marker of ultra-processing (MUP) profiles. The percentage of UPFs and MUP profiles were determined with the Siga methodology. UPF percentages were 53% in organic foods and 74% in conventional foods, and there was 8% more organic UPFs in conventional stores than in organic stores. The more additive MUPs are used, the greater the quantity of nonadditive MUPs. Conventional UPFs contained twice as many total MUPs as organic UPFs. Main MUPs in organic UPFs were refined oils, extracts and natural aromas, native starches, glucose syrup, lecithins and citric acid. Organic foods are, therefore, overall less ultra-processed although still containing high levels of nonadditive MUPs.


Ferulic acid esters and weight-loss promoting effects in rats.
We previously fed rats with an ester (90 ppm in a powdered AIN93G diet) synthesized from gallic acid and 1,2-dioleoyl glycerol and found that it promoted weight loss more effectively than either octyl gallate or gallic acid. Here, we esterified ferulic acid (FerA) with oleic acid, monooleoyl glycerol and dioleoyl glycerol to obtain oleoyl ferulic acid (FO), feruloyl monooleoyl glycerol (FMO) and feruloyl dioleoyl glycerol (FDO) esters, respectively. A mixture of AIN93G and 90 ppm of each ester and FerA was fed to 10-week-old male Wistar rats for 12 weeks. The FMO and FDO groups weighed less than the control group starting from approximately 16 weeks of age. At 21 and 22 weeks of age, weight significantly differed between the FMO and both groups, respectively, and controls. The FO, FerA and control groups did not significantly differ in terms of body, liver, kidney and retroperitoneal fat tissue weights and serum biochemical findings. We concluded that the hydroxyl group of FerA is essential for promoting weight loss and that the carboxyl group should be esterified with alcohol. In addition, monooleoyl glycerol and dioleoyl glycerol did not show any difference as the alcohol moiety of the ester in the weight loss effect.


C-terminal binding proteins: central players in development and disease.
C-terminal binding proteins (CtBPs) were initially identified as binding partners for the E1A-transforming proteins. Although the invertebrate genome encodes one CtBP protein, two CtBPs (CtBP1 and CtBP2) are encoded by the vertebrate genome and perform both unique and duplicative functions. CtBP1 and CtBP2 are closely related and act as transcriptional corepressors when activated by nicotinamide adenine dinucleotide binding to their dehydrogenase domains. CtBPs exert transcriptional repression primarily via recruitment of a corepressor complex to DNA that consists of histone deacetylases (HDACs) and histone methyltransferases, although CtBPs can also repress transcription through HDAC-independent mechanisms. More recent studies have demonstrated a critical function for CtBPs in the transcriptional repression of pro-apoptotic genes such as Bax, Puma, Bik, and Noxa. Nonetheless, although recent efforts have characterized the essential involvement of CtBPs in promoting cellular survival, the dysregulation of CtBPs in both neurodegenerative disease and cancers remains to be fully elucidated.