The D-2-hydroxyacid dehydrogenase incorrectly annotated PanE is the sole reduction system for branched-chain 2-keto acids in Lactococcus lactis.
Hydroxyacid dehydrogenases of lactic acid bacteria, which catalyze the stereospecific reduction of branched-chain 2-keto acids to 2-hydroxyacids, are of interest in a variety of fields, including cheese flavor formation via amino acid catabolism. In this study, we used both targeted and random mutagenesis to identify the genes responsible for the reduction of 2-keto acids derived from amino acids in Lactococcus lactis. The gene panE, whose inactivation suppressed hydroxyisocaproate dehydrogenase activity, was cloned and overexpressed in Escherichia coli, and the recombinant His-tagged fusion protein was purified and characterized. The gene annotated panE was the sole gene responsible for the reduction of the 2-keto acids derived from leucine, isoleucine, and valine, while ldh, encoding L-lactate dehydrogenase, was responsible for the reduction of the 2-keto acids derived from phenylalanine and methionine. The kinetic parameters of the His-tagged PanE showed the highest catalytic efficiencies with 2-ketoisocaproate, 2-ketomethylvalerate, 2-ketoisovalerate, and benzoylformate (V(max)/K(m) ratios of 6,640, 4,180, 3,300, and 2,050 U/mg/mM, respectively), with NADH as the exclusive coenzyme. For the reverse reaction, the enzyme accepted d-2-hydroxyacids but not l-2-hydroxyacids. Although PanE showed the highest degrees of identity to putative NADP-dependent 2-ketopantoate reductases (KPRs), it did not exhibit KPR activity. Sequence homology analysis revealed that, together with the d-mandelate dehydrogenase of Enterococcus faecium and probably other putative KPRs, PanE belongs to a new family of D-2-hydroxyacid dehydrogenases which is unrelated to the well-described D-2-hydroxyisocaproate dehydrogenase family. Its probable physiological role is to regenerate the NAD(+) necessary to catabolize branched-chain amino acids, leading to the production of ATP and aroma compounds.


Fulvestrant (AstraZeneca).
Fulvestrant (Faslodex) is an estrogen receptor (ER) downregulator under development by AstraZeneca for the potential treatment of breast cancer [172191], [237518], [314472], [349551]. In March 2001, an NDA was filed in the US for the second-line treatment of advanced breast cancer in postmenopausal women who have progressed on prior hormonal therapy [403574], [434825]; in December 2001, AstraZeneca was expecting to launch the compound in the US in thefirst half of 2002 [431887]. In August 2001, late-stage clinical trials were ongoing in Japan for breast cancer [422343]. Fulvestrant also has potential in the treatment of other estrogen-responsive tumors, such as uterine tumors [178081]. By 1997, fulvestrant was in phase II trials for uterine fibroids [272162], and by February 1999, it was reported that phase II trials for endometriosis were ongoing [314472], [336599]. However, no development has been reported for these indications since that time. In October 2001, Morgan Stanley expected launch in 2002, with estimated sales of $80 million in 2002 rising to $208 million in 2007 [429700]. Analysts at Lehman Brothers predicted in December 2001, that the product has a 90% chance of making it to market in 2002, with peak sales potential in this year of $800 million [434768].


Neoadjuvant chemotherapy with CPT-11 and cisplatin downstages locally advanced gastric cancer.
We examined the role of neoadjuvant therapy in downstaging locally advanced gastric cancer. Preoperative staging was performed with a combination of CT scans, endoscopic ultrasonography and/or laparoscopy, and laparoscopic ultrasonography. Patients with T > or =3 tumors and/or node-positive disease by preoperative clinical staging were eligible for entry. Neoadjuvant therapy consisted of two cycles of CPT-11 (75 mg/m(2)) with cisplatin (25 mg/m(2)) weekly four times every 6 weeks. This was followed by resection with D2 lymph node dissection and two cycles of intraperitoneal chemotherapy with floxuridine and cisplatin. Twenty-two patients were entered into the study (4 with T3N0 disease and 18 with T3N1 disease). Induction chemotherapy was well tolerated with major toxicities being neutropenia and diarrhea. A median of 78%/75% of the planned dosage of CPT-11/cisplatin was delivered. Two patients withdrew consent during the first cycle and were lost to follow-up. One patient progressed to stage IV disease during induction chemotherapy and did not undergo surgery. Nineteen patients underwent surgery. One patient had undetected stage IV disease (liver) and underwent a palliative R2 resection. Of the 18 remaining patients, 17 had curative R0 resections and one had a palliative R1 resection. A median of 21 lymph nodes (range 1 to 121) were examined histologically. There was one postoperative death. Surgical morbidity did not appear to increase after the neoadjuvant regimen. The median postoperative length of hospital stay was 9 days (range 3 to 75 days). Postoperative pathologic staging yielded 16% T3 lesions compared to 85% before treatment based on clinical staging; postoperative American Joint Committee on Cancer staging yielded 37% stage IIIA disease compared to 70% stage IIIA before treatment. With a median follow-up of 15 months, median survival has not yet been reached. We conclude that CPT-11-based neoadjuvant therapy downstages locally advanced gastric cancer. Further follow-up is necessary to determine the ultimate impact of this combination therapy on recurrence and survival.


Individualized model for predicting COVID-19 deterioration in patients with cancer: A multicenter retrospective study.
The 2019 novel coronavirus has spread rapidly around the world. Cancer patients seem to be more susceptible to infection and disease deterioration, but the factors affecting the deterioration remain unclear. We aimed to develop an individualized model for prediction of coronavirus disease (COVID-19) deterioration in cancer patients. The clinical data of 276 cancer patients diagnosed with COVID-19 in 33 designated hospitals of Hubei, China from December 21, 2019 to March 18, 2020, were collected and randomly divided into a training and a validation cohort by a ratio of 2:1. Cox stepwise regression analysis was carried out to select prognostic factors. The prediction model was developed in the training cohort. The predictive accuracy of the model was quantified by C-index and time-dependent area under the receiver operating characteristic curve (t-AUC). Internal validation was assessed by the validation cohort. Risk stratification based on the model was carried out. Decision curve analysis (DCA) were used to evaluate the clinical usefulness of the model. We found age, cancer type, computed tomography baseline image features (ground glass opacity and consolidation), laboratory findings (lymphocyte count, serum levels of C-reactive protein, aspartate aminotransferase, direct bilirubin, urea, and d-dimer) were significantly associated with symptomatic deterioration. The C-index of the model was 0.755 in the training cohort and 0.779 in the validation cohort. The t-AUC values were above 0.7 within 8 weeks both in the training and validation cohorts. Patients were divided into two risk groups based on the nomogram: low-risk (total points ≤ 9.98) and high-risk (total points > 9.98) group. The Kaplan-Meier deterioration-free survival of COVID-19 curves presented significant discrimination between the two risk groups in both training and validation cohorts. The model indicated good clinical applicability by DCA curves. This study presents an individualized nomogram model to individually predict the possibility of symptomatic deterioration of COVID-19 in patients with cancer.


A New Insight into Cross-Sensitivity to Humidity of SnO2 Sensor.
The efficiency of gas sensors varies enormously from fundamental study to practical application. This big gap comes mainly from the complex and unpredictable effect of atmospheric environment, especially in humidity. Here, the cross-sensitivity to humidity of a SnO2 sensor from local structural and lattice evolutions is studied. The sensing response of ethanol is found to be efficiently activated by adsorbing trace of water but inhibited as humidity increases. By X-ray diffraction, pair distribution function of synchrotron and ab initio calculations, the independent effect of water and ethanol on lattice and local structure are clearly revealed, which elucidate the intricate sensing reactions. The formation of hydrogen bonds and repulsion of ethoxides play key roles in the structural distortions, and also in adsorption energies that are critical to the sensitive behavior. The results show the sensor performance coupled with local structural evolution, which provides a new insight into the controversial effects of humidity on SnO2 sensors.


The impact of levothyroxine therapy on pregnancy and neonatal outcomes in euthyroid pregnant women with thyroid autoimmunity: A systematic review, meta-analysis and trial sequential analysis.
Background: At present, only one systematic review has investigated the effect of levothyroxine (LT4) in the treatment of euthyroid pregnant women with thyroid autoimmunity, but some problems [such as merging different types of research for meta-analysis, lacking neonatal outcomes, and so on] exist in this study, satisfactory results can not be provided. So, this systematic review was performed to investigate the effect of LT4 in euthyroid pregnant women with thyroid autoimmunity, in the hope of providing more comprehensive evidence for clinical use. Methods: Medline (Ovid), Embase (Ovid), and Cochrane Central Register of Controlled Trials were electronically searched from database inception to March 2022. We included cohort studies and RCTs that evaluated the impact of LT4 therapy on pregnancy and neonatal outcomes in euthyroid pregnant women with thyroid autoimmunity. Meta-analyses of different types of studies were performed separately, and meta-analyses were further performed by only including researches with low and moderate risk of bias. We used the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach to evaluate the quality of evidence, and used TSA to test the sufficiency of the evidence. Results: Finally, 2,901 euthyroid pregnant women with thyroid autoimmunity in six RCTs and five cohort studies were included. In all outcomes, no statistically significant differences were found between LT4 group and control group, including miscarriage [RR = 0.85, 95%CI (0.69,1.05), p = 0.14, I 2 = 1%], preterm birth [RR = 0.80, 95%CI (0.59,1.08), p = 0.14, I2 = 0%], preeclampsia [RR = 0.68, 95%CI (0.12, 3.91), p = 0.66, I 2 = 0%], placenta abruption [Peto' OR = 0.14, 95%CI (0.00, 6.94), p = 0.32, I 2 = 0%], birth weight [MD = -36.00, 95%CI (-170.41, 98.41), p = 0.60, I 2 = 0%], gestational age at delivery [MD = -0.10, 95%CI (-0.61, 0.41), p = 0.70, I 2 = 0%] and neonatal admission [RR = 1.33, 95%CI (0.21, 8.58), p = 0.76, I 2 = 0%]. The results for all outcomes were insufficient and inconclusive as demonstrated by TSA. The GRADE assessments showed that the quality of evidence of 4 outcomes (miscarriage, preterm birth, birth weight and gestational age at delivery) were moderate, and 3 outcomes (preeclampsia, placenta abruption and neonatal admission) were low or very low. Conclusion: For pregnancy and neonatal outcomes in euthyroid pregnant women with thyroid autoimmunity, we did not find benefit of LT4 treatment in this study. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022346745, identifier CRD42022346745.


Respiratory muscle fatigue following exercise in patients with interstitial lung disease.
It is not known whether respiratory muscle fatigue occurs as a consequence of exercise in patients with interstitial lung disease (ILD) and, if so, to what extent it is related to changes in dynamic lung volumes. To assess the development of respiratory muscle fatigue in patients with ILD and relate it to the respiratory pattern during exercise. Sixteen ILD patients (11 women) performed incremental, symptom-limited cycle ergometry with inspiratory capacity manoeuvres used to measure changes in end-expiratory lung volume (EELV). Twitch transdia-phragmatic pressure (TwPdi) and twitch gastric pressure (TwT10Pga), in response to magnetic stimulation, were used to assess the development of fatigue. TwPdi did not differ significantly before and after exercise (21.8 ± 8 vs. 20.2 ± 8 cm H2O; p = 0.10), while TwT10Pga fell from 28.6 ± 18 to 25.2 ± 14 cm H2O (p = 0.02). EELV fell from 2.18 ± 0.65 to 1.91 ± 0.59 liters following exercise (p = 0.04). The fall in TwT10Pga correlated with peak oxygen uptake at peak of exercise (r = -0.52, p = 0.041), increase in heart rate (r = 0.53, p = 0.032) and with the decrease of EELV during exercise (r = 0.57, p = 0.021). Abdominal muscle fatiguers (n = 9, 56%), defined as having a ≥10% fall in TwT10Pga, had a fall in EELV of 22 ± 22% compared to 0.7 ± 8% in non-fatiguers (p = 0.016). Abdominal muscle fatigue develops during exercise in some ILD patients in association with increased expiratory muscle activity manifested by reduced EELV.


Extrasynaptic GABA(A) channels activated by THIP are modulated by diazepam in CA1 pyramidal neurons in the rat brain hippocampal slice.
Single-channel currents were activated by THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) in cell-attached patches on CA1 pyramidal neurons in the rat hippocampal slice preparation. THIP activated GABA(A) channels after a delay that was concentration-dependent and decreased by 1 microM diazepam. The currents showed outward rectification. Channels activated at depolarized 40 mV relative to the chloride reversal potential had low conductance (<40 pS) but the conductance increased with time, resulting in high-conductance channels (>40 pS). The average maximal-channel conductances for 2 and 100 microM THIP were 59 and 62 pS (-Vp = 40 mV), respectively, whereas in 2 microM THIP plus 1 microM diazepam, it was 71 pS. The results show that in hippocampal neurons THIP activates channels with characteristics similar to those of channels activated by low concentrations (0.5-5 microM ) of GABA. The increase in the inhibitory conductance with membrane depolarization permits gradation of the shunt pathway relative to the level of the excitatory input.


Ways of Being in Generalist Practice: Using Five "T" Habits of Mind to Guide Ethical Behavior.
The practice of generalist medicine differs from the practice of other clinical disciplines. We postulate that the application of ethics in generalist practice similarly differs from its application in other healthcare settings. In contrast to the problem-focused practice of ethics in other medical specialties, the practice of ethics in generalist medicine blends habits of mind with behaviors applied routinely over time-an ethical way of being. Using a graphic summary and tabular matrix, we present five "T" habits of mind (time, talk, tact, touch, and trust), associate them with applicable practice characteristics, and link them to observable clinician behaviors to demonstrate how the application of ethics in generalist practice is a day-to-day endeavor and not simply a means to resolve episodic conflicts. We textually review key aspects of the matrix and present two case studies that illustrate how such habits of mind and practice behaviors inform the ethical way of being we espouse. We invite generalist practitioners to incorporate the five "T" habits and associated behaviors into their daily care of patients, and we encourage clinical ethicists and other clinical faculty members to consider using them as a model for ethics education with medical students and resident physicians.


UV-light-induced hydrogen transfer in guanosine-guanosine aggregates.
Aggregates of a lipophilic guanine (G) derivative have been studied in n-hexane by femtosecond-to-microsecond UV-visible broadband transient absorption, stationary infrared and UV-visible spectroscopy and by quantum chemical calculations. We report the first time-resolved spectroscopic detection of hydrogen transfer in GG aggregates, which leads to (G-H)(·) radicals by means of G(+)G(-) charge transfer followed by proton transfer. These radicals show a characteristic electronic spectrum in the range 300-550 nm. The calculated superimposed spectrum of the species that result from NH⋅⋅⋅N proton transfer agrees best with the experimental spectrum.


Preparation of vitamin B6-conjugated peptides at the amino terminus and of vitamin B6-peptide-oligonucleotide conjugates.
A series of N-(4'-pyridoxyl)peptides has been made by standard Fmoc chemistry and a solid-phase coupling procedure. The last Fmoc group of the peptide was removed on the synthesizer, and the free amino group was then condensed with pyridoxal. The Schiff base formed was selectively reduced using sodium cyanoborohydride. The product was cleaved from the resin using a standard procedure. No deleterious effects were found when using the protected amino acids Fmoc-L-Ala, Fmoc-L-Arg(Pmc), Fmoc-L-Asp(OtBu), Fmoc-L-His(Trt), Fmoc-L-Ser(tBu), Fmoc-L-Thr(tBu), and Fmoc-L-Cys(Trt) for peptide synthesis. A vitamin B6-peptide-oligonucleotide conjugate could be synthesized using a cysteinyl peptide and a suitably activated oligonucleotide.


[Surgical treatment of hyperparathyroidism in renal transplant patients].
The authors present their experience of surgery for persistent hyperparathyroidism in renal transplant recipients, based on a series of 944 patients transplanted between 1983 and 1992. 56 patients underwent subtotal parathyroidectomy for persistent secondary hyperparathyroidism. Control of serum calcium was excellent in 83% of patients: 2 patients retained a well controlled hypocalcaemia, 2 are still hypercalcaemic and 3 others have developed recurrent hyperparathyroidism. The postoperative course was marked by one death not related to parathyroidectomy and one recurrent laryngeal nerve palsy. Subtotal parathyroidectomy combined with removal of the thyrothymic tissue is an effective operation to control phosphorus and calcium metabolism in patients with persistent hyperparathyroidism after renal transplantation.


Dynamic interaction between WT1 and BASP1 in transcriptional regulation during differentiation.
The Wilms' tumour suppressor protein WT1 plays a central role in the development of the kidney and also other organs. WT1 can act as a transcription factor with highly context-specific activator and repressor functions. We previously identified Brain Acid Soluble Protein 1 (BASP1) as a transcriptional cosuppressor that can block the transcriptional activation function of WT1. WT1 and BASP1 are co-expressed during nephrogenesis and both proteins ultimately become restricted to the podocyte cells of the adult kidney. Here, we have analysed the WT1/BASP1 complex in a podocyte precursor cell line that can be induced to differentiate. Chromatin immunoprecipitation revealed that WT1 and BASP1 occupy the promoters of the Bak, c-myc and podocalyxin genes in podocyte precursor cells. During differentiation-dependent upregulation of podocalyxin expression BASP1 occupancy of the podocalyxin promoter is reduced compared to that of WT1. In contrast, the repressive WT1/BASP1 occupancy of the c-myc and Bak promoters is maintained and these genes are downregulated during the differentiation process. We provide evidence that the regulation of BASP1 promoter occupancy involves the sumoylation of BASP1. Our results reveal a dynamic cooperation between WT1 and BASP1 in the regulation of gene expression during differentiation.


Changes in liver biochemical tests at diagnosis and after propylthiouracil therapy for hyperthyroidism.
We investigated liver biochemical tests at diagnosis and after a 6-week treatment with propylthiouracil (PTU) in forty-three patients with hyperthyroidism. At diagnosis, 60.5% of the patients had at least one liver biochemical abnormality. Elevation of alkaline phosphatase (ALP), alanine (ALT) and aspartate (AST) aminotransferase, and gamma-glutamyl transpeptidase (GGT) levels were observed in 19 (44.2%). 10 (23.3%), 6 (14%) and 6 (14%) of the patients, respectively. After 6-week treatment with PTU, seven (16.3%) patients developed subclinical hepatotoxicity, as evidenced by elevation of ALT levels. Age, sex, type of goiter (either diffuse or multinodular) and presence or absence of abnormal liver biochemical tests at diagnosis were not significant in determining the possibility of the development of hepatotoxicity. These data suggest that liver biochemical test abnormalities are frequently observed in hyperthyroid. However, presence or absence of these abnormalities do not indicate to the development of subclinical hepatoxicity during 6-week PTU therapy.


Haemophilus influenzae type b in respiratory secretions.
Oral and respiratory secretions of 31 children who were healthy or had mild upper respiratory infection, and who had a positive throat culture for Haemophilus influenzae type b, were cultured to determine which secretions contain this organism and how long it can be recovered from fomites. Rhinorrhea was present in 11 of 31 (34%) children and nasal mucus was positive for H. influenzae type b in 10 (91%). In 5 of these children the concentration of H. influenzae type b in nasal mucus was 10(4) to 10(7) colony-forming units/ml3. H. influenzae type b in nasal mucus applied to fomites were recovered for 12 hours. Cultures of saliva and cough secretions compared with nasal mucus were less often positive (3 of 31, P less than 0.001; 3 of 25, P less than 0.001, respectively) and contained fewer H. influenzae type b (5 and 15 colony-forming units, respectively). H. influenzae type b was recovered from the hand of 2 of 27 (7%) children; both children had positive cultures of saliva. These data indicate that H. influenzae type b can be found in oral and respiratory secretions of pharyngeal carriers and can contaminate children's hands. Nasal mucus was the most consistently positive secretion and contained the largest number of bacteria. Careful management of nasal mucus secretions is warranted in settings where transmission could occur to susceptible children.


Broadband mid-infrared (2.5-5.5 µm) emission from Co2+/Fe2+ codoped chalcogenide glass ceramics.
Compact, mechanically robust, and cost-effective mid-infrared (MIR) light sources are key components in portable and field-deployable gas sensors. Capitalizing on an efficient energy transfer mechanism between Co2+ and Fe2+, we have demonstrated for the first time, to the best of our knowledge, that ultrabroadband 2.5-5.5 µm MIR emission can be achieved at room temperatures in chalcogenide (ChG) glasses that are pumped by a commercially available erbium-doped fiber amplifier emitting at 1.57 µm. These MIR-transparent ChG glass ceramics are embedded with Co2+/Fe2+ codoped ZnSe nanocrystals, and show sufficient MIR emission intensities and bandwidths to enable gas sensing for multiple target analytes such as butane and carbon dioxide. We also describe, to the best of our knowledge, the first observation of a unique "anomalous" increase in the MIR luminescence intensity as a function of temperature.


Context-specific temporal learning with non-conflict stimuli: proof-of-principle for a learning account of context-specific proportion congruent effects.
The conflict adaptation account proposes that participants adjust attention to target and distracting stimuli in response to conflict. This is argued to explain the proportion congruent effect, wherein the congruency effect decreases as the proportion of conflicting incongruent trials increases. Some reports further argue that this conflict adaptation process can be context-specific. This paper presents a proof-of-principle for a competing account. It is suggested that such context-specific effects might be driven by very basic temporal learning processes. In the reported experiment, we manipulated stimulus contrast in place of congruency. In one location, stimulus letters were mostly easy to identify (high stimulus contrast). In the other location, letters were mostly hard to identify (low stimulus contrast). Participants produced a larger contrast effect in the mostly easy context. Along with supplemental analyses investigating the role of context switching and previous trial response times, the results are consistent with the notion that different rhythms of responding are learned for an easy versus hard location context. These results suggest that context-specific proportion congruency effects might result, in whole or in part, from temporal learning. Conflict adaptation may or may not play an additional role.


Ultrasound aspects of fetal and extrafetal structures in pregnant cats.
Prenatal feline fetal growth and utero-placental development were ultrasonographically evaluated using an ultrasound scanner with a 10 MHz sector probe. Uterus, placenta, embryo, fetus and fetal membranes in 16 pregnant cats were monitored during the course of pregnancy; 13 subjects underwent an ovariectomy on specific days while three subjects went to term. Various anatomic structures, fixed in Carson-buffered formalin, were sectioned and then compared to ultrasound images. By ultrasound examination it is possible to evaluate every stage of the fetal development; the gestational chamber can be seen on the 10th and the embryo inside the chamber on the 14th day. By the 20th day it is possible to evaluate all the fetal membranes, and later it is possible to appreciate organs and structures such as the stomach, intestine, eyes (crystalline lens), kidneys and the cerebral choroid plexi, on the 30th, 40th, 50th, 39th and 40th day respectively. Based on our observations, it will be simpler to locate anomalies of development or pathologies during ultrasound examination of pregnant queens.


Therapy of hepatitis C in HIV-coinfection.
One third of all European and American HIV-patients are coinfected with hepatitis C. HIV accelerates hepatitis C virus liver disease especially when HIV-associated immune deficiency progresses. Indeed, liver cirrhosis rate is five times higher in HIV/HCV-coinfected patients than in HCV-monoinfected patients. With the introduction of pegylated interferon and ribavirin combination therapy sustained virological response rates of up to 40 % could be obtained in HIV/HCV-coinfected individuals. Moreover, cohort analyses could demonstrate that with the use of highly active antiretroviral therapy (HAART) an improved course of hepatitis C and a reduction in liver disease-associated mortality can be achieved. Under consideration of the increased rate of hepatotoxicity due to the presently available antiretroviral treatment regimens in HIV/HCV coinfected patients, however, the development of treatment strategies and guidelines for management of hepatitis coinfection in HIV remains of great clinical significance.


Detecting Bell Correlations in Multipartite Non-Gaussian Spin States.
We expand the toolbox for studying Bell correlations in multipartite systems by introducing permutationally invariant Bell inequalities (PIBIs) involving few-body correlators. First, we present around twenty families of PIBIs with up to three- or four-body correlators, that are valid for an arbitrary number of particles. Compared to known inequalities, these show higher noise robustness, or the capability to detect Bell correlations in highly non-Gaussian spin states. We then focus on finding PIBIs that are of practical experimental implementation, in the sense that the associated operators require collective spin measurements along only a few directions. To this end, we formulate this search problem as a semidefinite program that embeds the constraints required to look for PIBIs of the desired form.


Monolingual and bilingual preschoolers' use of gestures to interpret ambiguous pronouns.
Young children typically do not use order-of-mention to resolve ambiguous pronouns, but may do so if given additional cues, such as gestures. Additionally, this ability to utilize gestures may be enhanced in bilingual children, who may be more sensitive to such cues due to their unique language experience. We asked monolingual and bilingual four-year-olds and adults to determine referents of ambiguous pronouns given order-of-mention and co-referential localizing gestures. Results showed that bilingual children, like adults, but not monolingual children, used order-of-mention with gestures to resolve ambiguous pronouns. This highlights a wider implication of bilingualism for socio-cognitive development in children.


The distributed neuronal systems supporting choice-making in real-life situations: differences between men and women when choosing groceries detected using magnetoencephalography.
In this work, magnetoencephalography was used to study the temporal dynamics of neural responses in 16 subjects (eight women, eight men) choosing among different day-to-day consumer items. At short latencies (< 150 ms), the evoked responses showed striate and extrastriate cortical activation common to the processing of general objects. At about 300 ms, women activated preferentially left posterior cortices, whereas men activated preferentially right temporal cortices. This may reflect sex/gender differences in cognitive strategies, emphasizing category-specific knowledge in women and spatial memories in men. At latencies greater than 500 ms, right parietal cortices were preferentially activated when previously bought or used items were chosen. In contrast, left inferior and right orbital cortices were preferentially activated when selecting less-known items. This may be interpreted as representing the neural correlates of decisions where the outcome is consistent with previous experience, and of choices which are 'difficult' in some sense. Analysis of coherent gamma-oscillations (20-45 Hz) revealed neural activity over left anterior and right dorsolateral cortices at long latency (> 1500 ms) when brand knowledge is low. This is consistent with the late binding of (brand) memories and evaluation of multiple sources of information when a choice is not obvious. gamma-Activity showed that women may activate larger neural networks when preference is high, suggesting that men and women exhibit different patterns of neural activity even though their overt performances are similar.


Epidemic MRSA clone ST22-IV is more resistant to multiple host- and environment-related stresses compared with ST228-I.
ST22-IV is a successful hospital-associated MRSA clone. Due to its known ability to replace other MRSA clones in hospitals, it became a dominant clone in Europe and beyond. So far, there are no studies investigating the relationship between the epidemiological success of MRSA clones and their capacity to withstand commonly encountered stresses. We investigated the fitness of ST22-IV in comparison with the replaced clone ST228-I, evaluating its resistance to oxidative stress, autolytic activity, growth at high osmolarity and in acid and alkaline environments and survival under desiccation and heat shock. We also compared their phenotypic characteristics and examined the impact of antibiotic consumption on epidemiological success. Here we demonstrate that the dominance of ST22-IV is linked neither to changes in antibiotic consumption nor to acquisition of additional resistances over time. Strong α-haemolysin activity, the production of β-haemolysin and the presence of an active agr could partly explain the virulence of ST22-IV previously observed in a murine model of pneumonia. Most importantly, we show that ST22-IV compared with ST228-I, besides retaining susceptibility to most antibiotics over time, has a superior capacity to survive under all stress conditions tested, which bacteria commonly face during their life cycle. Our results support our hypothesis that ST22-IV has a fitness advantage over ST228-I. This fitness advantage could have allowed ST22-IV to displace ST228-I without acquiring additional resistances and could help explain its epidemic success in hospital settings and its spread in Europe and beyond.


Anger in palliative care: a clinical approach.
Anger in patients and families is a common problem in the care of persons with advanced disease. Whereas it is widely accepted that anger may be a justifiable reaction to significant illness and loss, it frequently creates difficulties for the doctors involved in care. In particular, there is often a personal impact on the doctor at whom anger is directed. This paper examines results of qualitative research with palliative care workers in the context of the broader published literature and the authors' clinical experiences. The ability to interact effectively with angry patients is a skill that is often learned with experience and is extremely useful in both transforming the patients' reaction into a more creative emotion and in developing a therapeutic relationship. Despite conscientious efforts, however, a few patients continue to be angry. A practical approach to anger, useful for the clinician directly involved in care, is outlined along with some strategies to adopt in the face of persistent anger.


Usefulness of indomethacin for patent ductus arteriosus in full-term infants.
The aim of this retrospective study was to evaluate the effectiveness of indomethacin therapy for patent ductus arteriosus (PDA) in full-term infants. The patients were 41 full-term infants with a PDA birth weight (BW) > or =2500 g and a gestational age (GA) > or =37 weeks. The echocardiographic evaluation and medical management of PDA in these infants was similar to that for PDA in low-birth-weight infants. Indomethacin (0.2-0.25 mg/kg/dose) was given intravenously at 12-24-hour intervals within 23 days of birth. Of the 41 infants, 12 showed complete closure, and 13 showed improvement of clinical symptoms. These 25 infants were classified as the responder group (61%). The other 16 infants, who did not show improvement in clinical symptoms, were classified as the nonresponder group. Statistical analysis revealed no difference between the two groups regarding GA, BW, Apgar score at 1 minute, minimum diameter of the DA before treatment, the average age at the initiation of treatment, and DA flow pattern. No severe adverse reactions were observed in any infant. Indomethacin therapy appears to be an effective medical treatment option for PDA in full-term symptomatic infants prior to considering surgical treatment.


Minimum detectable dose as a measure of bioassay programme capability.
This paper suggests that minimum detectable dose (MDD) be used to describe the capability of bioassay programmes for which intakes are expected to be rare. This allows expression of the capability in units that correspond directly to primary dose limits. The concept uses the well established analytical statistic minimum detectable amount (MDA) as the starting point, and assumes MDA detection at a prescribed time post-intake. The resulting dose can then be used as an indication of the adequacy or capability of the programme for demonstrating compliance with the performance criteria. MDDs can be readily tabulated or plotted to demonstrate the effectiveness of different types of monitoring programmes. The inclusion of cost factors for bioassay measurements can allow optimisation.


Pelvic cavity malignant solitary fibrous tumor with dedifferentiation and multifocal cytokeratin expression.
Pelvic cavity small-sized malignant solitary fibrous tumors are rare. Surgeons easily misjudge these tumors as benign lesions, and they are usually resected by laparoscopic surgery. When accompanied by dedifferentiation, malignant solitary fibrous tumors are difficult to diagnose by pathologists. Here, we describe a challenging case. A 47-year-old man was accidentally found to have a pelvic mass after three months. Surgeons assumed a diagnosis of a benign tumor according to the Computed Tomography and Ultrasonography reports. The patient underwent laparoscopic surgery to resect the tumor. After the operation, the patient was diagnosed as having a malignant solitary fibrous tumor with dedifferentiation. The patient had a recurrence one year later. This pelvic cavity malignant solitary fibrous tumor was a rare case because of its dedifferentiation and cytokeratin expression. The expression of cytokeratin and the absence of vimentin and CD34 were pitfalls to diagnosis. In this case, there was still a high amount of malignancy despite the small size of the tumor. Clinical image and pathologic multidisciplinary analysis and core needle biopsies before surgery had a great effect on diagnosis and therapy of this disease. The case is a cautionary tale not only for pathologists but also for surgeons.


Levodopa may improve orthostatic tremor: case report and trial of treatment.
Primary orthostatic tremor is a regular fast lower limb tremor causing unsteadiness on standing. Treatment is generally unsatisfactory. A patient with primary orthostatic tremor who 9 years later developed levodopa responsive idiopathic Parkinson's disease is described. The patient exhibited the classic features of primary orthostatic tremor with relief of the tremor by walking or sitting while treated with levodopa. However, in the "off" state, when the benefits of levodopa disappeared, this orthostatic tremor was continuous and severely compromised the patient's gait. On the basis of this finding eight patients with primary orthostatic tremor were treated with levodopa. Five patients experienced benefit and elected to remain on long term treatment. This study is the first trial of therapy in primary orthostatic tremor and suggests that levodopa can lead to good symptomatic relief in this potentially disabling condition.


Whole-body MRI, dynamic contrast-enhanced MRI, and diffusion-weighted imaging for the staging of multiple myeloma.
Magnetic resonance imaging (MRI) is the most sensitive imaging technique for the detection of bone marrow infiltration, and has therefore recently been included in the new diagnostic myeloma criteria, as proposed by the International Myeloma Working Group. Nevertheless, conventional MRI only provides anatomical information and is therefore only of limited use in the response assessment of patients with multiple myeloma. The additional information from functional MRI techniques, such as diffusion-weighted imaging and dynamic contrast-enhanced MRI, can improve the detection rate of bone marrow infiltration and the assessment of response. This can further enhance the sensitivity and specificity of MRI in the staging of multiple myeloma patients. This article provides an overview of the technical aspects of conventional and functional MRI techniques with practical recommendations. It reviews the diagnostic performance, prognostic value, and role in therapy assessment in multiple myeloma and its precursor stages.


[Genetic markers of the mumps virus].
Thermostability and propagation in different cell cultures and interferon-producing ability of three vaccine mumps virus strains (Jeryl Lynn, Leningrad-Zagreb and PZH-17) and ten wild viruses isolated from patients suffering from mumps were investigated. Considerable differences were found after vaccinal and wild virus strains were subjected to a temperature of 50 degrees C for 30 minutes. Wild strains were significantly more thermoresistant than the vaccinal ones. Differences in the propagation ability between wild an attenuated vaccinal strains were also found when tested in the Vero cell line and in primary cell cultures of human amnion. Wild strains propagated equally well in both cultures, while the vaccine strains propagated significantly better in the Vero cell line. The quantities of interferon produced by vaccinal and wild virus strains were determined by the micromethod titration technique. The vaccinal strains produced greater quantities of interferon than the wild ones, but from these differences no conclusions concerning the degree of their attenuation could be arrived at. From the results presented, it can be concluded that there is a correlation between the temperature marker and a difference in the propagation ability in the Vero cell cultures and the primary cell cultures of human amnion, and that these differences could be used as the genetic marker.


Gadolinium-loaded nanoparticles engineered from microemulsion templates.
Microemulsions (oil-in-water) have been used as templates to engineer stable emulsifying wax and Brij 72 (polyoxyl 2 stearyl ether) nanoparticles. The technique is simple, reproducible, and amenable to large-scale production of stable nanoparticles having diameters below 100 nm. Investigation of the process variables showed that the amount of surfactant used in the preparation of microemulsion templates had the greatest influence on the microemulsion window, as well as the properties and stability of the cured nanoparticles. Emulsifying wax and Brij 72 nanoparticles (2 mg/mL) made with 3 mM polyoxyl 20 stearyl ether and 2.3mM polysorbate 80, respectively, were the most stable based on retention of nanoparticle size over time. Gadolinium acetylacetonate (GdAcAc), a potential anticancer agent for neutron capture therapy (NCT), was entrapped in stable nanoparticles. The apparent water solubility of GdAcAc was increased more than 2000-fold by entrapment into nanoparticles. The entrapment efficiency of GdAcAc was about 100% for emulsifying wax nanoparticles and 86% for Brij 72 nanoparticles, as determined by gel permeation chromatography (GPC). Elution profiles were obtained with light scattering (counts per second) to detect nanoparticles and ultraviolet (UV) absorption of GdAcAc at 288 nm. Challenges of these cured nanoparticles in biologically relevant media such as 10% fetal bovine serum, 10 mM phosphate-buffered saline, 150 mM NaCl, and 10% lactose at 37 degrees C for 60 min demonstrated that these nanoparticles are stable. The ease of preparation of these very small and stable nanoparticles, and the ability to entrap lipophilic drugs such as GdAcAc with high efficiency, suggested that these systems may have potential in cell targeting, especially for specific delivery to tumor cells for NCT.


Detection and Separation of Single-Stranded DNA Fragments Using Solid-State Nanopores.
Many biological assays require effectively and sensitively sorting DNA fragments. Here, we demonstrate a solid-state nanopore platform for label-free detection and separation of short single-stranded DNA (ssDNA) fragments (<100 nt), based on their length-dependent translocation behaviors. Our experimental data show that each sized pore has a passable length threshold. The negative charged ssDNA fragments with length smaller than the threshold can be electrically facilitated driven through the correspondingly sized nanopore along the direction of electric field. In addition, the passable length threshold increases with the pore size enlarging. As a result, this phenomenon is able to be applicable for the controllable selectivity of ssDNA by tuning nanopore size, and the selectivity limitation is up to 30nt. Numerical simulation results indicate the translocation direction of ssDNA is governed by the competition of electroosmosis and electrophoresis effects on the ssDNA and offer the relationship between passable length threshold and pore size.


[FEATURES OF THE TREATMENT OF THE SPINE IN RHEUMATOID ARTHRITIS].
Rheumatoid arthritis (RA) refers to the most common inflammatory joint disease, which can lead to persistent disability and early mortality of patients, and one of the manifestations of RA is a frequent lesion of the spine, which significantly affects the quality of life of these patients. To evaluate spine lesion in patients with different types of current RA and factors that determine it. Under the supervision of the RA patient 131 was aged 18 to 79 years (mean 45 years) among them was 18% male and 82% female. Duration of disease was 10 years, I radiographic arthritis stage is set to 8% of cases, II - 38%, III - 35%, IV - 19%, by rheumatoid factor seropositivity was observed in 77% of patients studied, and by the presence of antibodies against cyclic citrullin peptide - y ¾. Extra-articular (systemic) form of the disease occurred in 43% of cases, systemic osteoporosis - 67%. lesions of the spine in the form of osteochondrosis and spondyloarthrosis observed at ½ of the number of RA patients, and clinically overt occurs in 35% of cases, which is directly related to patient age, involving in the process of wrist, elbow and hip joints, the presence of systemic osteoporosis and tendovaginitis, sensory and motor disorders due to peripheral neuropathy. Frequency ratio of mechanical, disfixtional, disgemic and inflammatory pain in the spine in RA is a 1: 2: 6: 14. Radiographs revealed ossification of the outer layers of the intervertebral discs and the formation sindesmofitov and spondylodiscitis. Involvement of joints is characterized by vagueness of the articular surfaces and narrowing gaps. Vertebral pathology affects heart disease symptoms (changes in electrical conductivity, the size of cameras, the left ventricular diastolic function), autonomic changes and severity of neuropathy and predictors are blood levels of rheumatoid factor and C-reactive protein. Due to the nature of spinal lesions in rheumatoid arthritis has been proposed a scheme of treatment with Actemra, Orcerin, Zoledro-Denk. Spondylopathies is a frequent manifestation of RA, is interconnected with many clinical and laboratory signs of the disease, and in the future early detection of spondylopathies in the patients with active RA will be useful for timely rehabilitation.


Selective Catalytic Reduction over Cu/SSZ-13: Linking Homo- and Heterogeneous Catalysis.
Active centers in Cu/SSZ-13 selective catalytic reduction (SCR) catalysts have been recently identified as isolated Cu2+ and [CuII(OH)]+ ions. A redox reaction mechanism has also been established, where Cu ions cycle between CuI and CuII oxidation states during SCR reaction. While the mechanism for the reduction half-cycle (CuII → CuI) is reasonably well-understood, that for the oxidation half-cycle (CuI → CuII) remains an unsettled debate. Herein we report detailed reaction kinetics on low-temperature standard NH3-SCR, supplemented by DFT calculations, as strong evidence that the low-temperature oxidation half-cycle occurs with the participation of two isolated CuI ions via formation of a transient [CuI(NH3)2]+-O2-[CuI(NH3)2]+ intermediate. The feasibility of this reaction mechanism is confirmed from DFT calculations, and the simulated energy barrier and rate constants are consistent with experimental findings. Significantly, the low-temperature standard SCR mechanism proposed here provides full consistency with low-temperature SCR kinetics.


UAV aided virtual cooperative spectrum sensing for cognitive radio networks.
Cooperative spectrum sensing (CSS) involves multiple secondary users (SUs) reporting primary user (PU) channel sensing states to the fusion center (FC). However, the high overheads associated with multi-user CSS impose power limitations that limit its usefulness in unmanned aerial vehicle (UAV) networks. To address this challenge, we propose a virtual CSS, where a single UAV conducts CSS while following a circular flight trajectory in the air. The novelty of our approach is presenting a working frame structure for the UAV flight, including sensing and data transmission periods with further division of the sensing time into mini-sensing slots. In the virtual CSS, UAV performs local sensing decisions in each mini-slot and accumulates them for a final decision. The proposed virtual CSS scheme exploits sequential decision fusion (SDF), which sequentially adds individual mini-slot decisions. Additionally, we leverage machine learning (ML), employing AdaBoost ensembling classifier (ENC), to inspect flight conditions and reconfigure mini-slot periods dynamically for both traditional decision fusion (TDF) and our proposed SDF schemes. Furthermore, we identify an optimal decision threshold (ODT) for the proposed SDF, enabling the comparison of sequential results with an adjustable threshold through majority voting. This novel approach results in energy efficiency and improved throughput for virtual CSS using SDF, surpassing the performance of TDF, which relies on collecting entire mini-slot reports for its final decision. Simulation results demonstrate the effectiveness of the proposed SDF following the ENCODT (SDF-ENCODT) scheme compared to existing techniques from the literature. We explore varying levels of UAV flight velocities, moving radius, detection probability demand, and channel signal-to-noise ratio (SNR), reinforcing the significance of our contribution. Our research highlights the motivation to address spectrum scarcity in UAV communication by proposing an innovative virtual CSS scheme based on SDF. The proposed approach enhances spectrum utilization, overcomes power limitations, and substantially improves CSS for UAV networks.


Idiopathic pericarditis and pregnancy.
The association of idiopathic pericarditis and pregnancy is described in 3 patients. The disease preceded the onset of pregnancy in 2 patients and appeared during the sixth month in the third. All pregnancies reached term and the deliveries were uneventful. One patient had mild heart failure before the pregnancy. This deteriorated slightly during its course. The remaining 2 patients had no signs of heart failure and none of the 3 had arrhythmias or embolic phenomena. Two patients were treated with aspirin and prednisone and one was treated for heart failure only. All patientts are still symptomatic and require treatment 9 months, 1 year and 21 years after the pregnancy. Two of the patients underwent partial pericardiectomy.


Peritoneovenous shunt for palliation of malignant ascites.
Forty patients with malignant ascites refractory to conventional medical management had peritoneovenous shunt for palliation. The shunt provided effective palliation in 28 with decrease in weight, abdominal girth, number of paracenteses required and increase in urine output. These patients also had improvement in strength, appetite and ambulation. Complications such as hemodilution, volume overload, and sepsis do not contraindicate surgery. In 12 patients with high ascitic fluid protein content (4.5 g/liter) and a large number of malignant cells, loculated ascites and prior severe renal and cardiac disease, the shunt did not provide palliation. Peritoneovenous shunt appears to provide effective palliation in carefully selected patients with refractory malignant ascites.


The expression of the neonatal sarcoplasmic reticulum Ca2+ pump (SERCA1b) hints to a role in muscle growth and development.
The neonatal isoform of sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 1 (SERCA1b) is a Ca2+ pump with a well-known developmentally regulated transcript level but an undefined protein expression and function. Specific antibodies were generated to show that SERCA1b is exclusively expressed in myoblasts and myotubes of cultured and regenerating muscle. However, the SERCA1b protein was not detectable in normal adult fast and slow muscles. Studies of the in vitro differentiating myogenic cell lines C2C12 and sol8 showed that SERCA1b is the main SERCA1 protein isoform induced during differentiation and that it is found in the myotubes. Remarkably in BC3H1 cells, which show incomplete differentiation and are reluctant to form myotubes, express the SERCA1b mRNA but not the corresponding protein. SERCA1b protein was also absent from stretched or denervated adult soleus, in spite of the fact that its mRNA level was upregulated. SERCA1b accounts for nearly the total of SERCA1 expression in the diaphragm of newborn mice, which suggests that the insufficient function and development of the diaphragm in the SERCA1 null mutant mice may be due to the lack of SERCA1b. Our studies point to an important regulation of SERCA1b expression at the protein level and hints to a role in the growth of the developing muscle.


1,3-Bis(prop-2-yn-yl)-1H-1,3-benzimid-azol-2(3H)-one.
In the title compound, C(13)H(10)N(2)O, the fused-ring system is essentially planar, the largest deviation from the mean plane being 0.015 (1) Å. The two propynyl groups are nearly perpendicular to the benzimidazole plane, making dihedral angles of 85 (3) and 80 (2) °, and point in opposite directions. There are two short inter-molecular C-H⋯O contacts to the carbonyl O atom, one involving the acetyl-enic H atom and the other a H atom of the methyl-ene group.


[Stalking of psychiatrists and psychotherapists : Results of an online survey].
Currently, there are clear indications that due to their exposed occupational position psychiatrists and psychotherapists are at a higher risk than the general public to become the victim of stalking by patients. This study investigated the frequency of stalking and its psychosocial impact among psychiatrists and psychotherapists in the Federal Republic of Germany. Analysis of an online survey among members of the German Association for Psychiatry, Psychotherapy and Psychosomatics (DGPPN) from 23 September 2015 until 22 October 2015. Of the respondents 26.5% reported having been the victim of stalking. In more than a third of the reported cases the stalking was described as severely or very severely debilitating. The majority of the perpetrators suffered from psychotic or personality disorders. Male victims were significantly more frequently stalked by a female perpetrator. Approximately 1 in 10 stalking victims continued the treatment of the perpetrator. The majority of the stalking victims did not obtain substantial support from their employer. The phenomenon of stalking within therapeutic relationships needs to be incorporated into the medical and psychotherapeutic professional training, e. g. by implementing specialized training courses and the systematic integration of this topic into clinical supervision. The institutional dealing with stalking by patients needs to optimized, e. g. by promptly transferring treatment of patients who stalk to other professionals and, where required, providing assistance in reporting stalking incidents to the police.


A disease progression model estimating the benefit of tolvaptan on time to end-stage renal disease for patients with rapidly progressing autosomal dominant polycystic kidney disease.
Tolvaptan was approved in the United States in 2018 for patients with autosomal dominant polycystic kidney disease (ADPKD) at risk of rapid progression as assessed in a 3-year phase 3 clinical trial (TEMPO 3:4). An extension study (TEMPO 4:4) showed continued delay in progression at 2 years, and a trial in patients with later-stage disease (REPRISE) provided confirmatory evidence of efficacy. Given the relatively shorter-term duration of the clinical trials, estimating the longer-term benefit associated with tolvaptan via extrapolation of the treatment effect is an important undertaking. A model was developed to simulate a cohort of patients with ADPKD at risk of rapid progression and predict their long-term outcomes using an algorithm organized around the Mayo Risk Classification system, which has five subclasses (1A through 1E) based on estimated kidney growth rates. The model base-case population represents 1280 patients enrolled in TEMPO 3:4 beginning in chronic kidney disease (CKD) stages G1, G2, and G3 across Mayo subclasses 1C, 1D, and 1E. The algorithm was used to predict longer-term natural history health outcomes. The estimated treatment effect of tolvaptan from TEMPO 3:4 was applied to the natural history to predict the longer-term treatment benefit of tolvaptan. For the cohort, analyzed once reflecting natural history and once assuming treatment with tolvaptan, the model estimated lifetime progression through CKD stages, end-stage renal disease (ESRD), and death. When treated with tolvaptan, the model cohort was predicted to experience a 3.1-year delay of ESRD (95% confidence interval: 1.8 to 4.4), approximately a 23% improvement over the estimated 13.7 years for patients not receiving tolvaptan. Patients beginning tolvaptan treatment in CKD stages G1, G2, and G3 were predicted to experience estimated delays of ESRD, compared with patients not receiving tolvaptan, of 3.8 years (21% improvement), 3.0 years (24% improvement), and 2.1 years (28% improvement), respectively. The model estimated that patients treated with tolvaptan versus no treatment spent more time in earlier CKD stages and had later onset of ESRD. Findings highlight the potential long-term value of early intervention with tolvaptan in patients at risk of rapid ADPKD progression.


[Knowing where the patients would like to die].
The majority of the population wishes to die at home. However, most patients die in hospitals or nursing homes. What do health care professionals know about the choices of their patients in this matter? This study concerns persons who died from natural causes during the 1st semester of 2013 in 2 districts of the canton of Vaud. 241 of their health care professionals answered a questionnaire. Only 35.6 % knew their patient's wishes pertaining to where their death should take place. Despite the opportunity to speak about it with one's GP, the issue is not usually raised. If the patients give oral or written advance directives, their wishes are respected in 66.8 % of cases. Given the high value placed nowadays on patient autonomy, providing training on end of life care to physicians could help them approach this subject with greater ease.


Novel clusters of receptors for sphingosine-1-phosphate, sphingosylphosphorylcholine, and (lyso)-phosphatidic acid: new receptors for "old" ligands.
The (lyso)phospholipid mediators sphingosine-1-phosphate (S1P), lysophosphatidic acid (LPA), sphingosylphosphorylcholine (SPC), and phosphatidic acid (PA) regulate diverse cellular responses such as proliferation, survival and death, cytoskeletal rearrangements, cell motility, and differentiation among many others. Signaling is complex and many signaling events are mediated through the activation of cell surface seven transmembrane (7TM) G protein coupled receptors. Five high affinity receptors for S1P have been identified so far and named S1P(1, 2,3,4,5) (formerly referred to as endothelial differentiation gene (edg)1, 5, 3, 6, 8). Recently, the orphan receptor GPR63 was identified a low affinity S1P receptor structurally distant from the S1P(1-5) family. The orphan GPR3, 6, 12 cluster, phylogenetically related to the edg and melanocortin receptors appears to be subject to modulation by S1P and SPC although all three receptors are strong constitutive stimulators of the Galphas-adenylyl cyclase (AC) pathway and would not require additional ligand stimulation but rather inverse agonism to control activity. Ovarian cancer G protein coupled receptor 1 (OGR1) and GPR4, two structurally closely related receptors were assigned in functional and binding studies as high affinity molecular targets for SPC. Very recently, however, both OGR1 and GPR4 were described as receptors endowed with the ability to signal cells in response to protons. LPA exerts its biological effects through the activation of G protein coupled LPA(1-3) receptors (formerly referred to as edg2, 4, 7). A fourth high affinity LPA receptor has been identified: P2Y9 (GPR23) structurally related to nucleotide receptors and phylogenetically quite distant from the high affinity LPA(1-3) cluster. This review attempts to give an overview about the existing families of lysophosholipid receptors and the spectrum of lipid agonists they use as high or low affinity ligands to relay extracellular signals into intracellular responses. Recently deorphaned lipid receptors, within and outside the known lipid receptor clusters will receive particular attention.


A controlled trial of choleretic and hepatoprotective actions of Livzon and dehydrocholic acid in a model of obstructive jaundice in albino rats.
The authors have tried to examine the hepatoprotective and cholerectic action of a new indigenised drug, Livzon (Hind Chemicals Ltd., Kanpur, India) and compared its action to Decholin (casella-Riedel Pharma GmbH, Frankfurt, Germany), a known hepatoprotective and choleretic agent. Albino rats were chosen as the experimental animals. Obstructive jaundice was created by ligating the common bile ducts after taking liver biopsies. The animals were divided into three groups: (i) Control group-no drug was given, (ii) Livzon trial group, (iii) Decholin group. The animals were reoperated, liver biopsies were taken and histologically examined. The study confirmed the hepatoprotective and choleretic actions of Livzon and Decholin. However, Decholin was more of a choleretic, the Livzon was more hepatoprotective.


Clinical application of neutrophil gelatinase-associated lipocalin in the revised chronic kidney disease classification.
A revised classification of chronic kidney disease (CKD) was proposed by the Kidney Disease: Improving Global Outcomes (KDIGO) in 2012. Neutrophil gelatinase-associated lipocalin (NGAL) was considered as one of the most promising biomarkers in clinical nephrology. The aim of this study was to examine the level of NGAL in patients with different impairment of GFR based on the new classification, and to evaluate whether NGAL in serum or urine was associated with different risk categories in CKD patients. A cross-sectional study was performed in 240 patients with CKD. NGAL, serum cystatin C, β₂-macroglobulin (β₂-MG), urine α₁-macroglobulin (α₁-MG) and albuminuria were tested in patients with various degrees of renal impairment. Good correlation was found between the NGAL and the cystatin C, β₂-MG and the α₁-MG (r > 0.7). The level of sNGAL in CKD stage 3b was more than that in CKD stage 3a (P = 0.025). The concentration of the NGAL increased progressively with the increasing of risk categories (proposed by the revised CKD classification). The cutoff value of NGAL was calculated from stage 2 to stage 5. ROC analysis showed good AUC (sNGAL > 0.8, uNGAL > 0.7) and high specificity (sNGAL > 87%, uNGAL > 90%) on the cutoff value of NGAL. The results confirm NGAL as a useful biomarker in clinical nephrology which is helpful to diagnosis and evaluate the categories for CKD proposed by the KDIGO.


Conversion of green fluorescent protein into a toxic, aggregation-prone protein by C-terminal addition of a short peptide.
A non-natural 16-residue "degron" peptide has been reported to convey proteasome-dependent degradation when fused to proteins expressed in yeast (Gilon, T., Chomsky, O., and Kulka, R. (2000) Mol. Cell. Biol. 20, 7214-7219) or when fused to green fluorescent protein (GFP) and expressed in mammalian cells (Bence, N. F., Sampat, R. M., and Kopito, R. R. (2001) Science 292, 1552-1555). We find that expression of the GFP::degron in Caenorhabditis elegans muscle or neurons results in the formation of stable perinuclear deposits. Similar perinuclear deposition of GFP::degron was also observed upon transfection of primary rat hippocampal neurons or mouse Neuro2A cells. The generality of this observation was supported by transfection of HEK 293 cells with both GFP::degron and DsRed(monomer)::degron constructs. GFP::degron expressed in C. elegans is less soluble than unmodified GFP and induces the small chaperone protein HSP-16, which co-localizes and co-immunoprecipitates with GFP::degron deposits. Induction of GFP::degron in C. elegans muscle leads to rapid paralysis, demonstrating the in vivo toxicity of this aggregating variant. This paralysis is suppressed by co-expression of HSP-16, which dramatically alters the subcellular distribution of GFP::degron. Our results suggest that in C. elegans, and perhaps in mammalian cells, the degron peptide is not a specific proteasome-targeting signal but acts instead by altering GFP secondary or tertiary structure, resulting in an aggregation-prone form recognized by the chaperone system. This altered form of GFP can form toxic aggregates if its expression level exceeds the capacity of chaperone-based degradation pathways. GFP::degron may serve as an instructive "generic" aggregating control protein for studies of disease-associated aggregating proteins, such as huntingtin, alpha-synuclein, and the beta-amyloid peptide.


[Adenocarcinoma of the third part of the duodenum].
Adenocarcinoma of the third part of the duodenum is a rare tumour (34 cases reported in the literature). The clinical signs are polymorphic and non-specific and the stenotic form is the most frequent (57%). Complications are numerous and frequent. The difficult radiological diagnosis reveals either a short stenosis, a filling defect or, more rarely, and enlarged duodenal shadow or an ulcer. Duodenal fibroscopy allows the histological diagnosis and the differential diagnosis with other duodenal tumours. Adenocarcinoma of the third part of the duodenum requires cephalic duodenopancreatectomy (operative mortality of about 16%), which is the only treatment allowing a 3-year survival in 50% of cases and a 5-year survival in 30-40% of cases.


Are we performing a lot of simple nephrectomies?
To assess the frequency of simple nephrectomies for benign diseases and compare it with the frequency of nephrectomies for malignant diseases. The observational study was conducted at the Armed Forces Institute of Urology, Rawalpindi, Pakistan, from October 2008 to September 2011, and comprised patients undergoing simple nephrectomy for benign disease who were followed up for one year. This was compared to all the other urological procedures performed during the study period, including nephrectomies for malignant diseases. Indications and the post-operative sequel of simple nephrectomies were documented. SPSS 16 was used for data analysis. Of the total 7518 procedures, 1995(26.5%) were open cases. A total of 295 nephrectomies were performed during this period, out of which 203 (68.8%) were simple nephrectomies for benign disease and 92 (31.1%) were radical nephrectomies for malignant causes. Simple nephrectomy (203 cases) represented 2.7% of the total and 26.5% of the open procedures. In contrast, the radical nephrectomies for malignant disease (92 cases) represented 1.2% and 4.6% respectively. Among the 203 cases of simple nephrectomy, the male-to-female ratio was 2.27:1 with 141(69.5%) males and 62(30.5%) females. The mean age was 40.21 + 17.243 years (range: 4-84 years) The most common indication of simple nephrectomy was non-functional kidney due to renal calculus disease 101(49.7%). This was followed by pelvi-ureteric junction obstruction causing renal damage 31(15.2%), chronic pyelonephritis 24(11.2%) and pyonephrosis 15(7.38%). Two (0.98%) patients had a fatal outcome.. The percentage of nephrectomies for benign diseases was more than the malignant diseases. Simple nephrectomies are being performed in a large percentage, indicating the advanced stage of benign diseases at the time of presentation.


Efficient sampling of thermal averages of interacting quantum particle systems with random batches.
An efficient sampling method, the pmmLang + RBM, is proposed to compute the quantum thermal average in the interacting quantum particle system. Benefiting from the random batch method (RBM), the pmmLang + RBM has the potential to reduce the complexity due to interaction forces per time step from O(NP2) to O(NP), where N is the number of beads and P is the number of particles. Although the RBM introduces a random perturbation of the interaction forces at each time step, the long time effects of the random perturbations along the sampling process only result in a small bias in the empirical measure of the pmmLang + RBM from the target distribution, which also implies a small error in the thermal average calculation. We numerically study the convergence of the pmmLang + RBM and quantitatively investigate the dependence of the error in computing the thermal average on the parameters such as batch size, time step, and so on. We also propose an extension of the pmmLang + RBM, which is based on the splitting Monte Carlo method and is applicable when the interacting potential contains a singular part.


Collimation of dense plasma jets created by low-energy laser pulses and studied with soft x-ray laser interferometry.
The physical mechanisms driving the collimation of dense plasma jets created by low-energy ( approximately 0.6 J) laser pulse irradiation of triangular grooves were studied for different target materials using soft-x-ray interferometry and hydrodynamic code simulations. The degree of collimation of jets created by irradiating C, Al, Cu, and Mo targets at intensities of I=1x10(12) W cm(-2) with 120 ps laser pulses was observed to increase significantly with the atomic number. Radiation cooling is found to be the cause of the increased collimation, while the main effect of the increase in mass is to slow the jet evolution.


The Arabidopsis tetratricopeptide repeat-containing protein TTL1 is required for osmotic stress responses and abscisic acid sensitivity.
Mutations in the Arabidopsis (Arabidopsis thaliana) TETRATRICOPEPTIDE-REPEAT THIOREDOXIN-LIKE 1 (TTL1) cause reduced tolerance to NaCl and osmotic stress that is characterized by reduced root elongation, disorganization of the root meristem, and impaired osmotic responses during germination and seedling development. Expression analyses of genes involved in abscisic acid (ABA) biosynthesis and catabolism suggest that TTL1 is not involved in the regulation of ABA levels but is required for ABA-regulated responses. TTL1 regulates the transcript levels of several dehydration-responsive genes, such as the transcription factor DREB2A, and genes encoding dehydration response proteins, such as ERD1 (early response to dehydration 1), ERD3, and COR15a. The TTL1 gene encodes a novel plant protein with tetratricopeptide repeats and a region with homology to thioredoxin proteins. Based on homology searches, there are four TTL members in the Arabidopsis genome with similar intron-exon structure and conserved amino acid domains. Proteins containing tetratricopeptide repeat motifs act as scaffold-forming multiprotein complexes and are emerging as essential elements for plant hormonal responses (such as gibberellin responses and ethylene biosynthesis). In this report, we identify TTL1 as a positive regulator of ABA signaling during germination and seedling development under stress.


Optimization of supercritical fluid extraction of oil from the fruit of Gardenia jasminoides and its antidepressant activity.
A response surface methodology was applied to optimize the variables affecting the supercritical fluid carbon dioxide extraction of oil from the fruit of Gardenia jasminoides using the Box-Behnken design. The optimum extraction parameters were an extraction temperature of 49.94 °C, an extraction pressure of 29.89 MPa and an extraction time of 93.82 min. Through a GC/MS analysis, we revealed 16 major components of the oil extract, which showed potent antidepressant effects in both of two behavior despair models in mice: tail suspension test and forced swimming test. Our results suggest that the oil extract of Gardenia jasminoides prepared using the supercritical fluid carbon dioxide extraction may contain effective constituents to be used for depression therapy.


Heterologous Biosynthesis of Spinosad: An Omics-Guided Large Polyketide Synthase Gene Cluster Reconstitution in Streptomyces.
With the advent of the genomics era, heterologous gene expression has been used extensively as a means of accessing natural products (NPs) from environmental DNA samples. However, the heterologous production of NPs often has very low efficiency or is unable to produce targeted NPs. Moreover, due to the complicated transcriptional and metabolic regulation of NP biosynthesis in native producers, especially in the cases of genome mining, it is also difficult to rationally and systematically engineer synthetic pathways to improved NPs biosynthetic efficiency. In this study, various strategies ranging from heterologous production of a NP to subsequent application of omics-guided synthetic modules optimization for efficient biosynthesis of NPs with complex structure have been developed. Heterologous production of spinosyn in Streptomyces spp. has been demonstrated as an example of the application of these approaches. Combined with the targeted omics approach, several rate-limiting steps of spinosyn heterologous production in Streptomyces spp. have been revealed. Subsequent engineering work overcame three of selected rate-limiting steps, and the production of spinosad was increased step by step and finally reached 1460 μg/L, which is about 1000-fold higher than the original strain S. albus J1074 (C4I6-M). These results indicated that the omics platform developed in this work was a powerful tool for guiding the rational refactoring of heterologous biosynthetic pathway in Streptomyces host. Additionally, this work lays the foundation for further studies aimed at the more efficient production of spinosyn in a heterologous host. And the strategy developed in this study is expected to become readily adaptable to highly efficient heterologous production of other NPs with complex structure.


Effects of chronic restraint stress on the global DNA methylation profile of rat lung cells: Modulation by physical exercise.
The potential of behavioral stress to affect epigenetic mechanisms of non-encephalic tissues is still underestimated. In the present study we evaluated the effects of chronic behavioral stress on the DNA methylation profile of rat lung cells. Furthermore, we evaluated the potential of physical exercise to modulate the changes evoked by behavioral stress in lung cells. Male Wistar rats were divided into four experimental groups: (1) animals submitted to chronic restraint stress (CRS) (ST group) during the period of the 67th-80th postnatal day (PND); (2) animals submitted to physical exercise (EX group) during the 53rd-79th PND; (3) animals submitted to swimming during the 53rd-79th PND and to CRS during the 67th-80th PND (EX-ST group); and (4) animals not submitted to stress or swimming protocols (CTL). Global DNA methylation was quantified using an ELISA-based approach and gene expression was evaluated by real time PCR. A decreased global DNA methylation profile was observed in the ST group, however physical exercise demonstrated protection of lung cells from this stress-related hypomethylation. Increased expression of the Dnmt1 gene was evidenced in the ST group, whereas physical exercise was shown to protect lung cells from this stress-related effect in the EX-ST group. Comparative analysis of the ST and EX groups revealed opposite effects on the expression of Dnmt3a and Dnmt3b; however, a stress-related increase in expression of Dnmt3a and Dnmt3b was not seen in the EX-ST group. Our data showed that behavioral stress induced significant changes in the DNA methylation profile of rat lung cells and that this could be modulated by physical exercise.


Combined use of scoring incisions and 2-octylcyanoacrylate adhesive during endonasal septoplasty to correct cartilaginous deviations.
Applying 2-octylcyanoacrylate (2-OCA) tissue adhesive onto scoring incisions may increase efficacy and prevent concavity recurrence after septal deviation treatment. The present study evaluates the utility of 2-OCA adhesive application during endonasal septoplasty. The postoperative outcomes were compared between two consecutive periods in a single surgical department. Between March 2011 and March 2012, 23 consecutive patients underwent septoplasty using scoring incisions without 2-OCA application (scoring alone group), and between April 2012 and April 2013, the scoring incision gaps were filled with 2-OCA in 27 patients (scoring + CA group). The patients were followed up for more than six months. A straight septum was achieved in 37.0% of patients in the scoring alone group versus 58.3% in the scoring + CA group. The postoperative symptom score for nasal obstruction was significantly improved in both groups. Persistent septal swelling developed in three (12.5%) patients in the scoring + CA group. Neither group experienced major complications such as septal hematoma, abscess, or septal perforation. Application of 2-OCA adhesive onto scoring incisions appears to be a reliable and effective technique to correct deviated cartilage during endonasal septoplasty. However, the volume of 2-OCA applied onto the septum should be minimized to avoid potential foreign body reaction. A long-term follow-up study is warranted.


Inhibiting albumin glycation in vivo ameliorates glomerular overexpression of TGF-beta1.
Glycated albumin has been causally linked to the pathobiology of diabetic renal disease through its ability to stimulate the expression of transforming growth factor-beta1 (TGF-beta1), activate protein kinase C (PKC) and extracellular signal-regulated kinase (ERK), and promote production of extracellular matrix proteins in cultured glomerular cells. Whether glycated albumin modulates glomerular TGF-beta1 expression in vivo is not known. To address this issue, we assessed glomerular TGF-beta1 expression and pathology in response to reducing the burden of glycated albumin in vivo. We measured serum glycated albumin, urine protein, glomerular TGF-beta1 expression and morphometry, and collagen IV and fibronectin mRNA in db/m and db/db controls and in db/db mice treated for eight weeks with a synthetic compound that inhibits the condensation of glucose with albumin. In situ hybridization studies showed markedly increased glomerular TGF-beta1 mRNA in control db/db mice, which was significantly reduced in db/db mice treated for eight weeks with test compound. The treatment protocol, which normalized serum glycated albumin, concomitantly reduced the elevated protein excretion and the renal overexpression of mRNAs encoding fibronectin and collagen IV, and significantly decreased the mesangial matrix expansion, observed in db/db control animals. These findings, to our knowledge, provide the first evidence that glomerular overexpression of TGF-beta1 in diabetes derives at least in part from elevated glycated albumin concentrations, and can be partially suppressed by inhibiting the formation of this glycated protein. The results further suggest that glycated albumin has an important nephropathogenic role in diabetes that is operative, and can be therapeutically addressed, independent of glycemic status.


Fetal left ventricular non-compaction cardiomyopathy with ascites: A case report.
Here we report a case of fetal left ventricular non-compaction cardiomyopathy with ascites and cardiac dysfunction at a gestational age of 34+5 weeks. Laboratory tests did not reveal any sign of viral infection in utero. A female neonate weighing 2436 g was delivered by emergency cesarean section due to non-reassuring fetal status. Postnatal echocardiography confirmed left ventricular non-compaction cardiomyopathy with severe cardiac failure. Although she was treated effectively during the acute period by continuous flow peritoneal dialysis, surgical ligation of a patent ductus arteriosus, and inhaled nitric oxide, she died on day 41 of life. Symptoms of severe cardiac dysfunction appeared antenatally in this patient and the outcome was poor.


Explored Normalized Cut With Random Walk Refining Term for Image Segmentation.
The Normalized Cut (NCut) model is a popular graph-based model for image segmentation. But it suffers from the excessive normalization problem and weakens the small object and twig segmentation. In this paper, we propose an Explored Normalized Cut (ENCut) model that establishes a balance graph model by adopting a meaningful-loop and a k-step random walk, which reduces the energy of small salient region, so as to enhance the small object segmentation. To improve the twig segmentation, our ENCut model is further enhanced by a new Random Walk Refining Term (RWRT) that adds local attention to our model with the help of an un-supervising random walk. Finally, a move-making based strategy is developed to efficiently solve the ENCut model with RWRT. Experiments on three standard datasets indicate that our model can achieve state-of-the-art results among the NCut-based segmentation models.


Cardiovascular and subjective effects of intravenous cocaine administration in humans.
Nine volunteer subjects were tested with intravenously administered cocaine hydrochloride in doses ranging from 4 to 32 mg, as well as 10 mg of dextroamphetamine sulfate. Measures of cardiovascular and subjective effects were made. Generally parallel dose-effect functions were obtained for heart rate, blood pressure, Addiction Research Center Inventory scores, Profile of Mood Scales, and subject ratings. A substantial effect on each of these variables was recorded after 8 mg of cocaine. The increase continued and peaked at approximately 16 mg after which it usually leveled off. Ten milligrams of dextroamphetamine generally had an effect comparable to 8 to 16 mg of cocaine.


Pathology of nonalcoholic steatohepatitis.
To date, histologic evaluation, most commonly in the form of liver biopsy, remains the gold standard in evaluation of nonalcoholic fatty liver disease (NAFLD). Histologic evaluation was fundamental to the initial studies that introduced and defined the concept of fatty liver as a liver disease. Currently, liver biopsy in NAFLD serves multiple roles: confirmation (or exclusion) of the diagnosis; distinction of steatohepatitis from "simple steatosis"; assessment of extent of necroinflammatory activity, fibrosis, and architectural alterations. Histopathologic studies have underscored the fact that not all obese and/or diabetic individuals with elevated liver tests have fatty liver disease; for example, hepatic glycogenosis and hepatosclerosis have been described in diabetics, and other significant liver diseases have been documented. Likewise biopsy studies have documented lesions of steatosis or steatohepatitis in unusual patient groups or clinical settings, such as lean individuals, individuals with normal liver tests, patients taking certain medications, patients with co-existent serologically-diagnosed liver disease, and pediatric patients. Biopsy studies have shown that the lesions of NASH may or may not persist in cirrhosis; prior evidence of NASH on liver biopsy serves as a benchmark for the concept that many cases of otherwise cryptogenic cirrhosis developed from NAFLD/NASH. Liver biopsy remains a significant feature of studies delineating long-term outcome of NAFLD, some of which have shown that "simple steatosis" is not always non-progressive and benign. Finally, investigators have noted correlations of proposed pathophysiologic processes in NASH with particular histologic features. Therapeutic trials for NASH rely on histologic evaluation as the most sensitive analysis to document effects of treatment. Treatment trials afford an opportunity to evaluate histologic features of resolution, and these trials have also provided an opportunity for correlations of particular histologic lesions with clinical and laboratory features in well-characterized patient populations. These kinds of studies are currently relatively few, but results of a recent study have reinforced the concept of necessary criteria for diagnosis. Current discussions in pathology include identification of lesions of concern for progression, reproducible methods of diagnosis and semiquantification of lesions, and appropriate nomenclature. Matteoni et al. proposed NAFLD types 1-4 based on long-term outcome studies; Brunt et al. proposed a system of grading and staging for NASH that follows methods of separate assessment for necroinflammatory lesions (grade) and fibrosis (stage) accepted in other forms of non-biliary chronic liver disease. Recently, the Pathology Committee of the NIDDK NASH Clinical Research Network has proposed a system of evaluation that encompasses the entire spectrum of NAFLD from steatosis to steatohepatitis with fibrosis for use in upcoming treatment trials. And, just as the clinician cannot distinguish steatosis and steatohepatitis, the pathologist cannot discern if alcohol abuse may be an underlying cause of the lesions. Proposed nomenclature to align with either extant terminology in other forms of chronic liver disease, or to align with our knowledge of underlying cause(s) (such as metabolic syndrome) will be discussed.


[Lung function and physical performance in patients with mucoviscidosis].
In the GDR are at present living more than 800 patients with cystic fibrosis, 113 of them are in the age of 18 years and over. The prognosis is in first place depending upon the state of the lung. Thus, a continuous observation of the lung function is mandatory. The alterations of the lung are starting in the small airways (inflammation with ulceration, stenoses, obliteration) with primary disturbances of the relation between ventilation and perfusion, and with obstructive disturbances of the ventilatory distribution. The periphery of the lung is considerably inflated (increase of RV/TLC, trapped air). With progressing disease, obstructions are also observed in the larger airways, and due to progressing loss of parenchyma, VC, FEV1, and TLC become reduced. In about one third of the patients bronchial hyperreactivity is developing. The efficacy of treatment with bronchodilating drugs is not uniform and must individually be checked. The physical performance is reduced in an extent which depends upon the severity of the disease.


Biocompatibility and osseointegration of beta-TCP: histomorphological and biomechanical studies in a weight-bearing sheep model.
The aim of the study was to investigate the biocompatibility, degradation, and biomechanical properties of beta-TCP (Cerasorb) in a weight-bearing sheep model. beta-TCP implant prototypes were implanted in the tibial head of adult merino sheep. After 6 and 12 months material explants were harvested for biomechanical, histological, and histomorphometrical analysis. Corresponding bone specimens of the intact bone of the contralateral leg were used as controls in the biomechanical test. Compression tests showed higher values for maximum fracture load, yield strength, and compression modulus after 6 and 12 months compared to control. Microscopically, the implants showed good osteoconduction and were incorporated into the bone; however, relevant amounts of beta-TCP were still present after 12 months. Histomorphological results revealed that beta-TCP had partially degraded between implantation and 6 months, but its share remained constant between 6 and 12 months. The bone volume fraction in the area of the implant (46% +/- 6.5%) was initially higher than in the corresponding bone area of the contralateral leg (31% +/- 9.6%), but after 12 months declined to 29% +/- 9.4% (control: 33% +/- 8.3%), while the share of beta-TCP remained constant at 36% +/- 12.2%. These findings were supported by microradiographic data. In conclusion, in a weight bearing implantation model beta-TCP showed good biocompatibility, osseointegration and beginning degradation, even though it was not further degraded between 6 and 12 months.


Evaluation of the anti-inflammatory and anti-proliferation tumoral cells activities of Antrodia camphorata, Cordyceps sinensis, and Cinnamomum osmophloeum bark extracts.
The extracts of chloroform (1) and methanol (2) from Antrodia camphorata (AC), and chloroform (3) and n-butanol (4) fractions of methanol extract from Cordyceps sinensis (CS), and hexane (5), ethyl acetate (6), and methanol (7) from Cinnamomum osmophloeum bark (CO) were evaluated for their anti-inflammatory as well as tumor-cell growth inhibitory activities in vitro. All the tested extracts dose dependently inhibited the enhanced production of inflammatory mediators such as nitric oxide (NO) through reducing inducible NO synthase expression, and cytokines (tumor necrosis factor (TNF)-alpha and interleukin (IL)-12 in LPS/IFN-gamma activated murine peritoneal macrophages. In addition, extracts 1 from AC, and 5 and 6 from CO significantly arrest the mitogen-stimulated spleen cells in G0/G1 stage. On the other hand, all these extracts were also evaluated for their tumor-cell proliferation activities in different type of cancer cell lines such as Jurkat, HepG2, PC 3, Colon 205, and MCF 7 as well as normal PBMCs. Compared to untreated controls, the extracts 1, 2, and 4-7 were most active and inhibited Jurkat cells with IC50 value of 22, 40, 18, 4, 5, and 45 microg/ml, respectively. In addition, the extracts 5, 6, and 7 from CO showed potent growth inhibition of HepG2 and PC 3 with IC50 values of 35, 80, 55 microg/ml; and 42, 125, and 50 microg/ml, respectively. Similarly, the extracts 1 and 5 inhibited the growth of Colon 205 and MCF 7 cells with IC50 values of 65, 33; and 95 and 30 microg/ml, respectively. Interestingly, none of the tested extract has shown cytotoxicity towards normal PBMCs up to the concentration range studies (0-150 microg/ml). Taken together, these data suggest that the anti-inflammatory and anti-cancer properties of AC, CS, and CO might result from the growth inhibition of NO, TNF-alpha and IL-12, and tumor cells proliferation, respectively.


Dosimetric comparison between stereotactic body radiotherapy and carbon-ion radiation therapy for prostate cancer.
Prostate cancer rates have been steadily increasing in recent years. As high-precision radiation therapy methods, stereotactic body radiation therapy (SBRT) and carbon-ion radiation therapy (CIRT) have unique advantages. Analyzing the dosimetric differences between SBRT and CIRT in the treatment of localized prostate cancer can help provide patients with more accurate, individualized treatment plans. We selected computed tomography positioning images and the contours of target volumes of 16 patients with localized prostate cancer who received radiotherapy. We delineated the organs at risk (OARs) on the CyberKnife (CK) treatment planning system (TPS) MultiPlan4.0, which were imported into the CIRT uniform scanning TPS HIMM-1 ci-Plan. Two treatment plans, SBRT and CIRT, were designed for the same patient, and we used SPSS 22.0 for the statistical analysis of data. Both SBRT and CIRT plans met the prescribed dose requirements. In terms of target volume exposure dose, D2 (P<0.001), D5 (P<0.001), D50 (P<0.001), D90 (P=0.029), D95 (P<0.001), D98 (P<0.001), and Dmean (P<0.001) under SBRT were significantly higher than those under CIRT; the conformity index (CI) under SBRT was significantly better than that under CIRT (P<0.001); the target volume coverage rate (V95%) and dose homogeneity index (HI) under CIRT were significantly better than those under SBRT (P<0.001). In terms of OAR exposure dosage, the Dmax of the bladder and rectum under SBRT was significantly lower than that under CIRT (P<0.001), but Dmean was in the other direction; the exposure dose of the intestinal tract under CIRT was significantly lower than that under SBRT (P<0.05); Dmax of the femoral head under CIRT was significantly lower than that under SBRT (P<0.05), and there was no statistical difference between them at other doses. In this study, we found that when CIRT was used for treating localized prostate cancer, the dose distribution in target volume was more homogeneous and the coverage rate was higher; the average dose of OARs was lower. SBRT had a better CI and higher dose in target volume; the dose hotspot was lower in OARs. It is important to comprehensively consider the dose relationship between local tumor and surrounding tissues when selecting treatment plans.


Training imperatives for volunteers caring for high-risk, vulnerable populations.
Today, vulnerable populations expand as the threats of homelessness and communicable diseases continue to grow. Volunteers are moved to serve in areas in which they may not be well prepared. We identify the caring needs of high-risk, vulnerable populations and the needs of volunteers; we also conceptualize, develop, implement, and evaluate a training program for volunteers who serve homeless persons and families. This training program and the imperatives that undergird it are presented as a model applicable to the training of volunteers serving high-risk, vulnerable populations.


Effects of shift changes on female workers at a dish factory.
This study investigated the effects of working night shifts on social and family life by examining changes in workers' daily life before and after a change in their shifts. Subjects were 40 women aged 27-59 years, working at a dish factory. During the health examination of night workers in autumn of 2000, the subjects were directly interviewed about changes in their lives induced by the shift change. Question parameters consisted of 8 items including 30 sub-items related to social and family life, such as sleep, rest, meals, sports, family time, hobbies, neighborhood association and social activities. The subjects selected one of four response categories: "becoming worse", "no change", "becoming better" and "difficult to determine." With regard to the percentage of "becoming worse", meal-related items ranked high in all of the shift types. "Family time" and "hobbies" showed high percentages in the subjects transferring from day shifts to night shifts, and in those transferring from early-morning shifts to night shifts. "Rest", "sports" and "hobbies" showed high percentages in the subjects transferring from night shifts to midnight shifts. Decreased sleeping hours were confirmed in all of the shift types, while the subjects tended to sleep more soundly. As the workers transfer to shifts at earlier hours, they were obliged to make sacrifices in various aspects of their social and family life. Therefore, much assistance in this regard should be given to them.


Food components and ocular pathophysiology: a critical appraisal of the role of oxidative mechanisms.
Three of the major ocular diseases, namely cataracts, age-related macular degeneration and glaucoma are associated with oxidative damage. Disease risk and progression may be reduced through consumption of dietary components. To critically examine the literature on dietary and supplemental intakes of fruit and vegetables, meat, antioxidants (vitamins C, E and A), calcium, folate, iron, and their association with ocular disease. Google Scholar and key references from texts and publications were searched using search terms (eye disease, antioxidants), (vision, nutrition), no date restriction, only articles in English were included. We found probable evidence that dietary intake of fruits and vegetables, and vitamin C lowered incidence of cataracts and age-related macular degeneration. In high supplemental doses, vitamin C increases macular degeneration risk. Vitamin A from food was protective for cataracts and glaucoma, but not in supplemental form. Vitamin A was associated with lower incidence of macular degeneration. We also found probable evidence that higher intakes of meat increased the risk of cataracts and macular degeneration. Dietary calcium and iron appeared protective against glaucoma, but not in supplemental form. While a nutrient rich diet high in fruit and vegetables, and associated antioxidants appeared to be protective, we would caution intake of supplementary antioxidants for those with ocular disease.


Structural, microstructural, and residual stress investigations of plasma-sprayed hydroxyapatite on Ti-6Al-4 V.
Plasma-spray (PS) is a classical technique usually employed to cover orthopaedic titanium implant surfaces with hydroxyapatite (HA - Ca(10)(PO(4))(6)(OH)(2)). The objective of the current study is to investigate the structure and microstructure of HA plasma-spray 50 mum thick coating on titanium alloy (Ti-6Al-4 V) and residual stress due to processing in the substrate and in HA coating. The structure of the coatings was determined by high-energy synchrotron X-ray diffraction in energy dispersive (HESXRD), selected area electron diffraction (saed), Scanning Electron Microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR). No impurity phases in the HA were identified by HESXRD to keep away from the decomposition of HA at high temperature. hcp phase of HA substrate was detected with slight amorphous background. FTIR spectrum of a HA powder shows a typical spectrum for HA material with the characteristic phosphate peaks for HA at wavenumbers of 1090, 1052, 963, 602, and 573 cm(-1) are present. The morphology of HA powder observed by SEM exhibits grains of ca. 0.1 mum well-adapted for cell proliferation. HA/Ti-6Al-4 V interface observed by cross-section scanning and transmission electron microscopy (TEM) presents microcracks. Residual stresses were analyzed by sin(2) Psi X-ray diffraction method on titanium substrates and HA coating. Although the Ti substrates are in a slightly tensile residual state, the coated ones show a compressive state.


Oral Pulse Betamethasone, Methotrexate, and Combination Therapy to Treat Severe Alopecia Areata: A Randomized, Double-blind, Placebo-controlled, Clinical Trial.
The purpose of this study is to compare oral betamethasone pulse therapy, methotrexate therapy and a combination of the two for patients with Alopecia Areata (AA) as an autoimmune disorder. In this study, 36 patients with severe AA were selected and classified into three groups of 12: 1- Oral betamethasone therapy (3 mg, once a week) with placebo; 2- Oral methotrexate (15 mg, once a week) with placebo; and 3- A combination of methotrexate (15 mg, once a week) and betamethasone (3 mg, once a week). The Severity Alopecia Tool (SALT) was used to measure improvements in the lesions through photographs, and the patients also rated their condition on the Visual Analogue Scale (VAS). Assessments were performed, and the results were compared at baseline and then at intervals of three months for nine months. The demographics and SALT score were similar in the three groups (P > 0.05). All the groups showed improvements in SALT, VAS and photographic scores three months after beginning the treatment (P < 0.001). Betamethasone therapy (P = 0.006) and combination therapy (P < 0.001) provided greater SALT improvement than methotrexate, and combination therapy led to a greater improvement in VAS and photographic findings compared to the two other groups (P < 0.05). Oral steroid, methotrexate and combination pulse therapy were effective treatments for AA, while oral steroid pulse therapy and combination therapy were superior to methotrexate.