[Different autoimmunity in Wegener's granulomatosis and microscopic polyangiitis].
Wegener's granulomatosis (WG) and microscopic polyangiitis (MP) are "small vessel" vasculitides which can serologically be discriminated measuring autoantibodies directed towards different target antigens (ANCA). In the present study we can demonstrate increased autoimmunity in patients with MP, as evaluated by measurement of thyroid microsomal and cardiolipin antibodies. Neither thyroid microsomal- nor myeloperoxidase-, nor cardiolipin antibodies were correlated to each other.


The relationship between cancer and medication exposure in patients with systemic lupus erythematosus: a nested case-control study.
Systemic lupus erythematosus (SLE) is associated with increased risk of cancer and the mechanism remains unclear. Here, we examined the level of auto-antibodies and disease activity index scores in SLE patients with cancers and analyzed whether medications for SLE management might contribute to the higher cancer risk in SLE patients. In this retrospective study, we carried out a nested case-control study in a large cohort of SLE patients. We screened 5858 SLE patients to identify the newly diagnosed and yet to be treated cancers. The following clinical features were evaluated: auto-antibodies levels, SLE disease activity index scores, and previous medication used for SLE management. Systemic glucocorticoid, cyclophosphamide, hydroxychloroquine (HCQ), methotrexate, and azathioprine were considered the main medication indices. Our analyses identified 51 SLE patients who also had cancer and 204 matched control patients who had SLE but not cancer. Of the 51 SLE patients, thyroid cancer (14/51, 27.45%), cervical cancer (10/51, 19.61%), and lung cancer (7/51, 13.73%) were the most common types. Our analyses did not reveal any significant differences in the levels of auto-antibodies in SLE patients with cancers relative to the control group. Further, we observed that disease activity was significantly lower in SLE patients with cancers relative to the matched control SLE group. There was no statistically significant association between the cancer risk and the use of systemic glucocorticoid, cyclophosphamide, methotrexate, or azathioprine. Importantly, the administration of HCQ was significantly lower in SLE patients suffering cancers relative to the cancer-free matched control group. Our analyses indicate that SLE patients with cancers might have a lower disease activity at the time of cancer diagnosis. HCQ was negatively associated with cancer risk in SLE patients. These findings highlight a potential and novel prevention strategy for SLE.


Polysaccharides from Agaricus blazei stimulate lymphocyte T-cell subsets in mice.
Subset analysis of splenic lymphocytes using flow cytometry showed that the percentages of Thy1.2-(pan T-cells), L3T4-(CD4, helper T-cells), and Lyt2-(CD8, cytotoxic T-cells) positive cell populations were significantly increased in mice orally administered a hot water-soluble fraction from Agaricus blazei as compared with mice treated only with saline. 13C-NMR data indicates that the main component in the active polysaccharide is the complex of alpha-1,6- and alpha-1,4-glucan, which had already been shown to have anti-tumor activity against Sarcoma 180. It seems that the polysaccharide from Agaricus blazei may be an effective prophylactic, protecting humans against cancer by stimulating lymphocytes such as cytotoxic T-cells.


Preoperative carbohydrate antigen 19-9 is most predictive of malignancy in older jaundiced patients undergoing pancreatic resection.
Given the increased detection of occult pancreatic neoplasms with modern imaging modalities, it is often difficult to determine the risk of malignancy before curative pancreatectomy. We reviewed patients who underwent pancreatectomy to determine factors predictive of malignancy with particular attention to the serum marker carbohydrate antigen 19-9 (CA19-9). One hundred eighteen patients underwent radical pancreatectomy for malignant (n = 59) or benign (n = 59) pancreatic lesions. Demographic data, preoperative CA19-9 levels (normal, <37 U/mL), and follow-up were obtained from patient charts. Logistic regression analysis was used to determine univariate and multivariate predictors of malignancy. Significant multivariate predictors of malignancy were increased CA19-9, age older than 50 years, and preoperative jaundice. The sensitivity and specificity of increased preoperative CA19-9 alone were 71% and 83%, respectively. The combination of age older than 50 years and jaundice was a more accurate predictor than CA19-9 (sensitivity, 76%; specificity, 92%). Increased CA19-9 was highly specific (97%) for malignancy in older jaundiced patients or when the preoperative level was greater than 150 U/mL. Age and preoperative jaundice are more predictive of malignancy than CA19-9 alone unless levels are greater than 150 U/mL. Preoperative CA19-9 levels should be interpreted within the context of these other clinical factors.


Identification of cerebral perfusion using arterial spin labeling in patients with seizures in acute settings.
This study aimed to explore the utility of arterial spin labeling perfusion-weighted imaging (ASL-PWI) in patients with suspected seizures in acute settings. A total of 164 patients who underwent ASL-PWI for suspected seizures in acute settings (with final diagnoses of seizure [n = 129], poststroke seizure [n = 18], and seizure mimickers [n = 17]), were included in this retrospective study. Perfusion abnormality was analyzed for: (1) pattern, (2) multifocality, and (3) atypical distribution against vascular territories. Perfusion abnormality was detected in 39% (50/129) of the seizure patients, most (94%, 47/50) being the hyperperfusion pattern. Of the patients with perfusion abnormality, multifocality or hemispheric involvement and atypical distribution against vascular territory were revealed in 46% (23/50) and 98% (49/50), respectively. In addition, seizures showed characteristic features including hyperperfusion (with or without non-territorial distribution) on ASL-PWI, thus differentiating them from poststroke seizures or seizure mimickers. In patients in whom seizure focus could be localized on both EEG and ASL-PWI, the concordance rate was 77%. The present study demonstrates that ASL-PWI can provide information regarding cerebral perfusion status in patients with seizures in acute settings and has the potential to be used as a non-invasive imaging tool to identify the cerebral perfusion in patients with seizures.


Retracted: Effects of major ingredients (grape syrup, milk powder, and walnut paste) levels on physiochemical, rheological, and sensory attributes of walnut spread.
Effects of major ingredients (grape syrup, milk powder, and walnut paste) levels on physiochemical, rheological, and sensory attributes of walnut spread, Food Science & Nutrition, 2022 (https://onlinelibrary.wiley.com/doi/full/10.1002/fsn3.3107). The above article, published online on October 20, 2022 in Wiley Online Library (https://wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor in Chief Y. Martin Lo, and Wiley Periodicals LLC. The retraction has been agreed due to an error in which the incorrect manuscript was sent to the production team and published instead of the manuscript that the journal had reviewed and accepted.


Directed polymers in random media under confining force.
The scaling behavior of a directed polymer in a two-dimensional random potential under confining force is investigated. The energy of a polymer with configuration {y(x)} is given by H({y(x)}) = sigma(x=1)(N) eta(x,y(x)) + epsilonW(alpha), where eta(x,y) is an uncorrelated random potential and W is the width of the polymer. Using an energy argument, it is conjectured that the radius of gyration Rg(N) and the energy fluctuation deltaE(N) of the polymer of length N in the ground state increase as Rg(N) approximately N(nu) and deltaE(N) approximately N(omega), respectively, with nu = 1/(1+alpha) and omega = (1+2alpha)/(4+4alpha) for alpha > or = 1/2. An algorithm of finding the exact ground state, with the effective time complexity of O(N3), is introduced and used to confirm the conjecture numerically.


Depression and associated factors among women within their first postnatal year in Erzurum province in eastern Turkey.
The aims of the study were to identify associated factors with depression, to estimate prevalence of depression among women in the postnatal first year in Eastern Turkey, and to compare the results with those obtained from western societies. We randomly selected 728 women in their postnatal first year. The data were collected in 2003 by using a structured questionnaire and the Edinburgh Postnatal Depression Scale. The percentage of the women who had scores > or = 13 was 34.6%. Having an unemployed husband, premenstrual symptoms, lack of husband's support, any stressful life event during the pregnancy, infant with a health problem, a temperamentally difficult child, and history of psychiatric condition were found to be associated factors with depression in women in this region. The percentage of women with high scores in Eastern Turkey was higher than the reported prevalence in many western countries, and significant relations were identified between depression and social factors.


Chinese cross-cultural adaptation and validation of the Well-being Numerical Rating Scales.
Well-being is a multi-domain concept that involves measuring physical, psychological, social, and spiritual domains. However, there are currently few multi-domain and comprehensive well-being instruments available. In addition, measures that do exist customarily contain a vast number of items that may lead to boredom or fatigue in participants. The Well-being Numerical Rating Scales (WB-NRSs) offer a concise, multi-domain well-being scale. This study aimed to perform the translation, adaptation, and validation of the Chinese version of WB-NRSs (WBNRSs-CV). A total of 639 clinical participants and 542 community participants completed the WB-NRSs-CV, the Single-item Self-report Subjective Well-being Scale (SISRSWBS), the World Health Organization Five-item Well-Being Index (WHO-5), the 10-item Perceived Stress Scale (PSS-10), and the Kessler Psychological Distress Scale (K10). High internal consistency and test-retest reliability were obtained for both samples. Additionally, WB-NRSs-CV was positively associated with SISRSWBS and WHO-5 and negatively associated with PSS-10 and K10. In the item response theory analysis, the model fit was adequate with the discrimination parameters ranging from 2.73 to 3.56. The diffculty parameters ranged from -3.40 to 1.71 and were evenly spaced along the trait, attesting to the appropriateness of the response categories. The invariance tests demonstrated that there was no difference in WB-NRSs-CV across groups by gender or age. The WB-NRSs-CV was translated appropriately and cross-culturally adapted in China. It can be used as a rapid and relevant instrument to assess well-being in both clinical and non-clinical settings, with its utility for well-being measurement and management among the Chinese people.


Reduced Gray Matter Volume Is Associated With Poorer Instrumental Activities of Daily Living Performance in Heart Failure.
Heart failure patients require assistance with instrumental activities of daily living in part because of the high rates of cognitive impairment in this population. Structural brain insult (eg, reduced gray matter volume) is theorized to underlie cognitive dysfunction in heart failure, although no study has examined the association among gray matter, cognition, and instrumental activities of daily living in heart failure. The aim of this study was to investigate the associations among gray matter volume, cognitive function, and functional ability in heart failure. A total of 81 heart failure patients completed a cognitive test battery and the Lawton-Brody self-report questionnaire to assess instrumental activities of daily living. Participants underwent magnetic resonance imaging to quantify total gray matter and subcortical gray matter volume. Impairments in instrumental activities of daily living were common in this sample of HF patients. Regression analyses controlling for demographic and medical confounders showed that smaller total gray matter volume predicted decreased scores on the instrumental activities of daily living composite, with specific associations noted for medication management and independence in driving. Interaction analyses showed that reduced total gray matter volume interacted with worse attention/executive function and memory to negatively impact instrumental activities of daily living. Smaller gray matter volume is associated with greater impairment in instrumental activities of daily living in persons with heart failure, possibly via cognitive dysfunction. Prospective studies are needed to clarify the utility of clinical correlates of gray matter volume (eg, cognitive dysfunction) in identifying heart failure patients at risk for functional decline and determine whether interventions that target improved brain and cognitive function can preserve functional independence in this high-risk population.


Phosphoproteome analysis of the MAPK pathway reveals previously undetected feedback mechanisms.
The RAS-RAF-MEK-ERK (MAPK) pathway is prevalently perturbed in cancer. Recent large-scale sequencing initiatives profiled thousands of tumors providing insight into alterations at the DNA and RNA levels. These efforts confirmed that key nodes of the MAPK pathway, in particular KRAS and BRAF, are among the most frequently altered proteins in cancer. The establishment of targeted therapies, however, has proven difficult. To decipher the underlying challenges, it is essential to decrypt the phosphorylation network spanned by the MAPK core axis. Using mass spectrometry we identified 2241 phosphorylation sites on 1020 proteins, and measured their responses to inhibition of MEK or ERK. Multiple phosphorylation patterns revealed previously undetected feedback, as upstream signaling nodes, including receptor kinases, showed changes at the phosphorylation level. We provide a dataset rich in potential therapeutic targets downstream of the MAPK cascade. By integrating TCGA (The Cancer Genome Atlas) data, we highlight some downstream phosphoproteins that are frequently altered in cancer. All MS data have been deposited in the ProteomeXchange with identifier PXD003908 (http://proteomecentral.proteomexchange.org/dataset/PXD003908).


Bone Lid Technique Using a Piezoelectric Device for the Treatment of a Mandibular Bony Lesion.
Different techniques for the enucleation of jaw cyst lesion in the oral and maxillofacial regions have been proposed, including the bone lid technique. The purpose of this case report is to describe the case of a cystic lesion, approached with the bone lid technique performed using a piezoelectric device, with an 8-month clinical and radiographic follow-up. A 14-year-old male patient was treated for a suspicious lesion detected on a panoramic radiograph. The concerned area was surgically accessed, and a radiographically predetermined bony window was drawn, and the beveled bony lid was removed. The underlying lesion was enucleated and sent for pathology as a routine procedure, and the removed bony lid was repositioned in situ and secured with a collagen tape. Healing was uneventful with limited swelling and reduced pain. A complete radiographic bone healing at the previously diseased site was confirmed with an 8-month cone beam computed tomography (CBCT) scan with no buccal bone resorption nor ridge collapse. The bone lid technique with a piezoelectric device was noninvasive and atraumatic in this case. Further studies are needed and could lead to the adaptation of this approach as a possible standard of care.


[Not Available].
Certain aspects are investigated in the development of Bulgarian natural science in connection with the 25th anniversary of the victory of the Socialist revolution in Bulgaria. An attempt is made to divide in periods the methodological re-organization of Bulgarian natural science. Some of the more significant achievements and weak points in dealing with the philosophical problems of Bulgarian natural science are analyzed; also natural history issues are outlined, the philosophical elucidation of which is forthcoming, closely related to the modern development of the science and the state of ideological struggle.


Extra- and intranuclear heat perception and triggering mechanisms in plants.
The escalating impact of global warming on crop yield and quality poses a significant threat to future food supplies. Breeding heat-resistant crop varieties holds promise, but necessitates a deeper understanding of the molecular mechanisms underlying plant heat tolerance. Recent studies have shed light on the initial events of heat perception in plants. In this review, we provide a comprehensive summary of the recent progress made in unraveling the mechanisms of heat perception and response in plants. Calcium ion (Ca2+), hydrogen peroxide (H2O2), and nitric oxide (NO) have emerged as key participants in heat perception. Furthermore, we discuss the potential roles of the NAC transcription factor NTL3, thermo-tolerance 3.1 (TT3.1), and Target of temperature 3 (TOT3) as thermosensors associated with the plasma membrane. Additionally, we explore the involvement of cytoplasmic HISTONE DEACETYLASE 9 (HDA9), mRNA encoding the phytochrome-interacting factor 7 (PIF7), and chloroplasts in mediating heat perception. This review also highlights the role of intranuclear transcriptional condensates formed by phytochrome B (phyB), EARLY FLOWERING 3 (ELF3), and guanylate-binding protein (GBP)-like GTPase 3 (GBPL3) in heat perception. Finally, we raise the unresolved questions in the field of heat perception that require further investigation in the future.


Effect of oxygen and temperature on the potassium efflux of irradiated, stored red blood cells.
Gamma irradiation of blood is performed to prevent transfusion-associated graft-versus-host disease and can result in an accelerated efflux of intracellular potassium (K+). The oxygen content of the blood and the temperature at which the irradiation is carried out are two variables reported to affect this shift; they were investigated in two separate studies. Study A-Four units of AS-5 red blood cells were each split equally into four transfer bags. One set of transfer bags was stored at 4 degrees C for 42 days (Control), the second set (IRR) was irradiated and stored. The third and fourth groups were oxygenated; the third set (+O2) was placed at 4 degrees C. The fourth set (IRR+O2) was irradiated, then stored. Supernatant K+ and hemoglobin increased in the IRR + O2 group over IRR and Control, +O2 did not rise compared to Control. Study B-Six units of CPDA-1 whole blood were each equally separated into four transfer bags. The first set of bags was placed at 4 degrees C, the second set was irradiated and then stored (IRR). The third group of bags was irradiated and given an 8-hour 22 degrees C incubation prior to storage at 4 degrees C (IRR-22). The fourth set was irradiated, placed at 37 degrees C for 2 hours, then stored. Supernatant K+ was lower during the first 7 days of storage for the IRR-22 and IRR-37 groups compared to IRR, but these increased to IRR levels by day 35. Irradiation of blood products results in an accelerated K+ shift that can be exacerbated by the presence of oxygen. The injury can be partially and temporarily corrected by a post-irradiation incubation at 22 degrees C or 37 degrees C.


Glycoconjugate vaccines: an update.
Globally, the three main pathogens causing serious infections are Haemophilus influenzae type b, Streptococcus pneumoniae and Neisseria meningitidis. Over the last 5 years, new vaccines protecting against these bacteria have been developed and introduced in various countries. This review describes the recently licensed glycoconjugates being used to protect against these encapsulated bacteria. Immunogenicity and safety data that led to licensure or licensure expansion of these glycoconjugates are discussed in addition to the resultant impact on the disease burden. The maintenance of robust immunisation programmes with high uptake rates is important in maintaining low rates of disease. Epidemiological surveillance systems are essential in monitoring any changes in infectious disease trends and in identifying emerging infections such as from non-typeable H. influenzae, pneumococcal serotype replacement disease and changes in the epidemiology of meningococcal serogroups. This is important to guide future vaccine development. Accessibility of these glycoconjugate vaccines in resource poor regions, which bear the highest disease burden from these pathogens, remains challenging largely due to high vaccine pricing. Recent aids from public and private funding, tiered vaccine pricing and the transfer of vaccine technology have helped in introducing these vaccines where they are most needed.


Effectiveness and feasibility of a motivational interviewing intake (MII) intervention for increasing client engagement in outpatient addiction treatment: an effectiveness-implementation hybrid design protocol.
Client discontinuation from outpatient addiction treatment programs is common, and the initial intake is the service delivery point with the highest attrition rate. Replacing the comprehensive intake assessment with a person-centered Motivational Interviewing (MI) intervention is a potential solution to address provider and client concerns about the disengaging, time-intensive nature of the typical initial intake. It remains unclear whether the use of an alternative to the standard intake at the initial visit can fit within typical organizational reporting requirements, whether it decreases attrition, and whether implementation of person-centered intake procedures within outpatient addiction treatment programs is feasible, acceptable, and can be sustained. To describe the methods and design of an effectiveness-implementation hybrid type 1 trial of a Motivational Interviewing at Intake (MII) intervention using the Consolidated Framework for Implementation Research (CFIR). The study will determine the effectiveness of two intake conditions: (1) standard comprehensive intake assessment (intake-as-usual [IAU]), and (2) MII consisting of a person-centered discussion between provider and client about the client's desire and intent to enter treatment. Although both interventions are focused on understanding client presenting complaints and needs for treatment, the delivery differs as the IAU uses a semi-structured assessment guide, while MII applies the theory of MI to have a conversation about treatment engagement. Adults seeking outpatient addiction treatment services will be randomly assigned to the MII condition (n = 75) or the IAU condition (n = 75). Primary outcomes will be client engagement (i.e., treatment entry, attendance, and completion) obtained from the electronic medical record. Secondary outcomes (client motivation and therapeutic alliance) will be putative mechanisms of client engagement assessed immediately before and after the intake. The trial also will explore determinants of effective, sustainable implementation using assessments of organizational readiness and capacity to change, as well as interviews on MII implementation feasibility. This trial of an MII intervention will investigate the feasibility of a motivational intervention as an initial contact with substance use treatment-seeking clients as well as indicators of intervention effectiveness within the systems where it is employed. Trial registration Clinicaltrials.gov identifier: NCT05489068.


All-Printed Flexible and Stretchable Electronics.
A fully automated additive manufacturing process that produces all-printed flexible and stretchable electronics is demonstrated. The printing process combines soft silicone elastomer printing and liquid metal processing on a single high-precision 3D stage. The platform is capable of fabricating extremely complex conductive circuits, strain and pressure sensors, stretchable wires, and wearable circuits with high yield and repeatability.


Prolonged Incubation of Acute Neuronal Tissue for Electrophysiology and Calcium-imaging.
Acute neuronal tissue preparations, brain slices and retinal wholemount, can usually only be maintained for 6 - 8 h following dissection. This limits the experimental time, and increases the number of animals that are utilized per study. This limitation specifically impacts protocols such as calcium imaging that require prolonged pre-incubation with bath-applied dyes. Exponential bacterial growth within 3 - 4 h after slicing is tightly correlated with a decrease in tissue health. This study describes a method for limiting the proliferation of bacteria in acute preparations to maintain viable neuronal tissue for prolonged periods of time (>24 h) without the need for antibiotics, sterile procedures, or tissue culture media containing growth factors. By cycling the extracellular fluid through UV irradiation and keeping the tissue in a custom holding chamber at 15 - 16 °C, the tissue shows no difference in electrophysiological properties, or calcium signaling through intracellular calcium dyes at >24 h postdissection. These methods will not only extend experimental time for those using acute neuronal tissue, but will reduce the number of animals required to complete experimental goals, and will set a gold standard for acute neuronal tissue incubation.


Effect of haemodialysis on retinal circulation in patients with end stage renal disease.
To investigate the effect of haemodialysis on retinal circulation in patients with end stage renal disease (ESRD). Seventeen consecutive patients with ESRD were recruited into the study. The authors simultaneously measured changes in vessel diameter and blood velocity and calculated the retinal blood flow (RBF) in the retinal veins in patients with ESRD before and after haemodialysis using a laser Doppler velocimetry system. In addition, the relations between the changes in systemic and retinal circulatory parameters were examined. There was a group averaged increase in vessel diameter (p = 0.003) after haemodialysis. However, the blood velocity and RBF values obtained after haemodialysis were not significantly different from those before haemodialysis (p = 0.66 and p = 0.63, respectively). The changes in vessel diameter were negatively (r = -0.549, p = 0.02) correlated with the change in MABP, but the changes in blood velocity and RBF were positively correlated with the change in MABP (r = 0.683, p<0.002 and r = 0.589, p<0.01, respectively). The change in RBF was also inversely correlated with the increase in haematocrit (r = -0.693, p<0.002) and the amount of fluid removed (r = -0.597, p<0.01). The results indicate that haemodialysis and the associated changes in systemic circulatory parameters may affect the retinal circulation in patients with ESRD.


Androgen-dependent expression, gene structure, and molecular evolution of guinea pig caltrin II, a WAP-motif protein.
We determined the cDNA and gene structures of guinea pig caltrin II, a unique member of the calcium transporter inhibitors containing a whey acidic protein (WAP) motif, and we established that it is a secretory protein with a potential 21-amino acid signal peptide in its N-terminus. Northern blot analysis and in situ hybridization histochemistry indicated that the expression of caltrin II is restricted to luminal epithelial cells in the seminal vesicles. Its message levels markedly decreased either after castration (and were restored by simultaneous administration of testosterone) or after treatment of the animals with estradiol, suggesting that the expression of caltrin II is androgen-dependent. Recombinant caltrin II had an elastase-inhibitor activity. Comparison of sequence between the caltrin II and related genes and their molecular evolutionary analyses revealed that caltrin II and seminal vesicle secretory proteins (SVPs) appear to be evolved from a common ancestor gene that is made by the fusion of semenogelin and trappin genes. Caltrin II and SVPs lost the transglutaminase substrate domain and the WAP motif, respectively, within a single exon, resulting in the exertion of different functions.


Semiclassical theory for spatial density oscillations in fermionic systems.
We investigate the particle and kinetic-energy densities for a system of N fermions bound in a local (mean-field) potential V(r) . We generalize a recently developed semiclassical theory [J. Roccia and M. Brack, Phys. Rev. Lett. 100, 200408 (2008)] in which the densities are calculated in terms of the closed orbits of the corresponding classical system to D>1 dimensions. We regularize the semiclassical results (i) for the U(1) symmetry breaking occurring for spherical systems at r=0 and (ii) near the classical turning points where the Friedel oscillations are predominant and well reproduced by the shortest orbit going from r to the closest turning point and back. For systems with spherical symmetry, we show that there exist two types of oscillations which can be attributed to radial and nonradial orbits, respectively. The semiclassical theory is tested against exact quantum-mechanical calculations for a variety of model potentials. We find a very good overall numerical agreement between semiclassical and exact numerical densities even for moderate particle numbers N . Using a "local virial theorem," shown to be valid (except for a small region around the classical turning points) for arbitrary local potentials, we can prove that the Thomas-Fermi functional tau(TF)[rho] reproduces the oscillations in the quantum-mechanical densities to first order in the oscillating parts.


Plasma levels of atrial natriuretic peptide in patients with chronic liver disease.
The plasma levels of atrial natriuretic peptide were determined by radioimmunoassay in 24 patients with chronic liver disease, including three patients with alcoholic liver disease, four with chronic active hepatitis, 13 with liver cirrhosis, and four with hepatocellular carcinoma. When compared with normal subjects (180 +/- 12 pg/ml), the plasma levels of atrial natriuretic peptide in cirrhotic patients (349 +/- 64 pg/ml) were significantly elevated (p less than 0.001) but not in other disease groups. In patients with chronic liver disease the plasma levels of atrial natriuretic peptide were correlated significantly with plasma renin activity but not with plasma aldosterone, and furthermore showed a negative correlation with indocyanine green disappearance rate. These results suggest that the increased plasma levels of atrial natriuretic peptide, which appear to be associated with an increase in plasma renin activity and with hepatic dysfunction, may participate in maintaining homeostasis of sodium and fluid volume in patients with chronic liver disease.


Gene expression of group II phospholipase A2 in intestine in ulcerative colitis.
It has been suggested that phospholipase A2 (PLA2) has an essential role in the pathogenesis of inflammatory bowel diseases. This study aimed at identifying cells in intestinal and mesenteric tissue samples that might express group II phospholipase A2 (PLA2-II) at the mRNA and enzyme protein levels in patients with ulcerative colitis. PATIENTS AND TISSUE SAMPLES: Tissue samples were obtained from the intestine, mesentery, skeletal muscle, and subcutaneous fat of six patients who underwent panproctocolectomy for severe ulcerative colitis. Mucosal biopsy specimens were obtained from the colon of another group of six patients with ulcerative colitis during routine diagnostic colonoscopies. Tissues from six patients without intestinal inflammatory diseases served as controls. Tissue samples were studied by light microscopy, immunohistochemistry for PLA2-II enzyme protein, and in situ hybridisation and northern hybridisation for PLA2-II mRNA. PLA2-II mRNA and PLA2-II protein were detected in metaplastic Paneth cells in six patients and in the columnar epithelial cells of colonic mucosa in four out of six patients with active ulcerative colitis. Positive findings were less numerous in patients with mild ulcerative colitis. Only two out of six control patients had a weak positive signal for PLA2-II mRNA and one of these two patients had a weak positive immunoreaction for PLA2-II in columnar epithelial cells in the colonic mucosa. None of the control patients had metaplastic Paneth cells. Metaplastic Paneth cells and colonic epithelial cells synthesise PLA2-II in ulcerative colitis. The activity of the PLA2-II synthesis seems to be related to the degree of inflammation in the diseased bowel.


Prevention of invasive fungal infections in liver transplant recipients: the role of prophylaxis with lipid formulations of amphotericin B in high-risk patients.
Invasive fungal infections (IFI) are associated with high mortality in liver transplant recipients. Prevention remains an elusive goal, especially for IFI caused by moulds. From January 1998, patients who fulfilled four or more variables identified as risk factors for IFI received a cumulative dose of 1-1.5 g of lipid formulations of amphotericin B (L-AmpB; AmBisome or Abelcet). The development of IFI in these patients was compared with historical patients. Two hundred and eighty liver transplant recipients were analysed over a period of 8 years. In the historical group, IFI were observed in 22 of 131 patients (17%) and invasive aspergillosis in 13 of them (10%). After January 1998, IFI were observed in nine of 149 (6%) (P < 0.01) and invasive aspergillosis in six patients (4%) (P = 0.08). In patients with four or more risk factors (high risk) for IFI, the administration of L-AmpB reduced the risk from 36% to 14% (P = 0.07), and the risk of aspergillosis from 23% to 5% (P = 0.08). Notably, prophylaxis reduced the risk of aspergillosis from 32% to 0% in dialysed patients (P = 0.03). Variables independently associated with IFI in high-risk patients were dialysis [odds ratio (OR) 3.9; 95% confidence interval (CI) 1-16.7] and surgical reintervention (OR 5.4; 95% CI 1.2-24.6), while L-AmpB was a protective factor in this multivariate analysis (OR 0.1; 95% CI 0.02-0.8). The analysis in these high-risk patients was not able to demonstrate an association between the administration of L-AmpB and higher survival. Selected risk factors are good predictors of IFI in liver transplant recipients. The administration of L-AmpB in high-risk patients is independently associated with a reduction of IFI.


[Effect of returning corn straw into soil on soil fertility].
Three-year field micro-plot experiment was conducted to study the effect of applying corn root stubble, corn straw, and the ordure of cattle fed with corn straw to improve soil fertility in northern Liaoning province. The results showed that chemical fertilizers could significantly increase the corn production, while organic fertilizers mainly improved the soil physical and chemical properties so as to increase soil fertility. In comparison with no fertilizer treatment, combination of chemical fertilizers and organic materials could increase soil organic matter by 3.06%-27.78%. The increments of soil organic matter by using different organic materials were in order of 100% corn straw > 50% corn straw > mixture of cattle ordure and soil > cattle ordure > 33% corn straw > corn root stubble. For maintaining and increasing soil organic matter, corn straw was better than mixture of cattle ordure and soil, and secondly better than cattle ordure if they contained the same carbon content. In addition, comparing with applying chemical fertilizers only, combination of chemical fertilizers and organic materials increased soil labile oxidization organic matter by 10.91%-20.67%, increased extractable humic acid by 1.43%-14.28%, raised slack/stable ratio of bonded humus by 0.07-0.19, and raised HA/FA ratio by 0.07-0.24. Meanwhile, this combination improved the soil nutrient status of N, P, and K, and the status of soil moisture and porosity, which demonstrated the increase of activity of soil organic matter and the improvement of soil fertility. So directly adding straw into soil without removing after harvest in autumn should be actively recommended, and the amount of corn straw added into soil should be 30 to 50 percent of the total production of corn straw.


Congenital duodenocolic fistula in a dog.
A one-year-old female cocker spaniel presented with a 6-month history of persistent diarrhoea. Abdominal ultrasonographic examination revealed mild diffuse thickening of the intestinal wall coupled with mesenteric lymphadenopathy. A connection between the duodenum and the colon was observed during an endoscopic procedure and confirmed by computed tomography. Surgical resection of the communication allowed remission of the diarrhoea. Histology showed a normal duodenal epithelium and muscular layer. A duodenocolic fistula is an abnormal connection within the digestive tract, which in humans is usually considered a complication of a local pathological condition. Due to the absence of a predisposing cause and, in view of the dog's age and histological results, a congenital origin was suspected.


Quark structure of the nucleon and angular asymmetry of proton-neutron hard elastic scattering.
We investigate an asymmetry in the angular distribution of hard elastic proton-neutron scattering with respect to the 90 degrees center of mass scattering angle and demonstrate that it's magnitude is related to the helicity-isospin symmetry of the quark wave function of the nucleon. Our estimate of the asymmetry within the quark-interchange model of hard scattering demonstrates that the quark wave function of a nucleon based on the exact SU(6) symmetry predicts an angular asymmetry opposite to that of experimental observations. We found that the quark wave function based on the diquark picture of the nucleon produces a correct asymmetry. Comparison with the data allowed us to show that the vector diquarks contribute around 10% in the nucleon wave function and they are in negative phase relative to the scalar diquarks. These observations are essential in constraining QCD models of a nucleon.


Analysis of plant RNA polymerase I transcript in chromatin and nuclei.
Chromatin isolated (pH 8.0) from soybean hypocotyl contains only RNA polymerase I activity as judged by its elution at low ionic strength (0.11 M ammonium sulfate) from DEAE-cellulose and DEAE-Sephadex, its total resistance to alpha-amanitin, and lack of preference for poly(dA-dT). The in vitro RNA product from this chromatin contains rRNA as a major component (36%) with little or no symmetry of transcription. The transcript from nuclei, where both RNA polymerases I and II are active, shows a dramatic increase in % rRNA (from 35 to 65%) when alpha-amanitin is present during synthesis. These observations suggest that plant RNA polymerase I is similar to animal RNA polymerase I in both its insensitivity to alpha-amanitin and preferential transcription of rRNA genes.


Work-based learning in health care environments.
In reviewing contemporary literature and theories about work-based learning, this paper explores recent trends promoting life-long learning. In the process the paper reviews and discusses some implications of implementing recent policies and fostering le arning in health care practice settings. Recent Government policies designed to provide quality health care services and to improve staffing levels in the nursing workforce, have emphasized the importance of life-long learning whilst learning-on-the-job and the need to recognize and credit experiential learning. Such calls include negotiation of personal development plans tailored to individual educational need and context-sensitive learning activities. To be implemented effectively, this policy cann ot be seen as a cheap option but requires considerable financial resourcing for preparation of staff and the conduct of such activities. Successful work-based learning requires investment in staff at all levels as well as changes to staffing structures in organizations and trusts; changes designed to free people up to work and learn collaboratively. Creating an organizational environment where learning is prized depends upon a climate of trust; a climate where investigation and speculation are fostered and where time is protected for engaging in discussions about practice. Such a change may be radical for many health care organizations and may require a review of current policies and practices ensuring that they include education at all levels. The nature of such education also requires reconceptualizing. In the past, learning in practice settings was seen as formal lecturing or demonstration, and relied upon behaviourist principles of learning. Contemporary thinking suggests effective learning in work-settings is multi-faceted and draws on previously acquired formal knowledge, contextualizes it and moulds it according to situations at hand. Thinking about work-based learning in this way raises questions about how such learning can be supported and facilitated.


The role of OXCT1 in the pathogenesis of cancer as a rate-limiting enzyme of ketone body metabolism.
Cancer cells are well documented to reprogram their metabolism in order to support the maintenance and reproduction. 3-oxoacid CoA-transferase 1 (OXCT1) is a key enzyme in ketone body metabolism that catalyzes the first and rate-determining step of ketolysis. The product of OXCT1 converts to acetyl-CoA and finally fed into the tricarboxylic acid cycle for oxidation and ATP production. However, little is known of its regulation right now. Recently, some studies suggested that OXCT1 participates in tumorigenesis and signaling in cancer cells. Furthermore, our recent work showed that a marked elevation of OXCT1 expression in different categories of cancer cells. Here we review the metabolic functions of OXCT1 and its surprising roles in supporting the biological hallmarks of malignancy. We also review recent efforts in exploring the mechanism responsible for the tumor promoting effect of OXCT1 and suggest a novel therapeutic target for cancer therapy.


[Efficacy of semiconductor laser therapy combined with botulinum toxin A type injection in treatment of temporomandibular disorders].
To observe the efficacy of semiconductor laser therapy in combination with botulinum toxin A type injection in treating temporomandibular disorders and the influence on serum levels of interleukin(IL)-1 and tumor necrosis factor(TNF)-α. Ninety patients with temporomandibular disorders were selected and randomly divided into control group and treatment group with 45 cases in each group. Patients in the control group received semiconductor laser therapy,once per day and 1 course for 1 week. Patients in the treatment group was given semiconductor laser therapy in combination with botulinum toxin A type. 50 U botulinum toxin A type were injected into the masseteric and temporal muscles with 5 injections at different sites in each side. The treatment course of patients was 2 weeks. Fricton scale indexes, pain index, and efficacy were compared between the two groups. Serum levels of IL-1 and TNF-α were detected in both groups. SPSS19.0 software package was used for data analysis. After treatment, PI, DI and CMI in the treatment group were significantly lower than the control group (P<0.01). After 1 and 2 weeks of treatment, VAS score of the treatment group was significantly lower than the control group (P<0.01). The total efficacy rate of the treatment group was 93.33%,which was significantly higher than control group (66.67%, P<0.05). Serum levels of IL-1 and TNF-α of the treatment group were significantly lower than the control group (P<0.01). The efficacy of semiconductor laser therapy in combination with botulinum toxin A type injection in treating temporomandibular disorders is significant,and may be related to decreased serum levels of IL-1 and TNF-α.


Characterization of ring-like F-actin structure as a mechanical partner for spindle positioning in mitosis.
Proper spindle positioning and orientation are essential for accurate mitosis which requires dynamic interactions between microtubule and actin filament (F-actin). Although mounting evidence demonstrates the role of F-actin in cortical cytoskeleton dynamics, it remains elusive as to the structure and function of F-actin-based networks in spindle geometry. Here we showed a ring-like F-actin structure surrounding the mitotic spindle which forms since metaphase and maintains in MG132-arrested metaphase HeLa cells. This cytoplasmic F-actin structure is relatively isotropic and less dynamic. Our computational modeling of spindle position process suggests a possible mechanism by which the ring-like F-actin structure can regulate astral microtubule dynamics and thus mitotic spindle orientation. We further demonstrated that inhibiting Plk1, Mps1 or Myosin, and disruption of microtubules or F-actin polymerization perturbs the formation of the ring-like F-actin structure and alters spindle position and symmetric division. These findings reveal a previously unrecognized but important link between mitotic spindle and ring-like F-actin network in accurate mitosis and enables the development of a method to theoretically illustrate the relationship between mitotic spindle and cytoplasmic F-actin.


The interaction between alpha-synuclein and mitochondrial dysfunction in Parkinson's disease.
Parkinson's disease (PD) is an aging-associated neurodegenerative disorder with the hallmark of abnormal aggregates of alpha-synuclein (α-syn) in Lewy bodies (LBs) and Lewy neurites (LNs). Currently, pathogenic α-syn and mitochondrial dysfunction have been considered as prominent roles that give impetus to the PD onset. This review describes the α-syn pathology and mitochondrial alterations in PD, and focuses on how α-syn interacts with multiple aspects of mitochondrial homeostasis in the pathogenesis of PD.


SelEXSIDE: fast and easy measurement of multiple-bond 1H,13C coupling constants for stereochemical analysis.
Long-range (1)H,(13)C coupling constants ((n)J(CH)) are underutilized parameters for stereochemical structure determination, primarily because they are not easy to measure. This report describes a rapid and easily interpreted method for the measurement of one or more (n)J(CH) values based on a (13)C band-selective EXSIDE (SelEXSIDE), which reduces experiment times from many hours down to a few minutes while allowing a simple and straightforward readout of (n)J(CH) values from the resulting in-phase doublet signal.


A comparison of the self-association behavior of the plant cyclotides kalata B1 and kalata B2 via analytical ultracentrifugation.
The recently discovered cyclotides kalata B1 and kalata B2 are miniproteins containing a head-to-tail cyclized backbone and a cystine knot motif, in which disulfide bonds and the connecting backbone segments form a ring that is penetrated by the third disulfide bond. This arrangement renders the cyclotides extremely stable against thermal and enzymatic decay, making them a possible template onto which functionalities can be grafted. We have compared the hydrodynamic properties of two prototypic cyclotides, kalata B1 and kalata B2, using analytical ultracentrifugation techniques. Direct evidence for oligomerization of kalata B2 was shown by sedimentation velocity experiments in which a method for determining size distribution of polydisperse molecules in solution was employed. The shape of the oligomers appears to be spherical. Both sedimentation velocity and equilibrium experiments indicate that in phosphate buffer kalata B1 exists mainly as a monomer, even at millimolar concentrations. In contrast, at 1.6 mm, kalata B2 exists as an equilibrium mixture of monomer (30%), tetramer (42%), octamer (25%), and possibly a small proportion of higher oligomers. The results from the sedimentation equilibrium experiments show that this self-association is concentration dependent and reversible. We link our findings to the three-dimensional structures of both cyclotides, and propose two putative interaction interfaces on opposite sides of the kalata B2 molecule, one involving a hydrophobic interaction with the Phe6, and the second involving a charge-charge interaction with the Asp25 residue. An understanding of the factors affecting solution aggregation is of vital importance for future pharmaceutical application of these molecules.


Unilateral stent implantation for renal function in bilateral atherosclerotic renovascular hypertension--a case report.
Renal artery stenting improves or preserves renal function in patients with bilateral renovascular disease and chronic renal insufficiency. An 80-year-old male was admitted to the hospital for elevated blood pressure accompanied by congestive heart failure. He had renal insufficiency and severe hypertension secondary to bilateral atherosclerotic renal artery stenosis. Unilateral renal artery stenting in the left kidney resulted in the recovery of renal function, whereas renal artery stenting in the right kidney was technically difficult due to a tortuous aorta. After the left unilateral stent implantation, the serum creatinine concentration decreased from 2.0 to 1.3 mg/dL, and control of his blood pressure required fewer antihypertensive drugs, namely a calcium antagonist, an angiotensin-converting enzyme inhibitor, and diuretics. Fifteen months after stenting, renal scintigraphy demonstrated improved function of the right kidney, despite severe renal artery stenosis, as well as improved function of the left kidney. Renal angioplasty or stenting should be attempted in bilateral atherosclerotic renovascular hypertension with renal insufficiency, even though it may only be successful unilaterally.


Is the serotonin transporter involved in the pathogenesis of pulmonary hypertension?
Investigations on the effects of serotonin (5-HT) and the serotonin transporter (5-HTT) on the pulmonary circulation are of special interest because of the reported increased risk of primary pulmonary hypertension (PPH) in patients who used some appetite suppressants that interfere with 5-HT. In addition to its vasoactive effects, 5-HT exerts mitogenic and comitogenic effects on pulmonary artery smooth muscle cells (PASMCs). These mitogenic and comitogenic effects require 5-HT internalization by the high-affinity 5-HTT, which can be competitively inhibited by specific drugs such as fluoxetine and paroxetine. In a recent study, we showed that hypoxia increases the rate of 5-HTT gene transcription in PASMCs and potentiates the growth-promoting effect of 5-HT on these cells. An increase in the levels of 5-HTT messenger ribonucleic acid was observed in smooth-muscle cells from remodeled pulmonary arteries in rats subjected to long-term hypoxia. Two series of especially relevant data further support the idea that 5-HT plays a key role in PASMC proliferation in vivo: (1) treatments that increase plasma 5-HT levels aggravate pulmonary hypertension in rats subjected to long-term hypoxia, and this effect can be prevented by combined simultaneous treatment with 5-HTT inhibitors; and (2) knockout mice with disruption of the 5-HTT gene exhibit lesser degree of hypoxic pulmonary hypertension and pulmonary vascular remodeling than control mice despite increased hypoxic pulmonary vasoconstriction. These observations indicate that 5-HTT expression, activity, or both in PASMCs contribute to pulmonary vascular remodeling and that the inducing effects of some appetite suppressants on pulmonary hypertension may be related to possible effects of these drugs on 5-HTT expression, activity, or both.


The chitin catabolic cascade in the marine bacterium Vibrio cholerae: characterization of a unique chitin oligosaccharide deacetylase.
Chitin, one of the most abundant organic substances in nature, is consumed by marine bacteria, such as Vibrio cholerae, via a multitude of tightly regulated genes (Li and Roseman 2004, Proc Natl Acad Sci USA. 101:627-631). One such gene, cod, is reported here. It encodes a chitin oligosaccharide deacetylase (COD), when cells are induced by chitobiose, (GlcNH(2))(2), or crude crab shells. COD was molecularly cloned (COD-6His), overproduced, and purified to apparent homogeneity. COD is secreted at all stages of growth by induced V. cholerae. The gene sequence predicts a 26 N-terminal amino acid signal peptide not found in the isolated protein. COD is very active with chitin oligosaccharides, is virtually inactive with GlcNAc, and slightly active with colloidal ([(3)H]-N-acetyl)-chitin. The oligosaccharides are converted almost quantitatively to products lacking one acetyl group. The latter were characterized by mass spectrometry (ESI-MS), and treatment with nitrous acid. COD catalyzes the following reactions (n = 2-6): (GlcNAc)(n)--> GlcNAc-GlcNH(2)-(GlcNAc)(n-2) + Ac(-). That is, COD hydrolyzes the N-acetyl groups attached to the penultimate GlcNAc residue. The gene bank sequence data show that cod is highly conserved in Vibrios and Photobacteria. One such gene encodes a deacetylase isolated from V. alginolytics (Ohishi et al. 1997, Biosci Biotech Biochem. 61:1113-1117; Ohishi et al. 2000, J Biosci Bioeng. 90:561-563), that is specific for (GlcNAc)(2), but inactive with higher oligosaccharides. The COD enzymatic products, GlcNAc-GlcNH(2)-(GlcNAc)(n), closely resemble those obtained by hydrolysis of the chitooligosaccharides with Nod B: GlcNH(2)-(GlcNAc)(3-4). The latter are key intermediates in the biosynthesis of Nod factors, critically important in communications between the symbiotic nitrogen fixing bacteria and plants. Conceivably, the COD products play equally important roles in cellular communications that remain to be defined.


Time-resolved near infrared light propagation using frequency domain superposition.
Time-resolved temporal point spread function (TPSF) measurement of near infrared spectroscopic (NIRS) data allows the estimation of absorption and reduced scattering properties of biological tissues. Such analysis requires an iterative calculation of the theoretical TPSF curve using mathematical and computational models of the domain being imaged which are computationally complex and expensive. In this work, an efficient methodology for representing the TPSF data using a superposition of cosines calculated in frequency domain is presented. The proposed method is outlined and tested on finite element realistic models of the human neck and head. Using an adult head model containing ~140k nodes, the TPSF calculation at each node for one source is accelerated from 3.11 s to 1.29 s within an error limit of ± 5% related to the time domain calculation method.


[Growth retardation in children with chronic renal disease].
Despite recent advances in the management of children with chronic renal disease (CRD), growth retardation remains its most visible comorbid condition. Growth retardation has adverse impact on morbidity and mortality rates, quality of life and education, and in adult patients on job family life, and independent leaving accomodation. Pathophysiology of impaired growth in CRD is complex and still not fully understood. The following complications are: anorexia, malnutrition, inflammation, decreased residual renal function, dialysis frequency and adequacy, renal anemia, metabolic acidosis, fluid/electrolyte imbalance, renal osteodistrophy, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) resistance. Malnutrition is most frequent and most important factor contributing to the degree of growth retardation in infancy. The degree of renal dysfunction is the major determinant of variability in growth from third year of age until puberty onset, while in puberty hypergonadotropic hypogonadism has negative effect. The main factors that influence growth after renal transplantation are the age of the recipient and glucocorticoid drugs dosage with negative effect and allograft function with positive effect. In order to improve growth in children with CRD it is necessary to include: diet with optimal caloric intake, correction of fluid/ electrolyte imbalance, correction of acidosis, renal osteodistrophy and anemia. If growth velocity is insufficient to normalize growth, it is necessary to start recombinant human GH (rhGH) therapy at 0.05 mg/kg per day (0.35 mg/kg per week or 28 IU/m2 per week) administered by subcutaneous injection.


Isolation of a dihydrobenzofuran lignan from South American dragon's blood (Croton spp.) as an inhibitor of cell proliferation.
Dragon's blood is a red viscous latex extracted from the cortex of various Croton spp. (Euphorbiaceae), most commonly Croton lechleri, Croton draconoides (or Croton palanostigma), and Croton erythrochilus. It is used in South American popular medicine for several purposes, including wound healing. Bioassay-guided fractionation of dragon's blood, using an in vitro test system for the stimulation of human umbilical vein endothelial cells, has resulted in the isolation of a dihydrobenzofuran lignan, 3',4-O-dimethylcedrusin or 4-O-methyldihydrodehydrodiconiferyl alcohol [2-(3',4'-dimethoxyphenyl)-3-hydroxymethyl-2,3-dihydro-7-methoxybenzo furan-5- propan-1-ol] [1] as the biologically active principle. A related compound, 4-O-methylcedrusin [2-(3',4'-dimethoxyphenyl)-3-hydroxymethyl-2,3-dihydro-7-hydroxybenzo furan-5- propan-1-ol] [2], and the alkaloid taspine [3], also isolated from dragon's blood, were not active in the same assay. A cell proliferation assay, measuring the incorporation of tritiated thymidine in endothelial cells, showed that compound 1 did not stimulate cell proliferation, but rather inhibited thymidine incorporation, while protecting cells against degradation in a starvation medium.


Molybdenum and Tungsten Imido Alkylidene N-Heterocyclic Carbene Catalysts Bearing Cationic Ligands for Use in Biphasic Olefin Metathesis.
Ionic Mo- and W-imido alkylidene N-heterocyclic carbene (NHC) olefin metathesis catalysts, [Mo{N-2,6-(Me2 )C6 H3 }(CHCMe2 Ph)(IMesH2 )(OTf)(PPS)]OTf (3), [Mo(N-2,6-(Me2 )C6 H3 )(CHCMe2 Ph)(IMesH2 )(OC6 F5 )(PPS)][B(ArF )4 ] (5), [Mo(NtBu)(CHCMe2 Ph)(4,5-dichloro-1,3-dimethylimidazol-2-ylidene)(OTf)(2,6-Ph-4-{2,4,6-Ph-pyridinium}phenolate)][OTf] (9), [Mo(NtBu)(CHCMe2 Ph)(4,5-dichloro-1,3-dimethylimidazol-2-ylidene)(2,6-Ph-4-{2,4,6-Ph-pyridinium}phenolate)][B(ArF )4 ]2 (10, PPS=pyridiniumpropanesulfonate, IMesH2 =1,3-dimesitylimidazolin-2-ylidene, OTf=CF3 SO3 , B(ArF )4 =tetrakis(3,5-bis(trifluoromethyl)phenyl)borate) were prepared from betaine-type ligands. Also, the first bis-NHC and a nitron-based bis(amido) bistriflate imido alkylidene complex, [Mo(NtBu)(CHCMe2 Ph)(4,5-dichloro-1,3-dimethylimidazol-2-ylidene)2 (THF)(2,6-Ph-4-{2,4,6-Ph-pyridinium}phenolate)][OTf]2 (11) and [Mo(N-2,6-Me2 -C6 H3 )(CHCMe2 Ph)(N-{1,4-diphenyl-1,3,4-triazol-2-ylium}-N-phenyl-amido)2 ][OTf]2 (14) along with ionic [W(N-2,6-iPr2 -C6 H3 )(CHCMe2 Ph)(N-2,5-Me2 C4 H2 )(IiPr)(2,6-tBu-4-PPh3 -phenolate)] (17, IiPr=1,3-diisopropylimidazol-2-ylidene) are reported. With these new catalysts, the first biphasic reaction setup with Group 6 metal alkylidene NHC complexes was successfully established using a pyrrole/heptane mixture as a liquid phase. Productivities under biphasic conditions were comparable to those of reactions in 1,2-dichloroethane or toluene. Metal concentrations of <2 ppm migrated into the nonpolar heptane phase as measured by inductively coupled plasma-optical emission spectroscopy.


Egg consumption and risk of cardiovascular events among Iranians: results from Isfahan Cohort Study (ICS).
The association between egg consumption and cardiovascular events remains controversial. This study aims to evaluate this association in cardiovascular events including myocardial infarction (MI), ischemic coronary heart disease (ICHD), stroke, cardiovascular disease (CVD), and CVD mortality in an Iranian population. This prospective cohort study included 6504 adults (age ≥ 35 years) with no history of CVD event at baseline. The frequency of egg consumption was assessed using a validated food frequency questionnaire. Participants were followed for 12 years and incidence of new CVD cases were determined through active examinations and linkages to multiple registries. Cox frailty models were conducted to calculate adjusted hazard ratios (HR)s for cardiovascular events associated with egg consumption. Over a median follow-up of 12 years, fully adjusted model [adjusted for age, sex, education, residency, smoking, daily physical activity, family history of CVD, metabolic syndrome, aspirin, body mass index and Global Dietary Index] revealed a null association between egg and cardiovascular events. Compared with non-consumers (<1 time/week), higher egg consumption (≥3 time/week) was not associated with incident MI (HR = 1.44, 95% CI: 0.86, 2.41; P = 0.48), ICHD (HR = 1.26, 95% CI: 0.80, 1.99; P = 0.41), stroke (HR = 0.79, 95% CI: 0.46, 1.38; P = 0.71) and CVD (HR = 1.05, 95% CI: 0.79, 1.40; P = 0.93). These findings suggest that higher egg consumption is not associated with increased risk of MI, ICHD, stroke, and CVD among Iranians. Larger studies with longer duration of follow-up are warranted to explore these associations in populations with higher egg consumption.


Physical Inactivity, Sedentary Behavior and Chronic Diseases.
New research into physical activity suggests that it is no longer sufficient just to meet minimum levels recommended by health guidelines in order to reduce cardiovascular risk. Both physical inactivity and sedentary behavior have their own health hazards and need to be addressed separately, in order to explore their different deleterious mechanisms. The aim of this review was to define and to characterize both concepts, and their relationship with major non-communicable chronic diseases. A PubMed database search was undertaken, using the following key words: physical activity, physical inactivity, sedentarism, sedentary behavior, and non-communicable chronic disease. This literature review provides an updated view on physical inactivity and sedentary behavior, and reevaluates their prevalence and association with major non-communicable chronic disease.


Transcriptional signature of flavopiridol-induced tumor cell death.
Flavopiridol has been shown to inhibit the proliferation of a variety of human tumor cells and is currently undergoing clinical evaluation in cancer treatment. Although the antiproliferative effect of flavopiridol has been attributed to the inhibition of cyclin-dependent kinases 2 and 4, recent reports indicate that the mechanism responsible for the cell death induced by this agent is more complex. To provide insight into the molecular processes mediating flavopiridol-induced cytotoxicity and to investigate the availability of markers indicative of its activity, we have applied cDNA microarray technology. Gene expression profiles were determined for four human tumor cell lines (prostate carcinomas PC3 and DU145 and gliomas SF359 and U251) following exposure to selected concentrations of flavopiridol. Treatment of these cell lines with a concentration of flavopiridol sufficient to reduce survival to 10% resulted in the identification of a set of 209 genes, the expression of which were altered in each of the cell lines. This common set of 209 gene expression changes suggested that flavopiridol-induced cell death can be defined in terms of a specific transcriptome. The flavopiridol death transcriptome consisted primarily of down-regulated genes; however, there were also a significant number of genes with increased expression. Whereas causal relationships were not established, these data suggest molecular events/processes that may be associated with flavopiridol-induced tumor cell death. Moreover, the identification of a set of gene expression changes in four human tumor cell lines suggests that such a transcriptome may be applicable to investigations of flavopiridol pharmacodynamics.


Molecular biomarkers in cardio-oncology: Where we stand and where we are heading.
Until recently, cardiotoxicity in the setting of a malignant disease was attributed solely to the detrimental effects of chemo- and/or radio-therapy to the heart. On this account, the focus was on the evaluation of well-established cardiac biomarkers for the early detection of myocardial damage. Currently, this view has been revised. Cardiotoxicity is not restricted to a single organ but instead affects the endothelium as a whole. Indeed, it has come into light that not only cancer therapy but also malignant cells per se can impair the cardiovascular system, through a paracrine and endocrine mode of action. Even more intriguingly, a clear interplay between molecular pathways involved in cancer and cardiovascular disease has become prevalent, suggesting a common nominator that governs the pathophysiology of these two entities. Taken together, our strategy in the quest of novel biomarkers in the emerging field of cardio-oncology should be critically reshaped.


Interaction of Drosophila inhibitors of apoptosis with thick veins, a type I serine/threonine kinase receptor for decapentaplegic.
Decapentaplegic (Dpp) is a Drosophila member of bone morphogenetic proteins, which belong to the transforming growth factor-beta superfamily. Members of this family regulate a variety of biological processes such as cell proliferation, morphogenesis, immune response, and apoptosis. Dpp plays a critical role in many aspects of Drosophila development. Members of the transforming growth factor-beta superfamily bind to two different types of serine/threonine kinase receptors, termed type I and type II. Type I receptors act as downstream components of type II receptors in the receptor complexes. Therefore, intracellular proteins that interact with the type I receptors are likely to play important roles in signaling. Several proteins have been identified through protein-protein interaction screenings. We identified Drosophila inhibitor of apoptosis (DIAP) 1 as an interacting protein of a Dpp type I receptor, Thick veins (Tkv). DIAP1 associates with Tkv in vivo. The binding region in DIAP1 is mapped to its C-terminal RING finger region. DIAP2, another Drosophila member of the inhibitor of apoptosis protein family, also interacts with Tkv in vivo. These data suggest that DIAP1 and DIAP2 may be involved, possibly as negative regulators, in the Dpp signaling pathway, which leads to cell apoptosis.


Diversion of ST-elevation myocardial infarction patients for primary angioplasty based on wireless prehospital 12-lead electrocardiographic transmission directly to the cardiologist's handheld computer: a progress report.
Time to reperfusion is critical for outcome in patients with ST-elevation myocardial infarction (STEMI). In our region, patients are routinely treated by primary percutaneous coronary intervention (pPCI), but rerouting patients from the primary receiving hospital to a catheterization center can cause unacceptable delays that may exceed 1 hour in the emergency department. Wireless transmission of prehospital electrocardiograms (ECGs) to receiving stations in hospitals has been shown to reduce time from symptom onset to reperfusion. However, transmission directly to a cardiologist's handheld digital device has not been investigated. To report preliminary data from a larger ongoing trial evaluating prehospital 12-lead ECG transmission to a cardiologist's handheld device in patients with symptoms suggesting an acute coronary syndrome. Patients suffering acute, nontraumatic chest pain have their prehospital ECG transmitted by wireless technology directly to a cardiologist's handheld device at an invasive hospital, allowing diversion of STEMI cases to rapid pPCI. Transmission failures are documented. Times for symptom onset, 911 alert, ECG recording, hospital arrival, and pPCI are obtained. All time intervals are summarized as median values and are compared with historic controls from the Danish multicenter study, DANAMI-2. During the first 15 months of the trial, prehospital ECGs were transmitted for 408 chest pain patients with an overall success rate of 93%. Cardiologist receiving the ECGs recommended that 113 patients (28%) be diverted for pPCI. Mean time from symptom onset to 911 alert was 2 hours 16 minutes (range, 1 minute to 23 hours 15 minutes), and the ambulance response interval was 5 minutes (range, 1-25 minutes). The ambulance on-scene time had increased by 7 minutes compared with historic controls (P<.05). Time from ECG recording to hospital arrival was 25 minutes. The total prehospital time was 2 hours 57 minutes. The hospital treatment time was substantially reduced among diverted patients. Hospital arrival to procedure start was 40 minutes, compared with 94 minutes in the DANAMI-2 historic control group (P<.01). These preliminary data suggest that transmission of prehospital 12-lead ECGs directly to the attending cardiologist using handheld devices is a technologically sound concept without major safety concerns and markedly reducing time to reperfusion in patients with STEMI.


Recent Progress on Multifunctional Thermally Conductive Epoxy Composite.
In last years, the requirements for materials and devices have increased exponentially. Greater competitiveness; cost and weight reduction for structural materials; greater power density for electronic devices; higher design versatility; materials customizing and tailoring; lower energy consumption during the manufacturing, transport, and use; among others, are some of the most common market demands. A higher operational efficiency together with long service life claimed. Particularly, high thermally conductive in epoxy resins is an important requirement for numerous applications, including energy and electrical and electronic industry. Over time, these materials have evolved from traditional single-function to multifunctional materials to satisfy the increasing demands of applications. Considering the complex application contexts, this review aims to provide insight into the present state of the art and future challenges of thermally conductive epoxy composites with various functionalities. Firstly, the basic theory of thermally conductive epoxy composites is summarized. Secondly, the review provides a comprehensive description of five types of multifunctional thermally conductive epoxy composites, including their fabrication methods and specific behavior. Furthermore, the key technical problems are proposed, and the major challenges to developing multifunctional thermally conductive epoxy composites are presented. Ultimately, the purpose of this review is to provide guidance and inspiration for the development of multifunctional thermally conductive epoxy composites to meet the increasing demands of the next generation of materials.


[A Case of Mitral Valvular Re-repair in a Patient with Hemolytic Anemia after Mitral Valvular Repair].
A 54-year-old woman was admitted for mitral valvular repair. After folding plasty to A3, a 30 mm Cosgrove-Edwards ring was placed. There was no mitral regurgitation jet observed by transesophageal echocardiography (TEE) during the operation. However, high blood pressure was monitored and treated in the intensive care unit, hemolytic anemia developed, and the serum lactate dehydrogenase level was elevated. Two weeks after the operation, serum lactate dehydrogenase was again elevated. TEE showed mild mitral regurgitation and the regurgitation jet colliding with the annuloplasty ring. Multiple transfusions of red blood cells were required. Repeat surgery was therefore undertaken. Lam and associates previously studying patients on hemolysis after mitral valvular repair noted high grade mitral regurgitation jets fragmented or accelerated. In the present case, mitral regurgitation was mild, but the high velocity and manner of regurgitation (collision with the annuloplasty ring) could cause hemolytic anemia. In the present case, high blood pressure might have caused chordae rupture. Furthermore, a flexible ring, such as the Cosgrove-Edwards ring, is likely to cause hemolytic anemia. As contributing factors to hemolysis after mitral valvular repair, perioperative blood pressure management and type of ring are significant.


Identification of eating disorder symptoms in Danish adolescents with the SCOFF questionnaire.
Eating disorders often develop in adolescence and, therefore, instruments are needed that are useful to detect risk behaviour in young people. The SCOFF is a 5-item screening instrument, named SCOFF as an acronym of keywords from the questions. It has been used widely in adult samples, but studies that evaluate the scale in adolescents are missing. The aim of this study was to test the psychometric properties of the SCOFF in adolescents aged 11-20 years and for the first time validate the questionnaire in Danish. A total of 184 adolescents completed the Danish version of the SCOFF and sub-scales from the Eating Disorder Inventory (EDI-3). The sample consisted of 87 patients (mean age = 16) from a specialized eating disorder department in the Region of Southern Denmark and 97 healthy adolescents (mean age = 17) from Danish primary and high schools. It was found that the reliability of the SCOFF was acceptable, and that cut-off 2 is useful to detect those with potential eating disorder pathology. Item 3 (weight loss) correlated poorly with EDI-3 sub-scales and might be reformulated by addressing the intentionality behind weight loss (due to unhappiness with body) rather than a specific amount of weight loss (1 stone), because this could have somatic reasons. The SCOFF is a very easily applicable questionnaire, which may fulfil the necessary psychometric properties for detection of ED symptoms in Danish adolescents. Before general screening can be recommended, conditions regarding benefits and potential adverse effects still remain to be addressed.


Nursing considerations for clofarabine in the treatment of acute lymphoblastic leukemia in children.
Each year, almost 3500 children are diagnosed with leukemia, representing approximately 30% of pediatric cancer cases. Acute lymphoblastic leukemia is the most common form of pediatric leukemia, accounting for approximately 80% of cases. A significant number of children fail to respond to existing chemotherapies or are unable to maintain remission. Their prognosis is poor, with little hope for long-term survival.


Determination of procainamide and N-acetylprocainamide in biological fluids by high-pressure liquid chromatography.
A modification of a high-pressure liquid chromatographic method for the simultaneous determination of procainamide and N-acetylprocainamide in plasma is described. The deficieicies in the specificity of the existing method were overcome by replacing the cation-exchange column and the mobile phase. The recovery and reproducibility of both procainamide and N-acetylprocainamide from human, dog, and rat plasma and urine spiked with either compound were excellent in the concentration range of 0.05--10 microgram/ml for plasma and 0.5--20 microgram/ml for urine. The comparison of this method with a specific extraction method for sets of plasma samples from human subjects and rats receiving N-acetylprocainamide and procainamide, respectively, showed no statistically significant difference.


Coil-In-Plug Technique Using the Amplatzer Vascular Plug II to Occlude a Portosystemic Shunt.
The family of Amplatzer Vascular Plugs (AVPs) is characterized by their precise deployment and high resistance to migration. However, a risk of recanalization of the embolized vessels has been reported. To augment the effectiveness of embolization, the coil-in-plug (CIP) technique was developed, exclusively using AVP I or IV. However, these plugs cannot be used for large vessels like portovenous shunt because of the size limitation. AVP II has a larger-sized model up to 22 mm. This article reports two cases of embolizing high-flow and large-caliber portosystemic shunts where the CIP technique with multilayer AVP II was effectively employed. The CIP technique using AVP II was utilized for one case with a portocaval shunt and another with a splenorenal shunt. CIP was established with wire penetration through the multilayer meshes, followed by a microcatheter insertion. After the microcatheter was positioned in the central lobe, the internal space was embolized tightly using pushable or detachable coils. A use of guidewire with a high tip load enabled an establishment of CIP and complete occlusion of the target vessels immediately without migration of the embolic devices in both cases. The symptom of encephalopathy improved after the procedure in both the case of the portocaval and the splenorenal shunt. The CIP technique with the AVP II was safe and effective to achieve complete occlusion of the large-caliber portosystemic shunts.


Strategies of disaster response in the health care system for tropical cyclones: experience following Typhoon Nari in Taipei City.
Natural disasters present significant potential for injuries and death. Unlike the experience of Hurricane Andrew that destroyed a vast surface area in the rural countryside, Typhoon Nari in Taipei proved that significant damages from natural disasters also can happen to modern health care systems in urban areas. To ameliorate such damages, specific structural, nonstructural, and administrative issues must be taken into account. Such issues include the location of the health facility, design of the infrastructure, storage of equipment and machines, maintenance, medical, and nonmedical operations. Specific considerations, such as early evacuation and securing the safety of the patients before a disaster, should be emphasized. Recovery plans that determine how soon medical service can be restored to the community should also be established. Emphasis on emergency-response preparedness, mitigation procedures, and recovery efforts should all be included in a comprehensive emergency plan against the destruction caused by natural hazards.


Stereotactic Radiotherapy and Particle Therapy for Pancreatic Cancer.
Pancreatic cancer is a devastating disease with poor survival outcomes. Recent studies have shown that the addition of radiotherapy to chemotherapy in the setting of locally advanced pancreatic cancer did not improve overall survival outcome. These studies commonly utilize conventional radiotherapy treatment fractionation and technique (typically 3-D conformal radiotherapy or intensity modulated radiotherapy). Although no clear benefit in overall survival was demonstrated in those studies, those who received radiotherapy did have a clear benefit in terms of local control. Therefore, there is increasing interest in exploring different techniques and/or modality of radiotherapy and dose/fractionation. Stereotactic radiotherapy, which employs a hypofractionated regimen, has the potential advantage of delivering a high dose of radiation to the tumor in a short period of time (typically over 5 days) with minimal dose to the surrounding normal structures. Particle therapy such as proton and carbon ion therapy are being explored as potential radiation modality that could cause greater biological damage to the tumor compared to photon treatment, with rapid dose falloff resulting in minimal to no dose to adjacent structures. This review will discuss the current literature and emerging roles of stereotactic radiotherapy and particle therapy in pancreatic cancer.


Linear-after-the-exponential polymerase chain reaction and allied technologies. Real-time detection strategies for rapid, reliable diagnosis from single cells.
Accurate detection of gene sequences in single cells is the ultimate challenge to polymerase chain reaction (PCR) sensitivity. Unfortunately, commonly used conventional and real-time PCR techniques are often too unreliable at that level to provide the accuracy needed for clinical diagnosis. Here we provide details of linear-after-the-exponential-PCR (LATE-PCR), a method similar to asymmetric PCR in the use of primers at different concentrations, but with novel design criteria to ensure high efficiency and specificity. Compared with conventional PCR, LATE-PCR increases the signal strength and allele discrimination capability of oligonucleotide probes such as molecular beacons and reduces variability among replicate samples. The analysis of real-time kinetics of LATE-PCR signals provides a means for improving the accuracy of single cell genetic diagnosis.


Low-density lipoprotein receptor family: endocytosis and signal transduction.
The low-density lipoprotein receptor (LDLR) family is composed of a class of single transmembrane glycoproteins, generally recognized as cell surface endocytic receptors, which bind and internalize extracellular ligands for degradation by lysosomes. Structurally, members of the LDLR family share homology within their extracellular domains, which are highlighted by the presence of clusters of ligand-binding repeats. Recently, information regarding the structural and functional elements within their cytoplasmic tails has begun to emerge, which suggests that members of the LDLR family function not only in receptor-mediated endocytosis, but also in transducing signals that are important during embryonic development and the pathogenesis of Alzheimer's disease. This review focuses on recent knowledge of the structural and functional aspects of LDLR family members in endocytosis and signal transduction. The relationship of these functions to the development of the neuronal system and in the pathogenesis of Alzheimer's disease is specifically discussed.


Public pension reform in Japan.
The March 2000 pension reform in Japan focused on the long-term financial sustainability of the country's two-tiered public pension system. The government opted for incremental changes in order to maintain pension solvency through 2060. Those changes could reduce future pension funding liability by an estimated one-third. Further, the decision to avoid structural reforms of its pension programs was based on fiscal considerations. Expanding general revenue funding for the first tier from the current share of one-third to cover the entire cost would require increases in the consumption tax that proved to be politically unacceptable. Fully privatizing the second, earnings-related tier would entail transition costs too great to bear at a time of rising budget deficits. In addition, the Japanese public generally supported the sharing of financial burden for public pension programs through a combination of benefit cuts, a raise in the pensionable age, and contribution rate increases. If current cost projections prove to be inaccurate, future pension reviews (scheduled every 5 years) will give the government further opportunity to fine-tune program changes.


A METHOD FOR TESTING THE CORRELATED EVOLUTION OF TWO BINARY CHARACTERS: ARE GAINS OR LOSSES CONCENTRATED ON CERTAIN BRANCHES OF A PHYLOGENETIC TREE?
A method is presented for assessing whether changes in a binary character are more concentrated than expected by chance on certain branches of a phylogenetic tree. It can be used to test for correlated evolution of two characters by asking whether changes in the first character are significantly concentrated on those branches on which the second character has a specified state. Thus, one could test whether this specified state is associated with, and thus might enable or select, gains or losses in the first character. The probability of achieving a concentration as or more extreme than that observed under the null hypotheses that changes are distributed randomly on the cladogram is obtained by calculating (a) the number of ways that n gains and m losses can be distributed on the cladogram and (b) the number of ways that p gains q losses can be distributed on the branches of interest given n gains and m losses in the cladogram overall. Summing (b) for appropriate p and q then dividing by (a) yields the desired probability. Simulations suggest that biases resulting from errors in parsimony reconstructions of ancestral states are not extreme.


Cell type-selective imaging and profiling of newly synthesized proteomes by using puromycin analogues.
We have developed a versatile antibody-assisted strategy for the imaging and profiling of newly synthesized proteomes in a cell-specific manner. This strategy remained highly selective even in heterogeneous co-cultured cells, thus enabling labeling and enrichment of nascent proteomes from targeted cells without the need for physical separation.


Kinetic and mechanistic study of the gas-phase reactions of a series of vinyl ethers with the nitrate radical.
NO(3) oxidation of methyl, ethyl, propyl, and butyl vinyl ethers has been studied under tropospheric conditions (atmospheric pressure and T = 293 +/- 3 K) in the LISA indoor simulation chamber. NO(3) was produced inside the reactor by thermal decomposition of N(2)O(5) previously added to the air-VOC mixture, and concentrations were monitored using FTIR spectrometry. All the kinetic experiments were carried out by relative rate technique using isoprene as reference compound, leading to the rate constants k(1) = (7.2 +/- 1.5) x 10(-13), k(2) = (13.1 +/- 2.7) x 10(-13), k(3) = (13.3 +/- 3.0) x 10(-13), and k(4) = (17.0 +/- 3.7) x 10(-13) cm(3) molecule(-1) s(-1) for methyl, ethyl, propyl, and butyl vinyl ethers, respectively. Main oxidation products have been identified like being formaldehyde and respectively methyl, ethyl, propyl, and butyl formates. Production yields of oxidation products were close to 50%. Oxygenated nitrates and peroxynitrates were also detected.


Biochemical characterisation of newly developed beta-etorphine and beta-dihydroetorphine derivatives.
The highly potent synthetic narcotic compound etorphine is known to cause strong analgesia, catatonia and blockade of conditioned reflexes in laboratory animals and is widely used for the immobilisation of game animals. In this study, a number of new structural analogues of etorphine, including C18-beta-structures, 3-O-methylether derivatives and saturated C7-C8 dihydro-compounds, were synthesised and examined in in vitro ligand binding experiments. Opiate receptor-mediated activation of G-proteins by these derivatives was also investigated using the [35S]GTPgammaS binding assay. The receptor binding affinity constant and G-protein stimulatory potency of the novel beta-etorphins were compared with those of the corresponding C18-alpha-derivatives. In rat brain membrane preparations, all the compounds tested displayed high affinity (K(i)'s ranging 0.4-22 nM) using [3H]naloxone in competition assays. The alpha-etorphines had somewhat higher affinity in comparison with the beta-structures. Methylether derivatives were consistently weaker than the corresponding phenolic compounds. Dihydroetorphine and beta-dihydroetorphine, which have a partially saturated ring structure, showed as good potency in the binding assays as did etorphine and beta-etorphine with C7-C8 double bonds. The etorphine derivatives were potent but naloxone-reversible activators of G-proteins in the [35S]GTPgammaS functional tests. It was also found that the C3 phenolic group is favourable for G-protein activation. On the basis of our experimental results, neither the configuration of C18 nor the saturation of the C7-C8 double bond appears to play a critical role in the biological activity of etorphines.


The physiology of lactate production by Lactobacillus delbreuckii in a chemostat with cell recycle.
The physiology of lactate production by Lactobacillus delbreuckii NRRL B-445 in a continuous fermenter with partial cell recycle has been studied and compared with that observed in a conventional chemostat. Partial cell recycle was achieved using a hollow-fiber ultrafiltration cartridge. The biomass growth yield was reduced in the recycle fermenter while culture viability and the cellular content of polysaccharide, protein, carbon, and nitrogen remained constant, suggesting an enlarged specific rate of glucose consumption for nonanabolic (e.g., maintenance) functions. The volumetric productivity of lactate was enhanced in the recycle fermenter due to the complete utilization of glucose. The yield of lactate from biomass and the molar product ratio, lactate: ethanol plus acetate, decreased with increasing recycle ratio. Enhanced formation of ethanol and acetate occurred in the recycle fermenter although lactate remained the major product. The change in product profile was due to glucose limitation. The specific activity of lactate dehydrogenase remained constant during recycle fermentation. These physiological observations have implications for the future application of cell recycle to production processes.


Rapid and low-cost multiplex synthesis of chemokine analogs.
Peptides represent a promising source of new medicines, but improved technologies are needed to facilitate discovery and optimization campaigns. In particular, longer peptides with multiple disulfide bridges are challenging to produce, and producing large numbers of structurally related variants is dissuasively costly and time-consuming. The principal cost and time drivers are the multiple column chromatography purification steps that are used during the multistep chemical synthesis procedure, which involves both ligation and oxidative refolding steps. In this study, we developed a method for multiplex parallel synthesis of complex peptide analogs in which the structurally variant region of the molecule is produced as a small peptide on a 384-well synthesizer with subsequent ligation to the longer, structurally invariant region and oxidative refolding carried out in-well without any column purification steps. To test the method, we used a panel of 96 analogs of the chemokine RANTES (regulated on activation normal T cell expressed and secreted)/CCL5 (69 residues, two disulfide bridges), which had been synthesized using standard approaches and characterized pharmacologically in an earlier study. Although, as expected, the multiplex method generated chemokine analogs of lower purity than those produced in the original study, it was nonetheless possible to closely match the pharmacological attributes (anti-HIV potency, capacity to elicit G protein signaling, and capacity to elicit intracellular receptor sequestration) of each chemokine analog to reference data from the earlier study. This rapid, low-cost approach has the potential to support discovery and optimization campaigns based on analogs of other chemokines as well as those of other complex peptide and small protein targets of a similar size.


Central estrogen inhibition of angiotensin II-induced hypertension in male mice and the role of reactive oxygen species.
It has been shown that reactive oxygen species (ROS) contribute to the central effect of ANG II on blood pressure (BP). Recent studies have implicated an antihypertensive action of estrogen in ANG II-infused female mice. The present study used in vivo telemetry recording and in vitro living mouse brain slices to test the hypothesis that the central activation of estrogen receptors in male mice inhibits ANG II-induced hypertension via the modulation of the central ROS production. In male wild-type mice, the systemic infusion of ANG II induced a significant increase in BP (Delta30.1 +/- 2.5 mmHg). Either central infusion of Tempol or 17beta-estradiol (E2) attenuated the pressor effect of ANG II (Delta10.9 +/- 2.3 and Delta4.5 +/- 1.4 mmHg), and the protective effect of E2 was prevented by the coadministration of an estrogen receptor, antagonist ICI-182780 (Delta23.6 +/- 3.1 mmHg). Moreover, the ganglionic blockade on day 7 after the start of ANG II infusions resulted in a smaller reduction of BP in central Tempol- and in central E2-treated males, suggesting that estrogen inhibits the central ANG II-induced increases in sympathetic outflow. In subfornical organ slices, the application of ANG II resulted in a 21.5 +/- 2.5% increase in ROS production. The coadministration of irbesartan, an ANG II type 1 receptor antagonist, or the preincubation of brain slices with Tempol blocked ANG II-induced increases in ROS production (-1.8 +/- 1.6% and -1.0 +/- 1.8%). The ROS response to ANG II was also blocked by E2 (-3.2 +/- 2.4%). The results suggest that the central actions of E2 are involved in the protection from ANG II-induced hypertension and that estrogen modulation of the ANG II-induced effects may involve interactions with ROS production.


The role of Exosomes in the Pathogenesis of Nasopharyngeal Carcinoma and the involved Clinical Application.
Exosomes are nanoscale membrane vesicles, which carry biologically active substances of their cell of origin and play an important role in signal transduction and intercellular communication. At present, exosomes have been identified as a promising non-invasive liquid biopsy biomarker in the tissues and circulating blood of nasopharyngeal carcinoma (NPC) and found to participate in regulating pathophysiological process of the tumor. We here review recent insights gained into the molecular mechanisms of exosome-induced cell growth, angiogenesis, metastasis, immunosuppression, radiation resistance and chemotherapy resistance in the development and progression of NPC, as well as the clinical application of exosomes as diagnostic biomarkers and therapeutic agents. We also discuss the limitations and challenges in exosome application. We hope this review may provide some references for the use of exosomes in clinical intervention.


Synthesis and anticancer activity comparison of phenylalkyl isoselenocyanates with corresponding naturally occurring and synthetic isothiocyanates.
Synthesis and identification of novel phenylalkyl isoselenocyanates (ISCs), isosteric selenium analogues of naturally occurring phenylalkyl isothiocyanates (ITCs), as effective cytotoxic and antitumor agents are described. The structure-activity relationship comparison of ISCs with ITCs and effect of the increasing alkyl chain length in inhibiting cancer cell growth were evaluated on melanoma, prostate, breast, glioblastoma, sarcoma, and colon cancer cell lines. IC(50) values for ISC compounds were generally lower than their corresponding ITC analogues. Similarly, in UACC 903 human melanoma cells, the inhibition of cell proliferation and induction of apoptosis were more pronounced with ISCs compared to ITCs. Further, ISCs and ITCs effectively inhibited melanoma tumor growth in mice following intraperitoneal xenograft. A similar reduction in tumor size was observed at 3 times lower doses of ISCs compared to corresponding ITCs.


Catena-poly[[diisothiocyanatocadmium(II)]-bis[mu-1,3-bis(1,2,4-triazol-1-ylmethyl)benzene-kappa2N4:N4']]: a double-chain coordination polymer.
The coordination geometry of the CdII atom in the title complex, [Cd(NCS)2(C12H12N6)2]n or [Cd(NCS)2(mbtz)2]n, where mbtz is 1,3-bis(1,2,4-triazol-1-ylmethyl)benzene, is a distorted compressed octahedron in which the CdII atom lies on an inversion centre, coordinated by four N atoms from the triazole rings of four mbtz ligands and two N atoms from two monodentate NCS- ligands. The structure is polymeric, with 24-membered spiro-fused rings extending along [100] and with the 24-membered ring containing two inversion-related mbtz molecules.


Integrating insulin-like growth factor 1 and sex hormones into neuroprotection: Implications for diabetes.
Brain integrity and cognitive aptitude are often impaired in patients with diabetes mellitus, presumably a result of the metabolic complications inherent to the disease. However, an increasing body of evidence has demonstrated the central role of insulin-like growth factor 1 (IGF1) and its relation to sex hormones in many neuroprotective processes. Both male and female patients with diabetes display abnormal IGF1 and sex-hormone levels but the comparison of these fluctuations is seldom a topic of interest. It is interesting to note that both IGF1 and sex hormones have the ability to regulate phosphoinositide 3-kinase-Akt and mitogen-activated protein kinases-extracellular signal-related kinase signaling cascades in animal and cell culture models of neuroprotection. Additionally, there is considerable evidence demonstrating the neuroprotective coupling of IGF1 and estrogen. Androgens have also been implicated in many neuroprotective processes that operate on similar signaling cascades as the estrogen-IGF1 relation. Yet, androgens have not been directly linked to the brain IGF1 system and neuroprotection. Despite the sex-specific variations in brain integrity and hormone levels observed in diabetic patients, the IGF1-sex hormone relation in neuroprotection has yet to be fully substantiated in experimental models of diabetes. Taken together, there is a clear need for the comprehensive analysis of sex differences on brain integrity of diabetic patients and the relationship between IGF1 and sex hormones that may influence brain-health outcomes. As such, this review will briefly outline the basic relation of diabetes and IGF1 and its role in neuroprotection. We will also consider the findings on sex hormones and diabetes as a basis for separately analyzing males and females to identify possible hormone-induced brain abnormalities. Finally, we will introduce the neuroprotective interplay of IGF1 and estrogen and how androgen-derived neuroprotection operates through similar signaling cascades. Future research on both neuroprotection and diabetes should include androgens into the interplay of IGF1 and sex hormones.


Migraines and perimenopause: helping women in midlife manage and treat migraine.
Migraine is more common in women than men, with lifetime prevalence rates between 15 percent and 26 percent for women. The World Health Organization ranks migraine as 12th among all causes of years lived with disability in women. This article reviews diagnostic criteria for migraine with and without aura, the impact of fluctuating hormones in perimenopause on the experience of migraine and medication and nonmedication approaches to managing migraine.