Reflex and nervous control of the tracheobronchial circulation.
Determinants of blood flow through the tracheobronchial vasculature include systemic arterial blood pressure, airway pressure, central venous and pulmonary vascular pressures, alveolar and arterial gas tensions, neural influences and chemical and humoral mediators. There is anatomical and physiological evidence of a role for cholinergic, adrenergic and peptidergic nerves in the control of the vasculature. Physiologically, adrenergic and peptidergic influences appear to be more important than cholinergic. The vasodilator response to inhalation of cold or dry air observed in the tracheobronchial vasculature of several species is unaffected by cholinergic or adrenergic blockade, but is attenuated by pretreatment with lignocaine, suggesting that it may be related to axon reflexes in sensory nerves resulting in release of tachykinins. This may also be the mechanism of the tracheobronchial vasodilator response to allergen challenge. The role of peptidergic nerves in other reflex responses of the tracheobronchial vasculature is at present unknown.


Developmental pathway for first onset of depressive disorders in females: from adolescence to emerging adulthood.
Although risk markers for depressive disorders (DD) are dynamic, especially during adolescence, few studies have examined how change in risk levels during adolescence predict DD onset during transition to adulthood. We compared two competing hypotheses of the dynamic effects of risk. The risk escalation hypothesis posits that worsening of risk predicts DD onset beyond risk level. The chronic risk hypothesis posits that persistently elevated risk level, rather than risk change, predicts DD onset. Our sample included 393 girls (baseline age 13.5-15.5 years) from the adolescent development of emotions and personality traits project. Participants underwent five diagnostic interviews and assessments of risk markers for DD at 9-month intervals and were re-interviewed at a 6-year follow-up. We focused on 17 well-established risk markers. For each risk marker, we examined the prospective effects of risk level and change on first DD onset at wave six, estimated by growth curve modeling using data from the first five waves. For 13 of the 17 depression risk markers, elevated levels of risk during adolescence, but not change in risk, predicted first DD onset during transition to adulthood, supporting the chronic risk hypothesis. Minimal evidence was found for the risk escalation hypothesis. Participants who had a first DD onset during transition to adulthood have exhibited elevated levels of risk throughout adolescence. Researchers and practitioners should administer multiple assessments and focus on persistently elevated levels of risk to identify individuals who are most likely to develop DD and to provide targeted DD prevention.


Lithium ion dynamics in LiZr2(PO4)3 and Li1.4Ca0.2Zr1.8(PO4)3.
High ionic conductivity, electrochemical stability and small interfacial resistances against Li metal anodes are the main requirements to be fulfilled in powerful, next-generation all-solid-state batteries. Understanding ion transport in materials with sufficiently high chemical and electrochemical stability, such as rhombohedral LiZr2(PO4)3, is important to further improve their properties with respect to translational Li ion dynamics. Here, we used broadband impedance spectroscopy to analyze the electrical responses of LiZr2(PO4)3 and Ca-stabilized Li1.4Ca0.2Zr1.8(PO4)3 that were prepared following a solid-state synthesis route. We investigated the influence of the starting materials, either ZrO2 and Zr(CH3COO)4, on the final properties of the products and studied Li ion dynamics in the crystalline grains and across grain boundary (g.b.) regions. The Ca2+ content has only little effect on bulk properties (4.2 × 10-5 S cm-1 at 298 K, 0.41 eV), but, fortunately, the g.b. resistance decreased by 2 orders of magnitude. Whereas, 7Li spin-alignment echo nuclear magnetic resonance (NMR) confirmed long-range ion transport as seen by conductivity spectroscopy, 7Li NMR spin-lattice relaxation revealed much smaller activation energies (0.18 eV) and points to rapid localized Li jump processes. The diffusion-induced rate peak, appearing at T = 282 K, shows Li+ exchange processes with rates of ca. 109 s-1 corresponding, formally, to ionic conductivities in the order of 10-3 S cm-1 to 10-2 S cm-1.


Clinical manifestations of early syphilis by HIV status and gender: results of the syphilis and HIV study.
Despite reports of unusual clinical presentations and therapeutic responses among HIV-infected patients with syphilis, syphilis has not been regarded as a serious opportunistic infection that predictably progresses among most HIV-coinfected patients. To define and describe differences in the presentation and response to treatment of early syphilis among HIV-infected and HIV-uninfected patients, to describe any differences by gender, and to determine if clinical presentation of central nervous system involvement predicted serologic failure. A prospective, multicenter, randomized, controlled trial of enhanced versus standard therapy to compare the benefit of enhanced therapy, the clinical importance of central nervous system involvement, and the clinical manifestations of early syphilis infection among HIV-infected and HIV-uninfected patients. The median number of ulcers was significantly greater among HIV-infected and HIV-uninfected patients, as was the percent of HIV-infected patients with multiple ulcers. Among patients diagnosed with secondary syphilis, a higher percentage of HIV-infected patients presented with genital ulcers [13/53 (25%)] than did HIV-uninfected patients [27/200 (14%)]. No differences between HIV-infected and HIV-uninfected patients were detected for other secondary syphilis manifestations. Although women presented more frequently with secondary syphilis than did men, no other gender differences in clinical manifestations were noted. Neurologic complaints were reported most frequently among patients with secondary syphilis [103/248 patients (42%)] compared with patients with primary syphilis [32/136 (24%)] and early latent syphilis [48/ 142, (34%)] (P < 0.05), but no differences in neurologic complaints were apparent by HIV status or CSF abnormalities. No neurologic complaints were significantly associated with serologic treatment failures at 6 months. Overall, HIV infection had a small effect on the clinical manifestations of primary and secondary syphilis. Compared with HIV-uninfected patients, HIV-infected patients with primary syphilis tended to present more frequently with multiple ulcers, and HIV-infected patients with secondary syphilis presented with concomitant genitals ulcers more frequently.


Two decades of research toward the treatment of locally advanced and metastatic pancreatic cancer: Remarkable effort and limited gain.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy that is diagnosed at the locally advanced or metastatic stage in approximately 80% of cases. Relative to other tumor types, progress in the treatment of this disease has been painfully slow. While agents targeting DNA repair have proven successful in a subset of patients, the majority of PDACs do not exhibit validated molecular targets. Hence, conventional chemotherapy remains at the forefront of therapy for this disease. In this review, we study two decades of efforts to improve upon the gemcitabine backbone - 67 phase II and III trials enrolling 16,446 patients - that culminated in the approvals of gemcitabine/nab-paclitaxel (Gem/NabP) and FOLFIRINOX. Today, these remain gold standards for the first-line treatment of locally advanced unresectable and metastatic PDAC, while ongoing efforts focus on improving upon the Gem/NabP backbone. Because real world data often do not reflect the data of randomized controlled trials (RCTs), we also summarize the retrospective evidence comparing the efficacy of Gem/NabP and FOLFIRINOX in the first-line setting - 29 studies reporting a median overall survival of 10.7 and 9.1 months for FOLFIRINOX and Gem/NabP, respectively. These values are surprisingly comparable to those reported by the pivotal RCTs at 11.1 and 8.5 months. Finally, there is a paucity of RCT data regarding the efficacy of second-line therapy. Hence, we conclude this review by summarizing the data that ultimately demonstrate a small but significant survival benefit of second-line therapy with Gem/NabP or FOLFIRINOX. Collectively, these studies describe the long journey, the steady effort, and the myriad lessons to be learned from 20 years of PDAC trials to inform strategies for success in clinical trials moving forward.


Factors Associated with Acute Malnutrition among Pregnant Women in Flood Affected Region.
Adequate nutrition before and during pregnancy is necessary to maintain women's reproductive health and to ensure healthy foetal outcome. Pregnant women are at high risk of acute malnutrition specifically during humanitarian crisis leading to adverse effects in foetal outcomes and women's health. This study aimed to assess the factors associated with acute malnutrition among pregnant women visiting Antenatal Clinics in two hospitals and a Primary Health Care Centre of Siraha district in the south-eastern plains of Nepal immediately after 2017 flash flood. A health-institution based cross-sectional study was conducted among 444 pregnant women of reproductive age (15-49 years) in second and third trimester in three health institutions. Data collection was done in the aftermath of 2017 flash floods through face to face interview. Multiple logistic regression analysis was used to identify the factors associated with acute malnutrition defined as Mid Upper Arm Circumference less than or equals to 21 centimetres. Out of 444 participants, 9.9% were found to be acutely malnourished. Participant's education (AOR[Adjusted Odds Ratio]: 3.09, 95% CI[Confidence Interval]: 1.43-6.70), occupation (AOR: 3.16, 95% CI: 1.08-9.22), husband's occupation (AOR: 6.61, 95% CI: 2.17-20.12), household food security (AOR: 3.39, 95% CI: 1.36-8.49) and participant's dietary diversity (AOR:10.06, 95% CI: 3.35-30.27) were found to be statistically significant factors associated with acute malnutrition among pregnant women. Participants' silliteracy, unemployment, husband not employed for cash, household food insecurity and low dietary diversity were found to be statistically significant predictors of acute malnutrition among pregnant women during flash floods.


White Light Induced E/Z-Photoisomerization of Diphenylamine-Tethered Fluorescent Stilbene Derivatives: Synthesis, Photophysical, and Electrochemical Investigation.
A facile synthesis and detailed photophysical investigation of E/Z-isomerization of fluorescent diphenylamine tethered stilbene derivatives (DPASs) under white light exposure have been carried out to understand the effect on fluorescence, electrochemical properties, and photostability under various activation/deactivation pathways. In solution state, in the dark, the E-isomer of DPASs (6a-d) exhibited high fluorescence quantum yields (Φfl ≈ 53% to 60% in DMSO). However, on white light exposure, 1H NMR and HPLC studies revealed that pure E-isomer of the DPAS 6a (∼9.5 mM) started converting into its Z-form by photoisomerization until it reaches to nearly equilibrium. At low concentrations (∼10 μM), the absorption band of the pure E-isomer in the range of 350-450 nm gradually decreased to adopt Z-conformation 6a' until a photostationary state was reached. The structure of the E-isomer 6a was unequivocally confirmed by X-ray diffraction analysis. The synthesized DPAS compounds 6a-d possessed positive solvatochromic properties, two photon absorption properties, and good thermal stability. The electrochemical investigations using DPASs showed reversible oxidation resulting in formation of a stable radical cation. Owing to useful photophysical, electrochemical and thermal properties, these DPAS derivatives are suitable for their application in biomedical imaging as well as in fabrication of electroluminescent materials.


Artificial Intelligence Algorithm-Based Differential Diagnosis of Crohn's Disease and Ulcerative Colitis by CT Image.
The aim of this study was to investigate the effect of low-dose CT enterography (CTE) based on modified guided image filtering (GIF) algorithm in the differential diagnosis of ulcerative colitis (UC) and Crohn's disease (CD). Methods. One hundred and twenty patients with suspected diagnosis of IBD were studied. They were randomly divided into control group (routine CT examination) and observation group (low-dose CTE examination based on improved GIF algorithm), with 60 cases in each group. Comprehensive diagnosis was used as the standard to assess the diagnostic effect. Results. (1) The peak signal-to-noise ratio (PSNR) (26.02 dB) and structural similarity (SSIM) (0.8921) of the algorithm were higher than those of GIF (17.22 dB/0.8491), weighted guided image filtering (WGIF) (23.78 dB/0.8489), and gradient domain guided image filtering (GGIF) (23.77 dB/0.7567) (P < 0.05); (2) the diagnostic sensitivity (91.49%), specificity (92.31%), accuracy (91.67%), positive predictive value (97.73%), and negative predictive value (75%) of the observation group were higher than those of the control group (P < 0.05); the sensitivity and specificity of CTE in the diagnosis of UD and CD were 96.77% and 81.25% and 98.33% and 93.33%, respectively (P < 0.05); there were significant differences in symmetrical intestinal wall thickening and smooth serosal surface between UD and CD (P < 0.05). Conclusion. (1) The improved GIF algorithm has a more effective application value in the denoising processing of low-dose CT images and can better improve the image quality; (2) the accuracy of CTE in the diagnosis of IBD is high, and CTE is of great value in the differential diagnosis of UD and CD.


[Effect of the structure of the prosthetic group on the catalytic properties of prostaglandin H synthetase].
The effect of vinyl groups of protohemin IX on its cofactor properties with respect to prostaglandin H synthetase has been studied. It was shown that substitution of ethyl groups or a hydrogen for vinyl groups affects neither binding of the prosthetic group to the apoenzyme nor catalytic properties of holo-prostaglandin H synthetase. Replacement of vinyl groups with bulkier substituents (hydroxyethyl or acetyl groups) decreases holoenzyme stability and catalytic activity. By comparison of the cofactor properties of protoporphyrin and hematoporphyrin macrocycles with different central ions (Fe3+, Mn2+, 2H+ in the case of protoporphyrin, and Fe3+, Mg2+, Cd2+ and Cu2+ in the case of hematoporphyrin), the presence of Fe3+ ions was shown to be mandatory for prostaglandin H synthetase activity. It was demonstrated that the cofactor structure modifications do not affect the holo-prostaglandin H synthetase inactivation rate constant in a reaction.


Prospective Randomized Trial Comparing Efficacy of Topical Loteprednol Etabonate 0.5% Versus Cyclosporine-A 0.05% for Treatment of Dry Eye Syndrome Following Hematopoietic Stem Cell Transplantation.
To evaluate the safety and efficacy of topical loteprednol etabonate (LE) 0.5% compared with cyclosporine A (CsA) 0.05% for the prophylaxis and treatment of dry eye syndrome (DES) after hematopoietic stem cell transplantation (HSCT). Seventy-five patients were randomized to LE (n = 76 eyes of 38 patients) or CsA (n = 74 eyes of 37 patients) pre-HSCT. Lissamine green and fluorescein staining, tear break-up time, tear osmolarity (Osm), Schirmer score (Sch), intraocular pressure, visual acuity, and Ocular Surface Disease Index were assessed pre-HSCT, 3, 6, 9, and 12 months post-HSCT. There were no differences in DES incidence (P = 0.22; log-rank test) or progression (P = 0.41; log-rank test) between the 2 treatment arms during the course of the study. Among eyes with no DES at enrollment, the Kaplan-Meier analysis yielded a 90% rate of DES development in cyclosporine-treated eyes and a 79% rate of DES development in LE-treated eyes by 12 months post-HSCT. The Kaplan-Meier analysis of eyes with DES at enrollment demonstrated a 38% rate of disease progression among cyclosporine-treated eyes and a 26% rate of disease progression among loteprednol-treated eyes by 12 months. No patient in either group had an elevation of 10 mm Hg or greater from baseline at any study visit, and no patients had their treatment discontinued for elevation in intraocular pressure. Pre-HSCT initiation of LE 0.5% appears to be safe and may be as effective as CsA 0.5% for the treatment and prophylaxis of DES following HSCT.


AMCXO and its test system.
In this paper, we introduce a novel temperature compensated crystal oscillator--analog memory compensated crystal oscillator (AMCXO), a microcomputer compensated crystal oscillator (MCXO) based on an analogue approach, and we compare the performance between MCXO and AMCXO, and analyze the necessity of developing AMCXO. Both AMCXO and MCXO, combined with their test systems, use computers to generate the control signals used for the compensated crystal oscillators according to temperature variation. However, the execution devices are much different from each other in the practical temperature compensated crystal oscillators. A MCXO uses a set of digital units, including a microprocessor, to realize the compensation. For it, equations or tables are used to express the relationship between the control signal and temperature. An AMCXO uses an analogue memory, which has the same functions as the digital units of MCXO. For AMCXO, a curve or figure based on the equations or tables is used to express the same relationship. Their test systems have obvious distinctions in temperature experiment, data acquisition, and processing. A better performance will be obtained by using a more complicated AMCXO test system, and the cost can be reduced at the same time.


Conserved Pseudoknots in lncRNA MEG3 Are Essential for Stimulation of the p53 Pathway.
Long non-coding RNAs (lncRNAs) are key regulatory molecules, but unlike with other RNAs, the direct link between their tertiary structure motifs and their function has proven elusive. Here we report structural and functional studies of human maternally expressed gene 3 (MEG3), a tumor suppressor lncRNA that modulates the p53 response. We found that, in an evolutionary conserved region of MEG3, two distal motifs interact by base complementarity to form alternative, mutually exclusive pseudoknot structures ("kissing loops"). Mutations that disrupt these interactions impair MEG3-dependent p53 stimulation in vivo and disrupt MEG3 folding in vitro. These findings provide mechanistic insights into regulation of the p53 pathway by MEG3 and reveal how conserved motifs of tertiary structure can regulate lncRNA biological function.


Targeting of an interrupted polypurine:polypyrimidine sequence in mammalian cells by a triplex-forming oligonucleotide containing a novel base analogue.
The DNA triple helix consists of a third strand of nucleic acid lying in the major groove of an intact DNA duplex. The most stable triplexes form on polypurine:polypyrimidine sequences, and pyrimidine interruptions in the purine strand are destabilizing. Sequence stringency is imparted by specific Hoogsteen hydrogen bonds between third strand bases and the purine bases in the duplex. Appropriate base and sugar modifications of triple helix-forming oligonucleotides (TFOs) confer chromosome targeting activity in living cells. However, broad utilization of TFOs as gene targeting reagents in mammalian cells has been limited by the requirement for homopurine target sequences. Although there have been a number of base analogues described that appear to be promising as candidates for triplex target expansion, none has been examined in a biological system. We have employed a postsynthetic strategy to prepare a collection of TFOs with base analogues at a defined position. Following assessment of affinity for a triplex target with a single C:G inversion, TFOs with a second generation of analogues were synthesized. One of these, TFO-5a, with 2'-OMe-guanidinylethyl-5-methylcytosine at the position corresponding to the C:G interruption in the target sequence, was further modified to confer bioactivity. The activity of this TFO, linked to psoralen, was measured in a mammalian cell line that was engineered by directed sequence conversion to carry a triplex target with a single C:G interruption. TFO-5a was active against this target and inactive against the corresponding target with an uninterrupted polypurine:polypyrimidine sequence.


Detection of occult bone metastases of lung cancer with fluorine-18 fluorodeoxyglucose positron emission tomography.
Accurate staging of cancer has a critical role in optimal patient management. Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG PET) is superior to CT in the detection of local and distant metastases in patients with non-small cell lung cancer. Although Tc-99 m methylene diphosphonate (MDP) bone scanning is well established in the evaluation of bone metastases, there are conflicting reports on the use of FDG PET in the evaluation of skeletal metastases. We report on a patient with locally advanced lung carcinoma in whom FDG PET accurately identified previously unsuspected widespread asymptomatic bone metastases (bone scan and X-rays negative, confirmed on MRI). Assessment of glucose metabolism with FDG PET might represent a more powerful tool to detect bone metastases in lung cancer compared with conventional bone scans.


Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants.
Variation in human lifespan is 20 to 30% heritable in twins but few genetic variants have been identified. We undertook a Genome Wide Association Study (GWAS) using age at death of parents of middle-aged UK Biobank participants of European decent (n=75,244 with father's and/or mother's data, excluding early deaths). Genetic risk scores for 19 phenotypes (n=777 proven variants) were also tested. In GWAS, a nicotine receptor locus(CHRNA3, previously associated with increased smoking and lung cancer) was associated with fathers' survival. Less common variants requiring further confirmation were also identified. Offspring of longer lived parents had more protective alleles for coronary artery disease, systolic blood pressure, body mass index, cholesterol and triglyceride levels, type-1 diabetes, inflammatory bowel disease and Alzheimer's disease. In candidate analyses, variants in the TOMM40/APOE locus were associated with longevity, but FOXO variants were not. Associations between extreme longevity (mother >=98 years, fathers >=95 years, n=1,339) and disease alleles were similar, with an additional association with HDL cholesterol (p=5.7x10-3). These results support a multiple protective factors model influencing lifespan and longevity (top 1% survival) in humans, with prominent roles for cardiovascular-related pathways. Several of these genetically influenced risks, including blood pressure and tobacco exposure, are potentially modifiable.


Leukocytoclastic angiitis induced by clindamycin.
A fifty-six-year-old white male diabetic developed leukocytoclastic angiitis after treatment with clindamycin for an infected foot ulcer. The eruption subsided following withdrawal of the drug, recurred when it was re-administered, and cleared after it was again withdrawn. Clindamycin or lincomycin allergy should be considered in the differential diagnosis of leukocytoclastic angiitis in patients who take these drugs.


The antioxidant tempol reduces carcinogenesis and enhances survival in mice when administered after nonlethal total body radiation.
There is significant interest in the development of agents that can ameliorate radiation damage after exposure to radiation has occurred. Here we report that chronic supplementation of the antioxidant Tempol in the diet of mice can reduce body weight without toxicity, decrease cancer, and extend survival when administered after nonlethal total body radiation (TBI). These effects were apparent in two different strains of mice (C3H, CBA) exposed to TBI (3 Gy). Notably, delaying administration of the Tempol diet one month after TBI could also enhance survival. Tempol reduced the incidence of hematopoietic neoplasms (lymphomas) in both strains, whereas both the onset and incidence of nonhematopoietic neoplasms were reduced in CBA mice. These results encourage further study of Tempol as a chemopreventive, to reduce the incidence of radiation-induced second malignancies after a course of definitive radiation therapy. Tempol may also find applications to reduce the risk of cancers in populations exposed to nonlethal radiation due to nuclear accidents or terrorist attacks.


Hepatitis B vaccination schedules in genitourinary medicine clinics.
To compare two vaccination schedules in delivering hepatitis B vaccine to at-risk genitourinary medicine clinic attenders. Genitourinary medicine clinic of St Thomas' Hospital, London, UK. Two vaccination protocols were compared. Between January 1991 and December 1992, individuals had doses of recombinant hepatitis B vaccine at 0, 1 and 6 months (standard). From January until October 1993 doses of vaccine were administered at 0, 1 and 2 months (accelerated), following which timing of a booster dose was made on the basis of hepatitis B surface antibody (anti-HBs) assessment. Case notes were reviewed with regard to compliance rates and anti-HBs levels. Two hundred and fourteen individuals were included (standard 104, accelerated 110). Of the standard group 80.8% and 61.5% attended for the 2nd and 3rd doses respectively compared with 80.0% and 75.5% of the accelerated group (attendance for the 3rd dose chi 2 = 4.19, p < 0.05). For both of these groups compliance was significantly better in those who requested vaccination rather than being offered it opportunistically (chi 2 = 4.86, p < 0.05). Seroconversion rates were not significantly different between the two groups (87.5% versus 83.1%). A significantly higher proportion of the standard group, however, achieved anti-HBs levels greater than 100 i.u./l. Completion of hepatitis B vaccination was improved by changing to a 0, 1 and 2 month protocol. Levels of anti-HBs achieved in the accelerated group, however, were lower. If it is confirmed that maintaining anti-HBs levels is not important in retaining protection against hepatitis B then the accelerated schedule has clear advantage. If not, the advantages may be nullified by the need, in some, for an early booster.


CDK1-SRC Interaction-Dependent Transcriptional Activation of HSP90AB1 Promotes Antitumor Immunity in Hepatocellular Carcinoma.
This study aimed to analyze multiomics data and construct a regulatory network involving kinases, transcription factors, and immune genes in hepatocellular carcinoma (HCC) prognosis. The researchers used transcriptomic, proteomic, and clinical data from TCGA and GEO databases to identify immune genes associated with HCC. Statistical analysis, meta-analysis, and protein-protein interaction analyses were performed to identify key immune genes and their relationships. In vitro and in vivo experiments validated the CDK1-SRC-HSP90AB1 network's effects on HCC progression and antitumor immunity. A prognostic risk model was developed using clinicopathological features and immune infiltration. The immune genes LPA, BIRC5, HSP90AB1, ROBO1, and CCL20 were identified as the key prognostic factors. The CDK1-SRC-HSP90AB1 network promoted HCC cell proliferation and migration, with HSP90AB1 being transcriptionally activated by the CDK1-SRC interaction. Manipulating SRC or HSP90AB1 reversed the effects of CDK1 and SRC on HCC. The CDK1-SRC-HSP90AB1 network also influenced HCC tumor formation and antitumor immunity. Overall, this study highlights the importance of the CDK1-SRC-HSP90AB1 network as a crucial immune-regulatory network in the HCC prognosis.


Sex differences in the behavioral and immune responses of mice to tumor growth and cancer therapy.
There is significant variability in the expression of cancer-related fatigue. Understanding the factors that account for this variation provide insight into the underlying mechanisms. One important, but often overlooked, variable is biological sex. While a few clinical studies have indicated that female patients report higher levels of fatigue, these studies are subject to potential socio-culture reporting biases. Only a limited number of preclinical studies have considered sex differences in animal model of fatigue and few have simultaneously considered both disease- and treatment-related factors. The present series of studies was initiated to address the current knowledge gap on the importance of sex differences in cancer-related fatigue. We selected a murine model of human papilloma virus-positive head and neck cancer based on heterotypic injection of the mEERL95 cell line that grows in both male and female mice and responds to a regimen of cisplatin plus irradiation. We also tested the impact of immunotherapy treatment targeting PD1. Voluntary wheel running was used to evaluate fatigue-like behavior. Male mice grew larger tumors than did female mice and showed more severe fatigue-like behavior. We confirmed that the tumor increased the expression of inflammatory cytokines in the liver, but no sex differences were observed. As a trend toward elevated Cd3 mRNA was observed in female mice, we tested the importance of T cells using female Rag2-/- mice. The Rag2-/- female mice had accelerated tumor growth and more severe fatigue-like behavior. In response to cisplatin alone non-tumor-bearing female mice showed a slower recovery of wheel running activity compared to males. However, in response to chemoradiation and anti-PD1 neutralizing antibody, tumor-bearing female mice showed a better tumor response to therapy than male mice, but no significant sex differences were observed for wheel running. These findings point to different mechanisms underlying tumor- and treatment-induced behavioral fatigue and indicate that the sex factor can intervene to modulate the expression of fatigue-like behavior in particular circumstances.


Hydroxylated Chalcones as Aryl Hydrocarbon Receptor Agonists: Structure-Activity Effects.
Hydroxylated chalcones are phytochemicals which are biosynthetic precursors of flavonoids and their 1,3-diaryl-prop-2-en-1-one structure is used as a scaffold for drug development. In this study, the structure-dependent activation of aryl hydrocarbon receptor (AhR)-responsive CYP1A1, CYP1B1, and UGT1A1 genes was investigated in Caco2 colon cancer cells and in non-transformed young adult mouse colonocytes (YAMC) cells. The effects of a series of di- and trihydroxychalcones as AhR agonists was structure dependent with maximal induction of CYP1A1, CYP1B1, and UGT1A1 in Caco2 cells observed for compounds containing 2,2'-dihydroxy substituents and this included 2,2'-dihydroxy-, 2,2',4'-trihydroxy-, and 2,2',5'-trihydroxychalcones. In contrast, 2',4,5'-, 2'3',4'-, 2',4,4'-trihydroxy, and 2',3-, 2',4-, 2',4'-, and 2',5-dihydroxychalcones exhibited low to non-detectable AhR activity in Caco2 cells. In addition, all of the hydroxychalcones exhibited minimal to non-detectable activity in YAMC cells, whereas 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced CYP1A1, CYP1B1, and UGT1A1 in Caco2 and YAMC cells. The activity of AhR-active chalcones was confirmed by determining their effects in AhR-deficient Caco2 cells. In addition, 2,2'-dihydroxychalcone induced CYP1A1 protein and formation of an AhR-DNA complex in an in vitro assay. Simulation and modeling studies of hydroxylated chalcones confirmed their interactions with the AhR ligand-binding domain and were consistent with their structure-dependent activity as AhR ligands. Thus, this study identifies hydroxylated chalcones as AhR agonists with potential for these phytochemicals to impact AhR-mediated colonic pathways.


Lethal pulmonary reactions associated with the combined use of amphotericin B and leukocyte transfusions.
Amphotericin B is used increasingly in high-risk patients with profound neutropenia and suspected sepsis. We have observed serious pulmonary reactions characterized by acute dyspnea, hypoxemia, and interstitial infiltrates on chest films in patients receiving amphotericin B and leukocyte transfusions. We reviewed 6 1/2 years of experience at the National Institutes of Health to determine whether this combination was associated with pulmonary toxicity not characteristic of either therapy alone. Amphotericin was used during 22 of 57 leukocyte-transfusion courses. Acute respiratory deterioration occurred during 14 (64 per cent) of these courses but in only two (6 per cent) of 35 courses without amphotericin (P less than 0.01). In seven cases, respiratory deterioration began during or immediately after amphotericin infusion, and it contributed to death in five patients. Diffuse intraalveolar hemorrhage was found when lung biopsy or autopsy was performed. Acute respiratory deterioration was not observed in comparably neutropenic patients given amphotericin but not leukocyte transfusions during the same period. It was mot common when amphotericin was begun with or after institution of daily leukocyte transfusions. Leukocyte transfusions may cause changes in the lungs that amplify the acute toxicity of amphotericin, thereby permitting severe pulmonary reactions.


[Effects of x-ray irradiation on circadian rhythm of the level of microsomal hemoproteins in the rat liver].
The influence of X-irradiation of 12 Gy on the state of biorhythms of microsomal hemoproteins P-450 and b5 of the liver in male rats was studied. The content of these cytochromes was measured at 4, 10, 12, 15 and 21 hours in the course of the first and second days after X-irradiation and also on the fourth day (day of mass death of the irradiated rats). It has been found that disturbance of diurnal rhythms of these cytochromes begins already with third hour after X-irradiation and revealed in expressed depression of their acrophase. The diurnal rhythm of level of cytochrome P-450 is smoothed and takes the character of slowing down process, biorhythm of cytochrome b5 not being traced.


Do authors of research funded by the Canadian Institutes of Health Research comply with its open access mandate?: A meta-epidemiologic study.
Since 2008, the Canadian Institutes of Health Research (CIHR) has mandated that studies it funds either in whole or in part are required to publish their results as open access (OA) within 12 months of publication using either online repositories and/or OA journals. Yet, there is evidence that authors are poorly compliant with this mandate. Specifically, there has been an apparent decrease in OA publication after 2015, which coincides with a change in the OA policy during the same year. One particular policy change that may have contributed to this decline was lifting the requirement that authors deposit their article in an OA repository immediately upon publication. We investigated the proportion of OA compliance of CIHR-funded studies in the period before and after the policy change of 2015 with manual confirmation of both CIHR funding and OA status. We identified CIHR-funded studies published between the years 2014 to 2017 using a comprehensive search in the Web of Science (WoS). We took a stratified random sample from all four years (i.e. 2014 to 2017), with 250 studies from each year. Two authors independently reviewed the final full-text publications retrieved from the journal web page to determine to confirm CIHR funding, as indicated in the acknowledgements or elsewhere in the paper. For each study, we also collected bibliometric data that included citation count and Altmetric attention score Statistical analyses were conducted using two-tailed Fisher's exact test with relative risk (RR). Among the 851 receiving CIHR funding published from 2014 to 2017, the percentage of CIHR-funded studies published as OA significantly decreased from 79.6% in 2014 to 70.3% in 2017 (RR = 0.88, 95% CI: 0.79-0.99, P = 0.028). When considering all four years, there was no significant difference in the percentage of CIHR-funded studies published as OA in both 2014 and 2015 compared to both 2016 and 2017 (RR = 0.97, 95% CI: 0.90-1.05, P = 0.493). Additionally, OA publications had significantly higher citation count (both in year of publication and in total) and higher attention scores (P<0.05). Overall, we found that there was a significant decrease in the proportion of CIHR funded studies published as OA from 2014 compared to 2017, though this difference did not persist when comparing both 2014-2015 to 2016-2017. The primary limitation was the reliance of self-reported data from authors on CIHR funding status. We posit that this decrease may be attributable to CIHR's OA policy change in 2015. Further exploration is warranted to both validate these studies using a larger dataset and, if valid, investigate the effects of potential interventions to improve the OA compliance, such as use of a CIHR publication database, and reinstatement of a policy for authors to immediately submit their findings to OA repositories upon publication.


[Nutritional evaluation and cardiovascular risk in executives submitted to a check-up].
To evaluate the nutritional status and cardiovascular risk among executives. In a cross-sectional study. 329 executives of both genders, aged 31 to 70 years, were evaluated during a health check-up in a private hospital in the city of São Paulo. The variables related to weight, height and waist circumference were measured and Body Mass Index - BMI (kg/m(2)) was determined. Blood pressure and serum levels of total cholesterol and fractions, triacylglycerol, glucose and uric acid were analyzed. Physical activity was evaluated by the International Physical Activity Questionnaire (IPAQ) and cardiovascular risk was estimated by the Framingham Scoring. The variance analysis and the Bonferroni methods were used for statistical treatment. The mean age was 44.6 (SD=6.8), with the male gender predominating (89.7%). As for lifestyle, 17% were tobacco smokers and 7.3% sedentary. The mean values found in the clinical and biochemical exams were the following: blood pressure of 117 x 78.6 mmHg (SD=12 x 8.3), total cholesterol of 200.5 mg/dL (SD=35.9), LDL-c of 121.8 mg/dL (SD=29.9), HDL-c of 52.2 mg/dL (SD= 10.9), triacylglycerol of 133.7 mg/dL (SD=76.8), glucose of 96.3 mg/dL (SD=20.5) and uric acid 4.2 and 6.0 mg/dL (SD=1.0 and 0.9) for men and women respectively. The BMI mean for all executives was classified as overweight (26.1 kg/m(2); SD=6.8). Waist circumference was normal in women (79.6 cm; SD=7.3) and indicated a high risk level of chronic disease for the men (96.1cm; SD=8.9). The average Framingham Risk was 5.7%. The executives were overweight and presented low cardiovascular risk, according to the Framingham Scoring.


Characterization of a novel alpha-amidated decapeptide derived from proopiomelanocortin-A in the trout pituitary.
Two complementary DNAs encoding distinct forms of POMC have been characterized in the trout pituitary. One of the POMC variants (POMC-A) possesses a C-terminal extension of 25 amino acids, which has no equivalent in other POMCs described to date. This C-terminal peptide contains three pairs of basic amino acids, suggesting that it may be the precursor of multiple processed peptides. In addition, the presence of a C-terminal glycine residue suggests that some of the processing products may be alpha-amidated. To characterize the molecular forms of the peptides generated from the C-terminal domain of trout POMC-A, we have developed specific antibodies against the C-terminal pentapeptide YHFQG and its alpha-amidated derivative YHFQ-NH2. Immunocytochemical labeling of pituitary sections with antibodies against YHFQ-NH2 revealed the presence of numerous immunoreactive cells in the pars intermedia and the rostral pars distalis. In contrast, the antibodies against YHFQG produced only weak immunostaining. HPLC analysis combined with RIA detection revealed that extracts of the pars intermedia and pars distalis contain several peptides derived from the C-terminal extension of trout POMC-A, with the predominant molecular form exhibiting the same retention time as ALGERKYHFQ-NH2. Tryptic digestion of this major form produced a peptide that coeluted with YHFQ-NH2. These data indicate that the processing of the C-terminal extension of trout POMC-A generates several novel peptides including the decapeptide amide ALGERKYHFQ-NH2.


Major depression is associated with significant diurnal elevations in plasma interleukin-6 levels, a shift of its circadian rhythm, and loss of physiological complexity in its secretion: clinical implications.
Major depressive disorder (MDD) is associated with increased risk for premature coronary heart disease and bone loss. Single time measurements of plasma IL-6, a good predictor of future risk for both cardiovascular disease and osteoporosis, revealed significant elevations in depressed patients. The objective of this study was to rigorously compare plasma IL-6 levels, measured over 24 h, in MDD patients and healthy controls. Given the activating role of IL-6 on the hypothalamic-pituitary-adrenal (HPA) axis, and the relevance of its dysregulation in MDD, we also analyzed the relations between IL-6 and cortisol levels. We studied nine patients and nine controls, individually matched by gender, age (+/-5 yr), body mass index (+/-2 kg/m2), and menstrual cycle phase. Diagnosis of MDD was confirmed by structured clinical interview based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Axis I diagnostic criteria. Self-reported mood ratings were assessed by multiple visual analog scales. The rhythmicity and complexity of IL-6 and cortisol secretion were tested by cosinor analyses, approximate entropy (ApEn) and cross-ApEn algorithms. MDD patients had significant mean IL-6 elevations from 1000-1200 h and at 1500 h (P ranging from <0.05 to <0.01) vs. controls. In addition, in MDD, the circadian rhythm of IL-6 was shifted by 12 h, and its physiological complexity was reduced, with no difference in the cross-ApEn of IL-6 and cortisol between the two groups, and significant time-lagged correlations only in the controls. IL-6 levels correlated significantly with mood ratings. We report profound morning elevations of plasma IL-6 and a reversal of its circadian rhythm in MDD patients, in the absence of hypercortisolism. These findings may be relevant to the increased risk for coronary heart disease and bone loss in MDD.


Perianal Paget's disease: distinguishing primary and secondary lesions using immunohistochemical studies including gross cystic disease fluid protein-15 and cytokeratin 20 expression.
Extramammary Paget's disease most commonly occurs on the female external genitalia and rarely occurs in the perianal region and male external genitalia. We present the clinical and pathologic features of 5 cases of perianal Paget's disease and review the literature. Clinical and pathologic data were recorded for 5 cases of perianal Paget's disease. Cases were studied retrospectively with special stains, including periodic acid-Schiff, mucicarmine, Alcian blue, carcinoembryonic antigen, S100 protein, pan-keratin, gross cystic disease fluid protein-15 (GCDFP-15), lysozyme, CD15 (Leu-M1), cytokeratin 7 (CK7), and cytokeratin 20 (CK20). Three (60%) of 5 patients had concurrent rectal adenocarcinomas. All cases reacted positively for pankeratin, although the intensity and distribution of staining varied. Both cases not associated with an underlying carcinoma showed strong GCDFP-15 and CK7 expression and an absence of CK20 expression. The 3 cases associated with an underlying malignancy demonstrated CK7 and CK20 expression and an absence of GCDFP-15 expression. All cases were negative for lysozyme and CD15 (Leu-M1). The 5 cases reported herein demonstrate that perianal Paget's disease is a heterogeneous entity. The high frequency of associated underlying malignancies and resultant poor clinical outcomes highlight the importance of an aggressive search for a second malignancy. In some cases, perianal Paget's disease merely represents a cutaneous manifestation of an underlying rectal adenocarcinoma and demonstrates a CK7+/CK20+/GCDFP-15-/lysozyme-/Leu-M1- immunophenotype and signet ring Paget's cells. Other cases represent primary adenocarcinomas of the skin, which are associated with a CK7+/CK20-/GCDFP-15+/lysozyme /Leu-M1- immunophenotype and an excellent prognosis if adequately resected. Immunohistochemical studies, particularly CK20 and GCDFP-15, are useful adjuncts in distinguishing primary and secondary perianal Paget's disease.


Stem cell transplantation in pediatric leukemia and myelodysplasia: state of the art and current challenges.
The role of stem cell transplantation in the treatment of leukemia and myelodysplasia (MDS) in children has changed over the past decade. In pediatric acute lymphoblastic leukemia (ALL), the overall cure-rate is high with conventional chemotherapy. However, selected patients with a high-risk of relapse are often treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in first remission (CR1). Patients with a bone-marrow relapse who attain a second remission frequently receive HSCT. High minimal residual disease (MRD) levels directly prior to HSCT determines the relapse risk. Therefore, MRD positive patients are eligible for more experimental approaches such as intensified or experimental chemotherapy pre-HSCT, as well as immune modulation post-HSCT. In pediatric acute myeloid leukemia (AML) the role of allo-HSCT in CR1 is declining, due to better outcome with modern multi-agent chemotherapy. In relapsed AML patients, allo-HSCT still seems indispensable. Targeted therapy may change the role of HSCT, in particular in chronic myeloid leukemia, where the role of allografting is changing in the imatinib era. In MDS, patients are usually transplanted immediately without prior cytoreduction. New developments in HSCT, such as the role of alternative conditioning regimens, and innovative stem cell sources such as peripheral blood and cord blood, will also be addressed.


Incorporating Diversity, Equity, And Inclusion Content Into Bioengineering Curricula: A Program-Level Approach.
Diversity, equity, and inclusion (DEI) are interconnected with bioengineering, yet have historically been absent from accreditation standards and curricula. Toward educating DEI-competent bioengineers and meeting evolving accreditation requirements, we took a program-level approach to incorporate, catalog, and assess DEI content through the bioengineering undergraduate program. To support instructors in adding DEI content and inclusive pedagogy, our team developed a DEI planning worksheet and surveyed instructors pre- and post-course. Over the academic year, 74% of instructors responded. Of responding instructors, 91% described at least one DEI curricular content improvement, and 88% incorporated at least one new inclusive pedagogical approach. Based on the curricular adjustments reported by instructors, we grouped the bioengineering-related DEI content into five DEI competency categories: bioethics, inclusive design, inclusive scholarship, inclusive professionalism, and systemic inequality. To assess the DEI content incorporation, we employed direct assessment via course assignments, end-of-module student surveys, end-of-term course evaluations, and an end-of-year program review. When asked how much their experience in the program helped them develop specific DEI competencies, students reported a relatively high average of 3.79 (scale of 1 = "not at all" to 5 = "very much"). Additionally, based on student performance in course assignments and other student feedback, we found that instructors were able to effectively incorporate DEI content into a wide variety of courses. We offer this framework and lessons learned to be adopted by programs similarly motivated to train DEI-competent engineering professionals and provide an equitable, inclusive education.


Prevalence of acute respiratory infections in women and children in Western Sierra Leone due to smoke from wood and charcoal stoves.
Combustion of biomass fuels (wood and charcoal) for cooking releases smoke that contains health damaging pollutants. Women and children are the most affected. Exposure to biomass smoke is associated with acute respiratory infections (ARI). This study investigated the prevalence of ARI potentially caused by smoke from wood and charcoal stoves in Western Sierra Leone, as these two fuels are the predominant fuel types used for cooking. A cross sectional study was conducted for 520 women age 15-45 years; and 520 children under 5 years of age in homes that burn wood and charcoal. A questionnaire assessing demographic, household and exposure characteristics and ARI was administered to every woman who further gave information for the child. Suspended particulate matter (SPM) was continuously monitored in fifteen homes. ARI prevalence revealed 32% and 24% for women, 64% and 44% for children in homes with wood and charcoal stoves, respectively. After adjusting for potential confounders for each group, the odds ratio of having suffered from ARI was similar for women, but remained large for children in homes with wood stoves relative to charcoal stoves (OR = 1.14, 95%CI: 0.71-1.82) and (OR = 2.03, 95%CI: 1.31-3.13), respectively. ARI prevalence was higher for children in homes with wood stoves compared with homes with charcoal stoves, but ARI prevalence for both types of fuels is higher compared with reported prevalence elsewhere. To achieve a reduction in ARI would require switching from wood and charcoal to cleaner fuels.


Confidence intervals for cost-effectiveness ratios: an application of Fieller's theorem.
Application of cost-effectiveness analysis (CEA) is growing rapidly in health care. Two general approaches to analysis are differentiated by the type of data available: (i) deterministic models based upon secondary analysis of retrospective data from one or more trials and other sources; and (ii) stochastic analyses in which the design of a randomized controlled trial is adapted to collect prospectively patient-specific data on costs and effectiveness. An important methodological difference between these two approaches is in how uncertainty is handled. Deterministic CEA models typically rely upon sensitivity analysis to determine the robustness of findings to alternative assumptions, whereas stochastic (CEA) analysis, as part of prospective studies, permits the use of conventional statistical methods on the cost and effectiveness data for both inference (hypothesis testing) and estimation. This paper presents a procedure for the statistical analysis of cost-effectiveness data, with specific application to those studies for which effectiveness is measured as a binary outcome. Specifically, Fieller's Theorem was used to calculate confidence intervals for ratios of the two random variables of between-treatment differences in observed costs and effectiveness, i.e. the incremental cost-effectiveness ratio.


Excitation and ionisation cross-sections in condensed-phase biomaterials by electrons down to very low energy: application to liquid water and genetic building blocks.
Electronic excitations and ionisations produced by electron impact are key processes in the radiation-induced damage mechanisms in materials of biological relevance, underlying important medical and technological applications, including radiotherapy, radiation protection in manned space missions and nanodevice fabrication techniques. However, experimentally measuring all the necessary electronic interaction cross-sections for every relevant material is an arduous task, so it is necessary having predictive models, sufficiently accurate yet easily implementable. In this work we present a model, based on the dielectric formalism, to provide reliable ionisation and excitation cross-sections for electron-impact on complex biomolecular media, considering their condensed-phase nature. We account for the indistinguishability and exchange between the primary beam and excited electrons, for the molecular electronic structure effects in the electron binding, as well as for low-energy corrections to the first Born approximation. The resulting approach yields total ionisation cross-sections, energy distributions of secondary electrons, and total electronic excitation cross-sections for condensed-phase biomaterials, once the electronic excitation spectrum is known, either from experiments or from a predictive model. The results of this methodology are compared with the available experimental data in water and DNA/RNA molecular building blocks, showing a very good agreement and a great predictive power in a wide range of electron incident energies, from the large values characteristic of electron beams down to excitation threshold. The proposed model constitutes a very useful procedure for computing the electronic interaction cross-sections for arbitrary biological materials in a wide range of electron incident energies.


Evaluating the venous experience in vascular surgery training.
There is an increasing recognition and treatment of venous disease in the United States; results of the Society for Vascular Surgery 2014 membership survey showed that venous disease represents 18.8% of a vascular surgeon's current practice. Despite this, there are no operative objectives or case requirements specific to venous disease for vascular surgery trainees. The objective of this study was to examine the current venous surgical training experience of graduating vascular surgery trainees. Following Institutional Review Board waiver and Association of Program Directors in Vascular Surgery and Residency Review Committee approval, results of the 2014 Association of Program Directors in Vascular Surgery Educational Needs Assessment Survey pertinent to venous training as well as the Vascular Surgery In-Training Examination (VSITE) venous scores were summarized. Using the Residency Review Committee case log database, venous case logs of 0/5 resident and 5/2 fellow vascular surgery graduates from 2012 to 2015 differentiated by Current Procedural Technology code were summarized. Venous case logs of 0/5 vascular surgery residents were compared with those of 5/2 fellows using a Student t-test, with results considered statistically significant at P < .05. Of the recent vascular surgery graduates, 15% thought they encountered training gaps in venous procedures; 54% thought this was due to a gap in vascular surgery training, whereas 43% thought this was due to evolution in technology. Venous VSITE scores were similar between 0/5 residents and 5/2 fellows (69% vs 76% correct answers, respectively), as were overall VSITE scores (70% vs 74% correct answers, respectively). The 0/5 residents completed between 11 and 264 cases and 5/2 fellows completed between 1 and 188 cases during their training. The 0/5 residents' venous cases were 8.1% of overall cases and the 5/2 fellows' cases were 4.3% of overall cases during their training. Current vascular surgery trainee experience is highly variable and not consistent with future vascular surgery clinical practice. Vascular surgery trainee fund of knowledge does not appear affected. Program directors should consider developing a better-defined venous curriculum that includes venous case minimums in defined categories.


[Effect of different storage methods on the viability of Halobacterium salinarum].
It has been established that the studied halobacteria are cryolabile and sensitive to the sharp change in osmotic pressure of the environment. Optimal temperature of their storage is +20 degrees C for suspension of native cells and +4 degrees C for the cells in anabiotic state. Their storage medium should have optimal osmotic pressure and contain NaCl and K+, Mg+ ions. It is recommended to keep halobacteria during one year in a form of suspension in nutrient medium, and during at least 4 years in lyophilized state. Other long-term storage methods: L-drying, freezing at low temperatures, are not recommended for halobacteria.


[Evaluation of nutritional recovery pattern of malnourished children examined at the center of Recovery and Educational Nutrition, Brazil].
To assess the pattern of nutritional recovery in malnourished children. This prospective analysis was conducted between September 1995 and November 1996 at the Center for Recovery and Nutrition Education (CREN) in São Paulo, Brazil. Of the thirty-eight children studied, 47.4% were infants (nine girls and nine boys) and 52.6% preschool children (twelve boys and eight girls). Thirty eight children were studied by velocity of W/A and H/A gain in standard deviation or Z score, according to weight and height median of NCHS. There was a statistically significant increase in the weight-for-age (W/A)(p = 0.012), height-for-age (H/A) (p = 0.001) from the time of admission. The difference in the velocity of W/A gain between infants (0.299-Z/year) and preschool children (0.684-Z/year) with more than six months of treatment, was found to be statistically significant (p = 0.038). The difference in the velocity of H/A gain for infants (0.794-Z/year) and for preschool children (0.506-Z/year), was not statistically significant (p = 0.166). In regards to gender, there was not a statistically significant difference between boys and girls in the velocity of W/A gain (0.540 and 0.524-Z/year, respectively). The difference in velocity of H/A gain was statistically significant, 0.485-Z/year for boys and 0.856-Z/year for girls (p = 0.043). These findings show that there are differences in the nutritional recovery patterns between gender and age groups.


The phenotypic and transcriptomic effects of developmental exposure to nanomolar levels of estrone and bisphenol A in zebrafish.
Estrone and BPA are two endocrine disrupting chemicals (EDCs) that are predicted to be less potent than estrogens such as 17β-estradiol and 17α-ethinylestradiol. Human exposure concentrations to estrone and BPA can be as low as nanomolar levels. However, very few toxicological studies have focused on the nanomolar-dose effects. Low level of EDCs can potentially cause non-monotonic responses. In addition, exposures at different developmental stages can lead to different health outcomes. To identify the nanomolar-dose effects of estrone and BPA, we used zebrafish modeling to study the phenotypic and transcriptomic responses after extended duration exposure from 0 to 5 days post-fertilization (dpf) and short-term exposure at days 4-5 post fertilization. We found that non-monotonic transcriptomic responses occurred after extended duration exposures at 1 nM of estrone or BPA. At this level, estrone also caused hypoactivity locomotive behavior in zebrafish. After both extended duration and short-term exposures, BPA led to more apparent phenotypic responses, i.e. skeletal abnormalities and locomotion changes, and more significant transcriptomic responses than estrone exposure. After short-term exposure, BPA at concentrations equal or above 100 nM affected locomotive behavior and changed the expression of both estrogenic and non-estrogenic genes that are linked to neurological diseases. These data provide gaps of mechanisms between neurological genes expression and associated phenotypic response due to estrone or BPA exposures. This study also provides insights for assessing the acceptable concentration of BPA and estrone in aquatic environments.


Antidiabetic and antiulcer effects of extract of Eugenia jambolana seed in mild diabetic rats: study on gastric mucosal offensive acid-pepsin secretion.
Diabetes has been reported to increase propensity to peptic ulceration through its effect both on offensive and defensive mucosal factors. Seeds of Eugenia jambolana (EJ) have been reported to have both antidiabetic as well as ulcer protective effects. The present study evaluates the antidiabetic effects of ethanolic extract of dried seed kernel of Eugenia jambolana (EJE) and its comparative effect on gastric ulceration and acid-pepsin secretion with standard antisecretory FL-blocker. Ranitidine and antidiabetic glibenclamide with a premise that Eugenia jambolana may show better ulcer healing effects by promoting defensive or reducing offensive mucosal factors in mild diabetes (MD) rats. MD was produced in adult rats by administration of streptozotocin (45 mg/kg, ip). EJE was given orally in the doses of 100-400 mg/kg for 10 days and in the dose of 200 mg/kg for 30 days respectively to study its dose- and time-dependent effects on various diabetic parameters like blood glucose, serum cholesterol and triglycerides, insulin level and glycosylated hemoglobin. For ulcer protective and gastric secretion studies, EJE (200 mg/kg) was given orally for 10 days against 2 h cold restraint stress (CRS)-, 4 h pylorus ligation (PL), aspirin (ASP, 200 mg/kg, 4 h)--and 95% ethanol (EtOH, 1 ml/200 g, 1 h)-induced gastric ulcers and offensive acid-pepsin secretion after 4 h PL with co-occurring MD in rats. EJE showed dose-dependent decrease in blood glucose level in MD rats. Blood glucose level remained stable in mild diabetic rats from 3rd day onwards after streptozotocin administration (taken as 1st day for treatment) and EJE (200 mg/kg) showed anti-hyperglycemic effect on 10th day of its administration. Further, EJE in the above dose also decreased cholesterol level with little or no effect on triglycerides level and reversed the decrease and increase in insulin and glycosylated hemoglobin level near to the normal level as observed alter 30 days treatment in MD rats. MD rats exhibited an increased propensity to gastric ulceration induced by CRS, ASP, EtOH and PL and caused increase in acid-pepsin secretion. EJE was not only effective in reversing the increased propensity to ulceration in diabetic rats but also decreased the acid-pepsin output better than glibenclamide. The ulcer protective effect of Eugenia jambolana seems to be due to its antidiabetic and gastric antisecretory effects.


Multiplex microsphere-based flow cytometric platforms for protein analysis and their application in clinical proteomics - from assays to results.
Advances in high-throughput screening, together with rapid progress in genomic and proteomic sciences, have considerably stimulated the development of a variety of biomarker discovery tools and have contributed to the improvement of clinical diagnosis. Major challenges include the obtaining of high-quality data sets based on assays that are rapid, reliable, and inexpensive, but still highly sensitive and easy to perform. The microsphere-based flow cytometric technology is a platform that is currently entering the diagnostic market. This article reviews the development and the applications of microsphere-based flow cytometric platforms in basic and applied proteomic research, and discusses bead-based assays used in clinical applications.


Members of the RSC chromatin-remodeling complex are required for maintaining proper nuclear envelope structure and pore complex localization.
The assembly, distribution, and functional integrity of nuclear pore complexes (NPCs) in the nuclear envelope (NE) are key determinants in the nuclear periphery architecture. However, the mechanisms controlling proper NPC and NE structure are not fully defined. We used two different genetic screening approaches to identify Saccharomyces cerevisiae mutants with defects in NPC localization. The first approach examined green fluorescent protein (GFP)-Nic96 in 531 strains from the yeast Tet-promoters Hughes Collection with individual essential genes expressed from a doxycycline-regulated promoter (TetO(7)-orf). Under repressive conditions, depletion of the protein encoded by 44 TetO(7)-orf strains resulted in mislocalized GFP-Nic96. These included STH1, RSC4, RSC8, RSC9, RSC58, ARP7, and ARP9, each encoding components of the RSC chromatin remodeling complex. Second, a temperature-sensitive sth1-F793S (npa18-1) mutant was identified in an independent genetic screen for NPC assembly (npa) mutants. NPC mislocalization in the RSC mutants required new protein synthesis and ongoing transcription, confirming that lack of global transcription did not underlie the phenotypes. Electron microscopy studies showed significantly altered NEs and nuclear morphology, with coincident cytoplasmic membrane sheet accumulation. Strikingly, increasing membrane fluidity with benzyl alcohol treatment prevented the sth1-F793S NE structural defects and NPC mislocalization. We speculate that NE structure is functionally linked to proper chromatin architecture.


Correlated coding of motivation and outcome of decision by dopamine neurons.
We recorded the activity of midbrain dopamine neurons in an instrumental conditioning task in which monkeys made a series of behavioral decisions on the basis of distinct reward expectations. Dopamine neurons responded to the first visual cue that appeared in each trial [conditioned stimulus (CS)] through which monkeys initiated trial for decision while expecting trial-specific reward probability and volume. The magnitude of neuronal responses to the CS was approximately proportional to reward expectations but with considerable discrepancy. In contrast, CS responses appear to represent motivational properties, because their magnitude at trials with identical reward expectation had significant negative correlation with reaction times of the animal after the CS. Dopamine neurons also responded to reinforcers that occurred after behavioral decisions, and the responses precisely encoded positive and negative reward expectation errors (REEs). The gain of coding REEs by spike frequency increased during learning act-outcome contingencies through a few months of task training, whereas coding of motivational properties remained consistent during the learning. We found that the magnitude of CS responses was positively correlated with that of reinforcers, suggesting a modulation of the effectiveness of REEs as a teaching signal by motivation. For instance, rate of learning could be faster when animals are motivated, whereas it could be slower when less motivated, even at identical REEs. Therefore, the dual correlated coding of motivation and REEs suggested the involvement of the dopamine system, both in reinforcement in more elaborate ways than currently proposed and in motivational function in reward-based decision-making and learning.


Oxidized fatty acids: A potential pathogenic link between fatty liver and type 2 diabetes in obese adolescents?
In this study, we sought to investigate the putative association of the oxidized metabolites derived from linoleic acid (OXFAs) with pediatric nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). We studied 80 obese adolescents (age 13.3 ± 3.31 years; body mass index 33.0 ± 6.79 kg/m(2)), who underwent an oral glucose tolerance test, a magnetic resonance imaging (MRI) to measure the hepatic fat content, and the measurement of OXFAs and caspase-cleaved Citokeratin18 fragment (CK-18), a robust biomarker of liver injury. In this study, we show that only in subjects with hepatic steatosis, the OXFAs are associated with the CK-18 and that this association is modulated by the PNPLA3 rs738409 variant. We also show that most of the OXFAs are associated with a lower insulin secretion and that adolescents with T2D have higher levels of OXFAs than subjects with impaired or normal glucose tolerance. These observations lead to the hypothesis that the OXFAs may be the pathogenic link between liver injury and T2D and that the novel therapeutic opportunities targeting the OXFAs are possible in adolescents with early-onset NAFLD and T2D.


Effects of porosity on drug release kinetics of swellable and erodible porous pharmaceutical solid dosage forms fabricated by hot melt droplet deposition 3D printing.
3D printing has the unique ability to produce porous pharmaceutical solid dosage forms on-demand. Although using porosity to alter drug release kinetics has been proposed in the literature, the effects of porosity on the swellable and erodible porous solid dosage forms have not been explored. This study used a model formulation containing hypromellose acetate succinate (HPMCAS), polyethylene oxide (PEO) and paracetamol and a newly developed hot melt droplet deposition 3D printing method, Arburg plastic free-forming (APF), to examine the porosity effects on in vitro drug release. This is the first study reporting the use of APF on 3D printing porous pharmaceutical tablets. With the unique pellet feeding mechanism of APF, it is important to explore its potential applications in pharmaceutical additive manufacturing. The pores were created by altering the infill percentages (%) of the APF printing between 20 and 100% to generate porous tablets. The printing quality of these porous tablets was examined. The APF printed formulation swelled in pH 1.2 HCl and eroded in pH 6.8 PBS. During the dissolution at pH 1.2, the swelling of the printing pathway led to the gradual decreases in the open pore area and complete closure of pores for the tablets with high infills. In pH 6.8 buffer media, the direct correlation between drug release rate and infills was observed for the tablets printed with infill at and less than 60%. The results revealed that drug release kinetics were controlled by the complex interplay of the porosity and dynamic changes of the tablets caused by swelling and erosion. It also implied the potential impact of fluid hydrodynamics on the in vitro data collection and interpretation of porous solids.


Arabidopsis WD repeat domain55 Interacts with DNA damaged binding protein1 and is required for apical patterning in the embryo.
CUL4-RING ubiquitin E3 ligases (CRL4s) were recently shown to exert their specificity through the binding of various substrate receptors, which bind the CUL4 interactor DNA damaged binding protein1 (DDB1) through a WDxR motif. In a segregation-based mutagenesis screen, we identified a WDxR motif-containing protein (WDR55) required for male and female gametogenesis and seed development. We demonstrate that WDR55 physically interacts with Arabidopsis thaliana DDB1A in planta, suggesting that WDR55 may be a novel substrate recruiter of CRL4 complexes. Examination of mutants revealed a failure in the fusion of the polar cells in embryo sac development, in addition to embryo and endosperm developmental arrest at various stages ranging from the zygote stage to the globular stage. wdr55-2 embryos suggest a defect in the transition to bilateral symmetry in the apical embryo domain, further supported by aberrant apical embryo localization of DORNROESCHEN, a direct target of the auxin response factor protein monopteros. Moreover, the auxin response pattern, as determined using the synthetic auxin-responsive reporter ProDR5:green fluorescent protein, was shifted in the basal embryo and suspensor but does not support a strong direct link to auxin response. Interestingly, the observed embryo and endosperm phenotype is reminiscent of CUL4 or DDB1A/B loss of function and thus may support a regulatory role of a putative CRL4(WDR55) E3 ligase complex.


Some current factors influencing the prescribing and use of psychiatric drugs.
A reprise of selected known factors about the influences affecting the prescribing and use of drugs, and some new developments in the drug marketplace, are the basis for this summary and observations about future expectations regarding psychotherapeutic agents. This information can be used to assist in formulating or updating, or both, conceptualizations and hypotheses for future policy and research planning in this area.


[The isolated living hair cell. A new model for the study of hearing function].
Living, predominantly outer hair cells were prepared from the guinea pig cochlea using a non-enzymatic, microsurgical approach. Viability of hair cells was demonstrated by dye-exclusion as well as by electrophysiogical patch-damp procedures. This allowed to measure a mammalian hair cell potential of -70 mV under direct visualisation. Furthermore, hair cells could be kept under cell culture conditions for 6-9 hrs. Isolated, mammalian cochlea hair cells are a new, useful model to investigate the molecular basis of hearing and hearing disorders located in sensory cells. As example this report shows experimental approaches to analyse membraneous and cytoplasmic functions of hair cells.


Lung cancer risk to personalise annual and biennial follow-up computed tomography screening.
All lung cancer CT screening trials used fixed follow-up intervals, which may not be optimal. We developed new lung cancer risk models for personalising screening intervals to 1 year or 2 years, and compared these with existing models. We included participants in the CT arm of the National Lung Screening Trial (2002-2010) who underwent a baseline scan and a first annual follow-up scan and were not diagnosed with lung cancer in the first year. True and false positives and the area under the curve of each model were calculated. Internal validation was performed using bootstrapping. Data from 24 542 participants were included in the analysis. The accuracy was 0.785, 0.693, 0.697, 0.666 and 0.727 for the polynomial, patient characteristics, diameter, Patz and PanCan models, respectively. Of the 24 542 participants included, 174 (0.71%) were diagnosed with lung cancer between the first and the second annual follow-ups. Using the polynomial model, 2558 (10.4%, 95% CI 10.0% to 10.8%), 7544 (30.7%, 30.2% to 31.3%), 10 947 (44.6%, 44.0% to 45.2%), 16 710 (68.1%, 67.5% to 68.7%) and 20 023 (81.6%, 81.1% to 92.1%) of the 24 368 participants who did not develop lung cancer in the year following the first follow-up screening round could have safely skipped it, at the expense of delayed diagnosis of 0 (0.0%, 0.0% to 2.7%), 8 (4.6%, 2.2% to 9.2%), 17 (9.8%, 6.0% to 15.4%), 44 (25.3%, 19.2% to 32.5%) and 70 (40.2%, 33.0% to 47.9%) of the 174 lung cancers, respectively. The polynomial model, using both patient characteristics and baseline scan morphology, was significantly superior in assigning participants to 1-year or 2-year screening intervals. Implementing personalised follow-up intervals would enable hundreds of participants to skip a screening round per lung cancer diagnosis delayed.


Virulence gene- and pandemic group-specific marker profiling of clinical Vibrio parahaemolyticus isolates.
Vibrio parahaemolyticus is a halophilic bacterium capable of causing food- and waterborne gastroenteritis, wound infections, and septicemia in humans. The organism has recently received increasing attention, as the emergence of a new clone, V. parahaemolyticus O3:K6, has resulted in the first documented pandemic spread of V. parahaemolyticus. We used microarray analyses to explore the presence of known virulence factors and genetic markers thought to be specific for V. parahaemolyticus O3:K6 and its clonal derivatives. Analyses of 48 human clinical isolates collected between 1997 and 2005 revealed that the V. parahaemolyticus chromosome 2 type III secretion system is not specifically associated with pandemic strains and can be found in tdh-negative (i.e., Kanagawa-negative) clinical isolates. These results highlight the genetic dynamism of V. parahaemolyticus and aid in refining the genetic definition of the pandemic group members.


Effect of streptozotocin in a case of glucagon-secreting malignant islets-cell tumor.
A case of a 65-year-old woman with a pancreatic tumor secreting insulin, glucagon, and associated with high PTH levels and hypercalcemia is reported. The patient underwent two Streptozotocin (STZ) treatments (1 g iv/week for 10 weeks) after liver metastases were found. Hormonal and metabolic parameters were monitorized . Before the first STZ treatment insulin levels ranged between 78 and 132 microU/ml. After STZ administration insulin decreased and then remained lower (8-48 microU/ml) until the death of the patient. Pre-treatment glucagon levels ranged between 1.3 and 3.9 ng/ml. STZ induced a decrease of glucagon to 0.5 ng/ml. Glucagon chromatography revealed the prevalence of high molecular weight (greater than 6,000 mol wt) immunoreactive glucagon (0.9 ng/ml) drastically reduced by STZ treatment (0.15 ng/ml). Hypoaminoacidemia was observed before STZ administration, but at the end of the therapy plasma amino acid concentrations were normal. Hypercalcemia too was sensitive to STZ, but not PTH value, which remained high. The second STZ treatment performed a year later was less effective and so a chemotherapeutic protocol was started. Our findings suggest a cytolitic effect of STZ on malignant A-cell, with reduction of glucagon levels and restoration of amino acid metabolism. This effect would be useful for medical treatment of non-operable glucagon secreting tumors.


Ethical issues in umbilical cord blood banking: a comparative analysis of documents from national and international institutions.
The issues of collection, storage, and use of cord blood (CB) stem cells have been addressed extensively in national and international guidelines, policies, and regulations. Many of these documents are not binding, but are nonetheless accorded considerable respect on account of the authority of the issuing organizations. Most discussion has to date focused on two topics: informed consent for collection, banking, and use and the debate between those who favor public storage for altruistic purposes and those who advocate private storage for autologous use. There is generally agreement or consensus in the guidelines that public storage for allogeneic transplants is preferable and that private storage should be discouraged. Given the consensus in national and international guidance on these two issues, it is time for other ethical issues to be examined in greater detail. These include additional uses of CB samples, for example, for research or for the production of blood-derived drugs, and the economic implications arising from the extensive international network for the exchange of CB for transplantation.


What does more time buy you? Another look at the effects of long-term residence on production accuracy of English /inverted r/ and /l/ by Japanese speakers.
This study tested the issue of whether extended length of residence (LOR) in adulthood can provide sufficient input to overcome age effects. The study replicates Flege, Takagi, and Mann (1995), which found that 10 out of 12 Japanese learners of English with extensive residence (12 years or more) produced liquids as accurately as native speakers of English (NS). Further, for both accuracy and native-like accentedness, the Japanese with extensive residence performed statistically better as a group than inexperienced Japanese (less than 3 years of residence). Results with a new sample of Japanese learners in this study found no statistical difference between the Japanese groups with extended versus short LOR although both reported equal levels of daily input in English. Additionally, both groups received statistically lower scores than NS. Moreover, LOR affected the two groups differently: The accuracy and native-like accentedness of words and sentences by Japanese with extensive residence declined with LOR (and chronological age when age of arrival was partialled out), while for Japanese with short residence accent improved with increased LOR (but not age). This study is the first to document a decline in second language production ability with LOR and age in older second language learners. However, this finding deserves to be addressed with further research, as the study was not designed to investigate this question and thus not all relevant factors, such as motivation or attitude, were controlled for. The results from the short-residence learners indicate that the initial one to two years of immersion may be the most important for improving phonological ability.


Epiphysiolysis of the proximal femur in very young children.
In 14 hips in 11 children under 3 years of age, proximal femoral epiphysiolysis occurred from varying degrees of trauma. The vulnerability of the blood supply of the upper femoral epiphysis, and its important weight-bearing function, demands early diagnosis, reduction, and adequate fixation. The nature of the injury, however, determines the eventual outcome. Early diagnosis and investigation of the underlying pathology is necessary to avoid such complications as varus deformity, avascular necrosis, heterotopic new bone formation, non-union, and premature closure of the growth plate.


Body temperature and resistance to evaporative water loss in tropical Australian frogs.
Although the skin of most amphibians measured to date offers no resistance to evaporative water loss (EWL), some species, primarily arboreal frogs, produce skin secretions that increase resistance to EWL. At high air temperatures, it may be advantageous for amphibians to increase EWL as a means to decrease body temperature. In Australian hylid frogs, most species do not decrease their resistance at high air temperature, but some species with moderate resistance (at moderate air temperatures) gradually decrease resistance with increasing air temperature, and some species with high resistance (at moderate air temperatures) abruptly decrease resistance at high air temperatures. Lower skin resistance at high air temperatures decreases the time to desiccation, but the lower body temperatures allow the species to avoid their critical thermal maximum (CT(Max)) body temperatures. The body temperatures of species with low to moderate resistances to EWL that do not adjust resistance at high air temperatures do not warm to their CT(Max), although for some species, this is because they have high CT(Max) values. As has been reported previously for resistance to EWL generally, the response pattern of change of EWL at high air temperatures has apparently evolved independently among Australian hylids. The mechanisms involved in causing resistance and changes in resistance are unknown.


Local Berry curvature signatures in dichroic angle-resolved photoelectron spectroscopy from two-dimensional materials.
Topologically nontrivial two-dimensional materials hold great promise for next-generation optoelectronic applications. However, measuring the Hall or spin-Hall response is often a challenge and practically limited to the ground state. An experimental technique for tracing the topological character in a differential fashion would provide useful insights. In this work, we show that circular dichroism angle-resolved photoelectron spectroscopy provides a powerful tool that can resolve the topological and quantum-geometrical character in momentum space. In particular, we investigate how to map out the signatures of the momentum-resolved Berry curvature in two-dimensional materials by exploiting its intimate connection to the orbital polarization. A spin-resolved detection of the photoelectrons allows one to extend the approach to spin-Chern insulators. The present proposal can be extended to address topological properties in materials out of equilibrium in a time-resolved fashion.


Merrihueite, A New Alkali-Ferromagnesian Silicate from the Mezo-Madaras Chondrite.
Merrihueite, a new mineral with the approximate chemical composition (K,Na)(2)(Fe,Mg)(5)Si(12)O(30), occurs with iron-rich olivine, iron-poor pyroxene, and nickel-iron in a few chondrules of the Mezö-Madaras chondrite. The refractive index lies between 1.559 and 1.592; the birefringence for each composition is low to moderate. X-ray powder data for merrihueite are nearly identical to those for osumilite, (K,Na,Ca)(Mg,Fe)(2)(Al,Fe)(3)(Si,Al)(12)O(30)-H(2)O, and very similar to those for synthetic K(2)Mg(5) Si(12) O(30). Merrihueite is interpreted as an alkali-ferromagnesian silicate mineral of the osumilite type. It is named in honor of the late Craig M. Merrihue, meteoriticist, of the Smithsonian Astrophysical Observatory.


Polymeric microspheres for the sustained release of a protein-based drug carrier targeting the PDGFβ-receptor in the fibrotic kidney.
Injectable sustained release drug delivery systems are an attractive alternative for the intravenous delivery of therapeutic proteins. In particular, for chronic diseases such as fibrosis, this approach could improve therapy by reducing the administration frequency while avoiding large variations in plasma levels. In fibrotic tissues the platelet-derived growth factor receptor beta (PDGFβR) is highly upregulated, which provides a target for site-specific delivery of drugs. Our aim was to develop an injectable sustained release formulation for the subcutaneous delivery of the PDGFβR-targeted drug carrier protein pPB-HSA, which is composed of multiple PDGFβR-recognizing moieties (pPB) attached to human serum albumin (HSA). We used blends of biodegradable multi-block copolymers with different swelling degree to optimize the release rate using the model protein HSA from microspheres produced via a water-in-oil-in-water double emulsion evaporation process. The optimized formulation containing pPB-HSA, showed complete release in vitro within 14days. After subcutaneous administration to mice suffering from renal fibrosis pPB-HSA was released from the microspheres and distributed into plasma for at least 7days after administration. Furthermore, we demonstrated an enhanced accumulation of pPB-HSA in the fibrotic kidney. Altogether, we show that subcutaneously administered polymeric microspheres present a suitable sustained release drug delivery system for the controlled systemic delivery for proteins such as pPB-HSA.


The Dependence of Running Speed and Muscle Strength on the Serum Concentration of Vitamin D in Young Male Professional Football Players Residing in the Russian Federation.
Background: Vitamin D insufficiency is prevalent among athletes, and it can negatively affect physical performance. At the same time, most of the available data were obtained from untrained individuals of various ages, and published studies performed in athletes led to contradictory conclusions. Methods: This cohort prospective study examined the serum concentration of 25-hydroxycalciferol (25(OH)D) and its association with running speed and muscle power in 131 young football players (mean age 15.6 ± 2.4 years). Results: 25(OH)D levels were below reference in 42.8% (serum 25(OH)D <30 ng/mL) and above reference in 30.5% of the participants (serum 25(OH)D 61-130 ng/mL). A comparison of the results of 5, 15, and 30 m sprint tests and the standing long jump test found no statistically significant differences between the two groups. Athletes from the 25(OH)D-insufficient group were treated with 5000 IU cholecalciferol supplement daily for 60 days. After the treatment, the 25(OH)D concentration increased by 79.2% and was within reference in 84% of the treated athletes (serum 25(OH)D 30-60 ng/mL). Testing was repeated after the end of treatment, and a statistically significant increase in the results of the 5, 15, and 30 m sprint tests was observed (Cohen's d was 0.46, 0.33, and 0.34, respectively), while the results of the standing long jump test remained unchanged. Body height, body weight, and lean body mass of the football players also increased. Conclusions: These findings indicate that there is likely no correlation between serum levels of 25(OH)D, muscle power, and running speed in young professional football players, and the changes observed post-treatment might have been caused by changes in the anthropometric parameters. During the study, all the anthropometric parameters changed, but the amount of lean body mass only correlated with the results of the 5 m sprint.


Solubilization and purification of rat liver 5'-nucleotidase by use of a zwitterionic detergent and a monoclonal-antibody immunoadsorbent.
1. A variety of detergents were used to solubilize 5'-nucleotidase from rat liver plasma membranes. 2. The zwitterionic detergent Sulphobetaine 14 gave optimal solubilization by the criteria of release into a high-speed-centrifugation supernatant and the formation of the smallest and least polydisperse active enzyme observed on polyacrylamide-gel electrophoresis. 3. The Sulphobetaine 14-solubilized enzyme from rat liver was purified by using the conventional techniques of ion-exchange chromatography and gel filtration, or by an immunoaffinity step with a monoclonal antibody immunoadsorbent. 4. 5'-Nucleotidase was purified at least 12 000-fold relative to liver homogenate by the immunoaffinity purification scheme and had a specific activity in the range 285-340 mumol/min per mg of protein. The yield was in the range 9-16%. 5. The purified enzyme shows a major polypeptide band of apparent Mr 70 000 on sodium dodecyl sulphate/polyacrylamide-gel electrophoresis and a minor band of apparent Mr 38 000. 6. A rational approach to the general problem of the purification of minor intrinsic membrane proteins is discussed, with the use of polyacrylamide-gel electrophoresis to determine the most appropriate detergent and monoclonal antibodies in subsequent immunoaffinity purification.


Nature and variability of human food consumption.
The early human diet was characteristically extremely varied, and a wide range of plant species and plant organs were consumed. Foods of animal origin included those taken opportunistically, such as invertebrates, amphibians, reptiles, small mammals, birds and their eggs, and the scavenging and hunting of larger mammals. Each of these types of food have characteristic nutritional compositions. Comparison of these compositional features shows that an adequate diet could be obtained in many different ways. The selection of food providing fat had substantial advantages in reducing the amount of plant foods to be gathered, in the satiety provided and in supplying essential micronutrients. Obtaining adequate water and energy would probably be the main physiological drives. Many plant foods contain natural toxicants, and would only have been suitable as major items in the diet once cooking had been developed, and the preference for sweet tastes would have protected humans from eating bitter, toxic plants.


The Role of Insulin-Like Growth Factors and Insulin-Like Growth Factor-Binding Proteins in the Nervous System.
The insulin-like growth factors (IGF-I and IGF-II) and their receptors are widely expressed in nervous tissue from early embryonic life. They also cross the blood brain barriers by active transport, and their regulation as endocrine factors therefore differs from other tissues. In brain, IGFs have paracrine and autocrine actions that are modulated by IGF-binding proteins and interact with other growth factor signalling pathways. The IGF system has roles in nervous system development and maintenance. There is substantial evidence for a specific role for this system in some neurodegenerative diseases, and neuroprotective actions make this system an attractive target for new therapeutic approaches. In developing new therapies, interaction with IGF-binding proteins and other growth factor signalling pathways should be considered. This evidence is reviewed, gaps in knowledge are highlighted, and recommendations are made for future research.


The Leeds regional quality control scheme for clinical biochemistry: a progress report.
The results from a regional quality control scheme for clinical biochemistry are analysed. Comparison with results from an earlier period shows that the quality of several of the 15 routine analyses has improved. The methods by which the sera are produced and distributed, and the weekly results are analysed, are described. Each of the 25 laboratories receives an individual weekly computer printout within 24 hours of the deadline for the receipt of results. At the end of each six-month period a printout is produced ranking each laboratory for ;accuracy' and ;precision' for each test.


Green tea improves metabolic biomarkers, not weight or body composition: a pilot study in overweight breast cancer survivors.
Overweight status after breast cancer treatment may increase a woman's risk for recurrent disease and/or early onset cardiovascular disease. Green tea has been proposed to promote weight loss and favourably modify glucose, insulin and blood lipids. This pilot study tested the effect of daily decaffeinated green tea consumption for 6 months on weight and body composition, select metabolic parameters and lipid profiles in overweight breast cancer survivors. The effect of daily decaffeinated green tea intake on weight, body composition and changes in resting metabolic rate, energy intake, glucose, insulin, homeostasis model assessment--insulin resistance (HOMA-IR) and lipids was evaluated in overweight breast cancer survivors. Participants had a mean weight of 80.2 kg; body mass index (BMI) 30.1 kg m⁻²; and body fat 46.4%. Participants (n = 54) were randomised to 960 mL of decaffeinated green or placebo tea daily for 6 months. Mean (SD) tea intake among study completers (n = 39) was 5952 (1176) mL week⁻¹ and was associated with a significant reduction in energy intake (P = 0.02). Change in body weight of -1.2 kg (green tea) versus +0.2 kg (placebo) suggests a weight change effect, although this was not statistically significant. Decaffeinated green tea intake was associated with elevated high-density lipoprotein (HDL) levels (P = 0.003) and nonsignificant improvements in the HDL/LDL ratio and HOMA-IR (-1.1 ± 5.9: green tea; +3.2 ± 7.2: herbal). Intake of decaffeinated green tea for 6 months was associated with a slight reduction in body weight and improved HDL and glucose homeostasis in overweight breast cancer survivors.


Thermal cycling-hyperthermia in combination with polyphenols, epigallocatechin gallate and chlorogenic acid, exerts synergistic anticancer effect against human pancreatic cancer PANC-1 cells.
Hyperthermia (HT) has shown feasibility and potency as an anticancer therapy. Administration of HT in the chemotherapy has previously enhanced the cytotoxicity of drugs against pancreatic cancer. However, the drugs used when conducting these studies are substantially conventional chemotherapeutic agents that may cause unwanted side effects. Additionally, the thermal dosage in the treatment of cancer cells could also probably harm the healthy cells. The purpose of this work was to investigate the potential of the two natural polyphenolic compounds, epigallocatechin gallate (EGCG) and chlorogenic acid (CGA), as heat synergizers in the thermal treatment of the PANC-1 cells. Furthermore, we have introduced a unique strategy entitled the thermal cycling-hyperthermia (TC-HT) that is capable of providing a maximum synergy and minimal side effect with the anticancer compounds. Our results demonstrate that the combination of the TC-HT and the CGA or EGCG markedly exerts the anticancer effect against the PANC-1 cells, while none of the single treatment induced such changes. The synergistic activity was attributed to the cell cycle arrest at the G2/M phase and the induction of the ROS-dependent mitochondria-mediated apoptosis. These findings not only represent the first in vitro thermal synergistic study of natural compounds in the treatment of pancreatic cancer, but also highlight the potential of the TC-HT as an alternative strategy in thermal treatment.


Suppression of T lymphocyte function by measles virus is due to cell cycle arrest in G1.
Measles virus suppresses T lymphocyte functions in vitro. When measles virus-infected T lymphocytes are stimulated with PHA or 12-O-tetradecanoylphorbol-13-acetate, plus calcium ionophore, the cells secrete IL-2 and express the IL-2R or Tac Ag to a similar extent as uninfected cells, yet proliferation is reduced by 50 to 90%. Stimulated infected T cells also express the cell surface activation Ag 4F2, transferrin R, and HLA-DR. The secretion of IFN-gamma by infected T cells in response to PHA is not suppressed at 24 to 72 h after stimulation. Total RNA synthesis at 48 and 72 h after stimulation is reduced in infected T lymphocytes. Infectious measles virus progeny are produced during this interval. Thus infected T lymphocytes can become activated in response to mitogenic stimuli and the cells support efficient viral replication before the block in cell proliferation.


Experimental approach to follow the spatiotemporal wood degradation in fungal microcosms.
To investigate the spatiotemporal growth dynamics in fungal microcosms and to follow the spatial degradation effects of fungal lignocellulose fermentation, a new and flexible experimental setup was developed and tested. White and brown rot fungi were cultivated under solid-state conditions in beech wood-filled silicon tubes for 5 weeks. After inoculation of wood material at one end of the tube, the culture vessels were aerated and moistured by flushing air through alkaline and aqueous solutions. After incubation, the silicon tubes were harvested and segmented to follow different growth and degradation parameters. This new approach holds great potential since it allows the use of different growth substrates, variable aeration or moisturization conditions and is therefore a useful tool for diverse degradation studies, e.g. respiration/mineralization studies involving flow meters or carbon dioxide sensors or for molecular biological approaches.